A Concise Review Based on Analytical Methods for Estimation of Dapagliflozin and Linagliptin in Pharmaceutical Dosage Form

Hiral S. Popaniya¹*, Dinesh K. Dangar², Chintankumar J. Tank³

¹Research Scholar, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

²Associate Professor, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

³Professor, School of Pharmacy, Dr. Subhash University, Junagadh (362001), Gujarat, India.

*Corresponding Author E-mail: hpopaniya@gmail.com, dineshdangar@gmail.com, chintankumartank@gmail.com

ABSTRACT:

Dapagliflozin and linagliptin are two oral antidiabetic drugs that are commonly used in combination to treat type 2 diabetes. Dapagliflozin is a sodium-glucose cotransporter 2(SGLT2) inhibitor that works by increasing the excretion of glucose in the urine. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that works by increasing the levels of incretin hormones, which stimulate the pancreas to produce more insulin and reduce the production of glucagon. There are a variety of analytical methods that can be used to estimate the concentration of dapagliflozin and linagliptin in dosage forms. These methods include high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS/MS), and high-performance thin-layer chromatography (HPTLC). This review provides an overview of the different analytical methods that have been developed for the estimation of dapagliflozin and linagliptin in pharmaceutical dosage forms. The focus of the review is on the development and validation of these methods, as well as their application to the analysis of pharmaceutical formulations.

KEYWORDS: Dapagliflozin, Linagliptin, Analytical Methods, High Performance Liquid Chromatography, UV Spectroscopy.

INTRODUCTION:

Dapagliflozin and Linagliptin are used medications for the treatment of type-2 diabetes mellitus (T2DM). The combined use of Dapagliflozin and Linagliptin for managing T2DM is reasonable and attractive because of their different but complementary mechanisms of action and separate paths of degradation thereby avoiding possible drug interactions, which is important for harnessing drug pharmacodynamics and reducing the risk of unexpected adverse events. The combined use of sodium-glucose co transporter 2 inhibitor and Dipeptidyl Peptidase -4 inhibitor is significantly associated with a decrease in glycemic control, body weight, and systolic blood pressure.^1,2

Dapagliflozin (DAPA) operates as an irreversible and selective inhibitor of sodium-glucose co-transporter 2 (SGLT2) with dynamic properties. Its mechanism involves impeding glucose reabsorption within the liver, leading to an augmented excretion of glucose through urine. This effect contributes to improved regulation of blood sugar levels in individuals with type 2 diabetes mellitus. Chemically, it is described as (1S)-1, 5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl) methyl]-D-glucitol. The molecular structure of Dapagliflozin is depicted in Figure 1. According to the European Medicines Agency (EMA), Dapagliflozin falls under category III of the Biopharmaceutical Classification System (BCS), indicating higher solubility but relatively low permeability.³

Linagliptin belongs to the novel class of oral hypoglycemic drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors.4 Its chemical designation is 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl) methyl]-4,5-dihydropurine-2,6-dione, as illustrated in Figure 2. This medication, which acts on enzymes, is utilized either as a standalone treatment alongside dietary and exercise measures or in conjunction with metformin or a thiazolidinedione. Its purpose is to enhance the regulation of blood sugar levels in adults dealing with type 2 diabetes mellitus.^5-9

Linagliptin competes with an enzyme called dipeptidyl peptidase-4 (DPP-4), leading to a heightened presence of active incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). As a consequence, the release of glucagon is diminished while insulin secretion is increased.¹⁰

Figure- 1 Dapagliflozin¹¹

Figure- 2 Linagliptin¹²

In this comprehensive review, we have compiled the reported analytical methods available for the analysis of formulations and biological samples of Dapagliflozin and Linagliptin, both individually and in combination with other drugs. These methods encompass a range of techniques, including spectrophotometry, high-performance chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and high-performance thin layer chromatography (HPTLC). Among these methods, HPLC stands out as the most extensively utilized technique for analytical estimation. The physicochemical properties and mechanism of action for both drugs are given in table 1.

Table-1 Physiochemical Properties of Dapagliflozin and Linagliptin^13-15

Parameters	Description
Drug Name	Dapagliflozin	Linagliptin
CAS Number	461432-26-8	668270-12-0
Category	Antidiabetic Agent, SGLT2 inhibitor	Antidiabetic Agent, DPP-4 inhibitor
Chemical Formula	C21H25ClO6	C25H28N8O2
Molecular Weight	408.9 gm/mole	472.5gm/mole
Physical State and Appearance	White to Pale Yellow Solid	White to yellow solid
Melting point	74-78°C	190-196°C
Solubility	Methanol, Ethanol, Dimethyl formamide	Soluble in methanol; sparingly soluble in ethanol; very slightly soluble in isopropanol
Mechanism of Action	The sodium-glucose cotransporter 2 (SGLT2), which controls the reabsorption of glucose from the tubular lumen, is inhibited by DAPA in the proximal renal tubule. increases the excretion of glucose in urine, decreases the renal glucose threshold, and inhibits the reabsorption of glucose.	Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this catalyst slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP) 3,5. GLP-1 and GIP stimulate the secretion of insulin from beta cells in the pancreas while suppressing secretion of glucagon from pancreatic beta cells. These effects together decrease the breakdown of glycogen in the liver and boost the insulin release in response to glucose
Drug approved by USFDA	January, 2014	May, 2011

Table: 2 Analytical Methods for estimation of Dapagliflozin

Sr. No	Drug Name	Analytical Method	Description	Ref. No.
1.	Dapagliflozin	UV-Spectrophotometry	Linearity: 5-40μg/mL Solvent: Methanol: water Wavelength: Method I (Zero order): 224nm Method II (Area Under Curve): 218-230nm Method III (1º derivative): 220nm Method IV (2º derivative): 224nm, 235.5nm.	16
2.	Dapagliflozin	UV-Spectrophotometry	Linearity: 10-35μg/ml Solvent: Ethanol: Phosphate Buffer (1:1) (pH 7.2) Wavelength: 233.65nm	17
3	Dapagliflozin	RP-HPLC	Stationary phase: Waters C-18, 5μm particle size, 25cm × 4.6 mm i.d. Mobile phase: Phosphate buffer and acetonitrile (60:40 v/v) Flow rate: 1.0ml min^-1 Detection: 237nm Concentration range: 10-60μg/ml	18
4	Dapagliflozin	RP-HPLC	Stationary phase: Princeton C18 column Mobile phase: Acetonitrile: 0.1% Triethylamine pH-5.0 (50:50 v/v) Flow rate: 1.0ml min-1 Detection: 224nm Concentration range: 10-70μg/mL	19
5	Dapagliflozin	Stability indicating RP-HPLC	Stationary phase: BDS column Mobile phase: Acetonitrile and Ortho phosphoric acid (55:45) Flow rate: 1.0ml min-1 Detection: 245nm Concentration range: 25-150μg/ml.	20
6	Dapagliflozin	RP-HPLC	Stationary phase: hypersil BDS (250mm × 4.6mm, 5μ) Mobile phase: Orthophosphoric acidbuffer: Acetonitrile (60:40 V/V) Flow rate: 1.0ml min-1 Detection: 245nm Concentration range: 25-150ppm.	21
7	Dapagliflozin	RP-HPLC and UV-Spectrophotometry	RP-HPLC Stationary phase: BDS column Mobile phase: Orthophosphoric acidbuffer: Acetonitrile (45:55 V/V) Flow rate: 1.0ml min-1 Concentration range: 25-150μg/ml. UV-Spectroscopy Concentration range: 1-5μg/ml Wavelength: 203nm Solvent: Methanol	22
8	Dapagliflozin	RP-HPLC	Stationary phase: Symmetry C18, 25cm x 4.6mmi.d. 5µm, Particle size Mobile phase: Methanol: Acetonitrile: ortho phosphoric acid (75:25:05) Flow rate: 1.0ml min-1 Detection: 246nm Concentration range: 20-70μg/ml	23
9	Dapagliflozin	Stability indicating HPLC	Stationary phase: C18 (4.6ml *150,5μm) Mobile phase: Acetonitrile: di-potassium hydrogen phosphate with pH-6.5 adjusted with OPA (40:60 %v/v) Flow rate: 1.0ml min-1 Detection: 222nm Concentration range: 50-150μg/ml	24
10	Dapagliflozin	HPTLC	Stationary phase: Merck precoated silica gel aluminum plate 60 F254 Mobile phase: Chloroform: Methanol (9:1v/v) Detection: 223nm using Camag TLC Scanner. Concentration range: 400ng/band to 1200ng/band	25

Table: 3 Analytical Methods for Dapagliflozin with another drug combination

Sr. No	Drug Name	Analytical Method	Description	Ref. No.
1	Dapagliflozin and Metformin HCL	RP-HPLC	Stationary phase: Phenomenex C18 250mm x 4.6 mm Mobile phase: Water: Methanol (50:50 v/v) Flow rate: 1.0ml min-1 Detection: 230 nm Concentration range: 2 - 7μg/ml (Metformin HCl), 60 – 210μg/ml (Dapagliflozin)	26
2	Dapagliflozin and Metformin HCL	UV-Spectrophotometry including force degradation	Simultaneous equation method: Concentration range: - 2 – 32μg/ml (Dapagliflozin) and 1 – 20μg/ml (Metformin). Detection Wavelength: 222nm (Dapagliflozin) and 232nm (Metformin). Solvent: Water	27
3	Dapagliflozin propanediol monohydrate andSitagliptin	UV-Spectrophotometry	1st order derivative spectroscopic Method Sitagliptin at zero cross over- 275nm and Dapagliflozin zero cross over point - 232 nm Concentration range: 25-125μg/ml (Dapagliflozin) 2.5-12.5μg/ml and (Sitagliptin) Solvent: Methyl alcohol	28
4	Dapagliflozin and Saxagliptin	Stability indicating RP-HPLC	Stationary phase: BDS C18 (150 x 4.6mm, 5.0μ) Mobile phase: Ammonium acetate buffer: ACN (40:60 %v/v) Flow rate: 1.0ml min^-1 Detection: 220nm Concentration range: 0-15μg/ml (Dapagliflozin) and 0-8μg/ml (Saxagliptin)	29
5	Dapagliflozin propanediol monohydrate andSitagliptin	RP-HPLC	Stationary phase: Inertsil ODS C18 Mobile phase: Methyl Nitrile (25 parts) and 0.02 M KH2PO4 buffer 0.02 M having 1 ml triethylamine with neutral pH adjusted by orthophosphoric acid (75 parts) in isocratic mode Flow rate: 1.0ml min^-1 Detection: 210nm Concentration range: 5–15μg/ml (Dapagliflozin) and 50-150μg/ml  (Sitagliptin)	30
6	Dapagliflozin and Saxagliptin	RP-HPLC	Stationary phase: Symmetry C8 (4.6 × 150mm, 3.5μm, Make: XTerra) Mobile phase: Buffer: acetonitrile 70:30 %v/v (pH 3) Flow rate: 1.0ml min^-1 Detection: 221nm Concentration range:25-125μg/ml (Dapagliflozin) and 12.5-62.5μg/ml (Saxagliptin)	31
7	Dapagliflozin and Saxagliptin	RP-HPLC	Stationary phase: XTerra C18 column (150mm x 4.6mm x5μm particle size) Mobile phase: Phoaphate buffer (pH 4) and Acetonitrile (50:50v/v) Flow rate: 1.0ml min^-1 Detection: 225nm Concentration range:and Saxagliptin 10120μg/ml (Dapagliflozin), 20-60μg/ml respectively	32
8	Dapagliflozin and Saxagliptin	RP-HPLC	Stationary phase: Discovery C18 column (250mm, 4.6mm, and 5μm). Mobile phase: acetonitrile and ortho phosphoric acid (0.1%) 50:50 ratio Flow rate: 0.98ml min-1 Detection: 210nm Concentration range: Dapagliflozin and Saxagliptin25-150 μg/mL and 12.5-75 μg/mL respectively	33
9	Metformin, Dapagliflozin, and Saxagliptin	Stability indicating RP-HPLC	Stationary phase: Kromasil C18 column (150 × 4.6 mm, 5 μm) Mobile phase: phosphate buffer (pH - 3) and acetonitrile (60: 40%) Flow rate: 1 ml min-1 Detection: UV detection at 230 nm Concentration range: Metformin, Dapagliflozin, and Saxagliptin125–750 μg/mL, 1.25–7.5 μg/mL, and 0.625–3.75 μg/mL respectively	34
10	Dapagliflozin and Saxagliptin	RP-HPLC	Stationary phase: XTerra C 18 column (150mm x 4.6mm x5μm particle size). Mobile phase: phosphate buffer (pH 4) and Acetonitrile (50:50v/v) with Flow rate: 1 ml min-1 Detection: UV detection at 225 nm Concentration range: Dapagliflozin, and Saxagliptin100-1500 μg/mL, 20–300μg/mL respectively	35
11	Dapagliflozin and Saxagliptin	RP-HPLC	Stationary phase: Phenomenex Hyperclone C18 column (250×4.6 mm, 5μ) Mobile phase: methanol: 20 mM phosphate buffer (pH3.0) (70:30, v/v) Flow rate: 1 ml min-1 Detection: UV detection at 220 nm Concentration range: Dapagliflozin, and Saxagliptin4-24 μg/mL, 2-12 μg/mL respectively	36
12	Dapagliflozin, Saxagliptin, and Metformin	UV spectrophotometric method (Simultaneous estimation)	Simultaneous equation method: Concentration range: - 5-25 μg/ml (Dapagliflozin) and 10-50 μg/ml (Metformin) and 1-5 μg/ml (Saxagliptin) Detection Wavelength: 272 nm (Dapagliflozin), 232 nm (Metformin) and 212nm (Saxagliptin) Solvent: methanol: water (80:20 v/v)	37

Table: 4 Analytical methods for estimation of Linagliptin

Sr. No	Drug Name	Analytical Method	Description	Ref. No.
1	Linagliptin	UV Spectrophotometer	Linearity: 5-30μg/ml. Solvent: Methanol Wavelength: 294 nm	38
2	Linagliptin	UV Spectrophotometer	Linearity: 6- 16 μg/ml Solvent: Methanol: water (15:85, v/v) Wavelength: 290 nm	39
3	Linagliptin	UV Spectrophotometer	Linearity: 2-10 μg/ml Solvent: Methanol Wavelength: 295 nm	40
4	Linagliptin	UV Spectrophotometer	Linearity: 1- 10 μg/ml Solvent: Distilled water Wavelength: 295 nm	41
5	Linagliptin	UV Spectrophotometer	Linearity: 6– 22 μg /ml Solvent: Methanol: water Wavelength: 297 nm	42
6	Linagliptin	RP-HPLC	Stationary phase: C18 column (4.6 x 100 mm, 5 mm, Make: Phenomenex) Mobile phase: Phosphate buffer (pH 3) : methanol (50%: 50%) Flow rate: 0.8 ml min-1 Detection: UV detection at 238 nm Concentration range: 10-50 μg/ml	43
7	Linagliptin	RP-HPLC	Stationary phase: C18 column (150 x 4.6 mm i.d., 5μm particle size) Mobile phase: 70:30 v/v mixture of phosphate buffer (pH 6.8±0.2) and acetonitrile Flow rate: 1 ml min-1 Detection: UV detection at 239 nm Concentration range: 40 - 60 μg/ml	44
8	Linagliptin	RP-HPLC	Stationary phase: C18 column (100 mm × 2.5 mm,3μm) Mobile phase: 0.1% ortho phosphoric acid (70:30 v/v) Flow rate: 0.8 ml min-1 Detection: UV detection at 299 nm Concentration range: 2.5– 15 μg/ml	45
9	Linagliptin	Stability Indicating HPLC	Stationary phase: Zorbax eclipse XDBC18( 4.6×150MM,5μm) column. Mobile phase: Methanol: Water (40:60%v/v). Flow rate:1ml/min. Detection: 225nm. Concentration range: 1–50 μg/mL.	46
10	Linagliptin	LC-MS/MS (Bioanalytical method)	Stationary phase: Waters, X-Bridge, C18, 5μm column, 4.6×50 mm internal diameter Mobile phase: acetonitrile and 0.1 % formic acid (90:10 v/v) Flow rate: 0.6 ml min-1 Concentration range: 10ng/mL to 5000ng/mL	47
11	Linagliptin	Stability Indicating HPLC	Stationary phase: Grace C18 column (150x4.6 mm i.d. Mobile phase: Methanol: Water (Triethylene amine 1 ml) 80: 20, v/v Flow rate:1ml/min. Detection: 294 nm. Concentration range: 5–30 μg/mL.	48

Table: 3 Analytical Methods for Linagliptin with another drug combination

Sr. No	Drug Name	Analytical Method	Description	Ref. No.
1	Linagliptin and Metformin	Stability Indicating RP-HPLC	Stationary phase: Zorbax SB-Aq 250 * 4.6 mm, 5 μm column Mobile phase: KH2PO4 buffer, MeOH and ACN Flow rate: 1 ml min-1 Detection: UV detection at 225 nm Concentration range:	49
2	Linagliptin and Metformin	RP-HPLC	Stationary phase: C18 column Mobile phase: 70:30 (v/v) mixture of methanol and 0.05 M potassium dihydrogen orthophosphate (pH adjusted to 4.6 with orthophosphoric acid) Flow rate: 0.6 ml min-1 Detection: UV detection at 267 nm Concentration range: Linagliptin and metformin 2–12 μg/mL and 400–2400 μg/mL respectively.	50
3	Linagliptin and Metformin	UV spectrophotometric method (Simultaneous estimation)	Solvent: Methanol Linearity: 1-11μg /ml LINA and 3-13 MET  Wavelength: 227 nm and 237 nm Linagliptin and Metformin Respectively	51
4	Linagliptin and Metformin	UV spectrophotometric method	Solvent: Methanol: Water (40:60) Linearity: 10- 18μg /ml LINA and 3-11 MET  Wavelength: 295 nm and 234 nm Linagliptin and Metformin Respectively	52
5	Empagliflozin and Linagliptin	RP-HPLC	Stationary phase: Thermo C18 column (250 mm ×4.6, 5μm) Mobile phase: acetonitrile: methanol 50:50% v/v Flow rate: 1 ml min-1 Concentration range: 5-25μg/ml and 1-5μg/ml for EMPA and LINA respectively	53
6	Empagliflozin and Linagliptin	UV spectrophotometric method	Solvent: Methanol Linearity: 6– 22 μg /ml Wavelength: 276 nm and 293 nm Empagliflozin and Linagliptin Respectively	54
7	Empagliflozin and Linagliptin	UV spectrophotometric method	Solvent: 0.1M Urea Wavelength: 260 nm and 300 nm Empagliflozin and Linagliptin Respectively Linearity: 2– 10μg /ml	55
8	Metformin hydrochloride, Linagliptin and Empagliflozin	Stability Indicating RP-HPLC	Stationary Phase: Agilent Eclipse XDBC18( 250mm× 4.6mm, 5 μm). Mobile Phase: 0.1% Triethylamine(pH-3) Buffer: Acetonitrile (40:60%v/v) Flow rate: 1 ml/min Detection wavelength: 240nm Concentration range:	56
9	Linagliptin, Metformin hydrochloride and Empagliflozin	RP-HPLC	Stationary Phase: Phenomenex C18 column (250 mm × 4.6 mm, 5 μm) Mobile Phase: Acetonitrile: Methanol: Water (27: 20: 53, v/v/v) pH 4 adjusted with 1% Ortho-phosphoric acid Flow rate: 1 ml/min Detection wavelength: 223 nm Concentration range: Empagliflozin, Linagliptin and Metformin HCl- 0.5–5 μg/ml, 0.25–2.5 μg/ml, and 50–500 μg/ml, respectively.	57
10	Linagliptin, Metformin hydrochloride and Empagliflozin	RP-HPLC	Stationary Phase: Kromosil 250 x 4.6 mm, 5μm Mobile Phase: Buffer: Acetonitrile (45:55v/v) Flow rate: 1 ml/min Detection wavelength: 233 nm Concentration range: Empagliflozin, Linagliptin and Metformin HCl- 2.5-15 μg/ml, 1.25-37.5μg/ml, and 250-1500 μg/ml, respectively.	58

CONCLUSION:

This review has summarized the reported spectroscopic and chromatographic methods for the estimation of dapagliflozin and linagliptin. It is evident that a variety of methods are available for the individual determination of each drug, but there is a lack of combination methods for the simultaneous determination of both drugs. However, the methods that are available are generally simple, accurate, economical, precise, and reproducible. Nearly all of the methods use RP-HPLC with UV absorbance detection, as these methods provide the best reliability, repeatability, analysis time, and sensitivity.

The lack of combination methods for the simultaneous determination of dapagliflozin and linagliptin is a potential area for future research. Such methods would be useful for the quality control of combined dosage forms of these drugs. Additionally, the development of more sensitive and selective methods would be beneficial for the analysis of these drugs in biological matrices.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENT:

We are thankful to Dr. Subhash University for providing guidance and support for this review work.

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Received on 23.04.2024      Revised on 08.06.2024

Accepted on 15.07.2024   Published on 10.12.2024

Available online on December 30, 2024

Asian Journal of Pharmaceutical Analysis. 2024; 14(4):275-282.

DOI: 10.52711/2231-5675.2024.00049

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