Application of experimental design in HPLC method optimization and robustness for the simultaneous determination of canagliflozin, empagliflozin, linagliptin, and metformin in tablet

Abstract

Gliflozins and gliptins represent two different pharmacological drug classes that exert different and potentially complementary glucose-lowering effect in patients with type II diabetes mellitus. A novel, selective, and sensitive HPLC method was developed for the determination of canagliflozin, empaglifozin, linagliptin, and metformin in pure form, in laboratory prepared mixtures, and in pharmaceutical dosage form. Experimental design optimization was applied by using Plackett-Burman and face-centered composite designs to achieve the best resolution with minimum experimental trials. Three significant variables affecting optimization, namely buffer pH, percentage of methanol, and percentage of acetonitrile, were studied. Chromatographic separation was achieved using an Agilent Eclipse C 8 column, and column temperature was kept at 45 C. The mobile phase was composed of dipotassium hydrogen phosphate buffer (0.05 M, adjusted to pH 6 using o-phosphoric acid):acetonitrile:methanol (50:25:25, v/v/v) at a flow rate of 1.5 mL/min. Sharp and wellresolved peaks of the cited drugs were obtained. The method was fully validated in terms of linearity, accuracy, precision, selectivity and robustness in agreement with the International Council of Harmonization (ICH) guidelines Q2 (R1). Satisfactory results were obtained by the analysis of tablets through applying the developed method. Therefore, it could be performed for the analysis of the cited drugs in quality control laboratories.

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method

“…Separation quality is important; thus, the typical key response is good resolution between critical analyte peaks [ 56 , 57 , 58 ]. Similar work has been reported on different drugs in which the resolution was the only response, while buffer pH, percentage acetonitrile, and flow rate had a significant effect on the response [ 51 , 52 , 53 , 58 ]. The three-level face-centered central composite design suggested by the software and the resolution results are tabulated below ( Table 1 ).…”

“…The quadratic effect of acetonitrile concentration, pH, and flow rate had a substantial impact on the resolution between RE and VD, whereas only acetonitrile concentration and pH exhibited a substantial effect on the resolution between VD and MF. The reported methods for the optimization of chromatographic conditions for the separation of metformin with other drugs showed a much lower effect due to the use of RP-HPLC, where metformin was eluted first [ 52 , 53 ]. The assessed model F -values were found to be 26.06 and 33.40 ( p < 0.0001) for RS1 and RS2, respectively.…”

“…The literature features the use of surface response methodologies, such as central composite design for the development of the HILIC method [ 50 , 51 ]. Furthermore, Musaa et al [ 52 ] reported the optimization of chromatographic conditions, by examining the effect of pH of the mobile phase, and percentage acetonitrile on the resolution between metformin, linagliptin, empagliflozin, and canagliflozin peaks as a response using face-centered central composite design (CCD). A chromatographic method was developed for the quantification of an antidiabetic formulation containing metformin using face-centered CCD, by optimizing the buffer pH, percentage acetonitrile, and percentage surfactant using the resolution as a response [ 53 ].…”

Thermodynamic and Computational (DFT) Study of Non-Covalent Interaction Mechanisms of Charge Transfer Complex of Linagliptin with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Chloranilic acid (CHA)

“…A comprehensive review of the available literature found that a number of analytical techniques, such as spectrophotometric [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], colorimetric [ 31 , 32 , 33 ], spectrofluorometric [ 33 , 34 , 35 ], and high-performance liquid chromatographic [ 36 , 37 , 38 , 39 ] methods, were described for the detection of linagliptin. It has been determined that colorimetric is more specific than spectrophotometry (UV region).…”

Efficacy of Yishen Huashi Granules Combined with Linagliptin Tablets on Blood Glucose and Renal Function in Patients with Type 2 Diabetic Nephropathy

“…DN has an insidious onset, which progresses rapidly by the proteinuria stage in the clinic, with symptoms such as edema, dyslipidemia, and continuous decline in renal function. However, conventional hypoglycemic agents are limited in DN treatment, and most oral hypoglycemic agents cannot be used in stages 3-4 of chronic kidney disease (CKD) [4][5][6]. In contrast, as a new type of a dipeptidyl peptidase 4 (DPP-4) inhibitor, linagliptin tablets can be excreted through the intestine and can be used even in patients with renal insufficiency or on dialysis, with a good hypoglycemic effect.…”