An Overview on Analytical Method Development and Validation for Ertugliflozin in Bulk and Pharmaceutical Dosage form
Priyanka M. Sagar*, S.D. Mankar, S. B. Dighe
Department of Quality Assurance Techniques, Pravara Rural College of Pharmacy,
Pravaranagar, Tal: Rahta, Dist: Ahmednagar 413737, India.
*Corresponding Author E-mail: priyankasagar3322@gmail.com
ABSTRACT:
Diabetes mellitus (DM) is a metabolic condition characterized by hyperglycemia, glycosuria, hyperglycemia, a negative nitrogen balance, and occasionally ketonemia. The type 2 sodium-dependent glucose co-transporters (SGLT), which are in charge of roughly 90% of the reabsorption of glucose from the glomerulus, are subject to strong and selective inhibition by ertugliflozin. This review's primary objective is to highlight the development and validation of analytical methods employing chromatographic and spectrophotometric techniques for ertugliflozin and combination products in bulk and pharmaceutical dose forms. RP-HPLC, UV, UPLC, and LC-MS techniques are used to determine the dosage of ertugliflozin when it is combined with metformin and sitagliptin. Spectrometric techniques for ertugliflozin in combination with metformin or sitagliptin contain parameters like solvent, wavelength, linearity, LOD, LOQ, etc., and HPLC methods for ertugliflozin in combination with metformin or sitagliptin include parameters like stationary phase, mobile phase, RT, detection wavelength, LOD, LOQ, etc. Discussions on the separation requirements for ertugliflozin in combination with metformin or sitagliptin are also addressed throughout this review.
KEYWORDS: Ertugliflozin, SGLT2 Inhibitors, RP-HPLC, UV, UPLC, LC-MS/MS.
INTRODUCTION:
Diabetes mellitus (DM) is a chronic metabolic condition characterized by persistent hyperglycemia1. Type 2 diabetes mellitus, which is estimated to affect 541 million people globally2 and requires lifelong anti-diabetic medication, is characterized by polydipsia, polyuria, and polyphagia3.
A medication called ertugliflozin is used to treat type 2 diabetes. It is an inhibitor of the SGLT2 sodium glucose co-transporter.
Fasting and postprandial blood glucose levels are decreased by SGLT2 inhibitors, which also enhance urine glucose excretion and decrease renal glucose reabsorption. It is marketed as a standalone medicine as well as in combination with metformin hydrochloride and sitagliptin4.
The Food and Drug Administration approved its use in the country for monotherapy as well as a fixed dose combination with either sitagliptin or metformin. It was authorized for use as a monotherapy or combination treatment in Europe in March 2018. In the family of medications known as gliflozins, ertugliflozin is a sodium/glucose cotransporter 2(SGLT2) inhibitor. Segluromet is sold in combination with metformin, while Steglujan is marketed in combination with sitagliptin6.
Drug Profile 6-13
Table 1 – Drug Profile on Ertugliflozin, Sitagliptin and Metformin:
|
Parameter |
Ertugliflozin |
Sitagliptin |
Metformin |
|
Approval Date |
2017 |
2006 |
1994 |
|
Category |
anti-diabetic drug in sodium-glucose co-transporter 2 (SGLT2) inhibitors (Antidiabetic) |
anti-diabetic drug in dipeptidyl peptidase-4 (DPP-4) inhibitors (Antidiabetic) |
anti-diabetic drug in the biguanide class |
|
Chemical Name |
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo [3,2,1] octane-2,3,4-triol;(2S)-5-oxopyrrolidine-2-carboxylic acid |
(R)-3-Amino-1-(3-(Trifluoromethyl)-5,6-Dihydro- [1,2,4] Triazolo[4,3-A] Pyrazin-7(8h)-Yl)-4-(2,4,5-Trifluorophenyl) Butan-1-One |
N, N-dimethylimidodicarbonimidic diamide |
|
Chemical Formula |
C16H15F6N5O |
||
|
Molecular Weight |
436.9 |
407.31 |
129.16 |
|
Melting Point |
65 - 660C |
110-120° C |
223-226 °C |
|
Solubility |
DMSO, Ethanol |
||
|
BCS Class |
Class I |
Class I |
Class III |
|
Storage Temperature |
20-25 °C |
20-25 °C |
20-25 °C |
Pharmacodynamics14-17:
Table 2 – pharmacodynamics on Ertugliflozin, Sitagliptin and Metformin:
|
pharmacodynamics Parameter |
Ertugliflozin |
Sitagliptin |
Metformin |
|
Routes of administration |
Oral Administration |
Oral Administration |
Oral Administration |
|
Absorption |
well absorbed and had an oral bioavailability of 70-90% |
Sitagliptin is 87% orally bioavailable |
absolute bioavailability of a metformin 500 mg tablet is about 50%-60% |
|
Volume of Distribution |
215.3 L |
198L |
654 ± 358 L |
|
Protein Binding |
Ertugliflozin is highly bound to plasma proteins and it binds in a range of 94-96% |
Binding to plasma proteins is low (38%) |
Metformin is negligibly bound to plasma proteins. |
|
Metabolism |
metabolic profile of ertugliflozin in liver microsomes and hepatocytes is formed by reactions of monohydroxylation, O-demethylation and glucuronidation |
79% of the dose excreted in the urine and Minor metabolic pathways are mediated mainly by cytochrome p450(CYP)3A4 and to a lesser extent by CYP2C8 |
metformin is excreted as unchanged drug in the urine and does not undergo hepatic metabolism |
|
Elimination Half Life |
11-17 hours |
12.4 hours |
6.2 hours |
MECHANISM OF ACTION:
SGLT2, which is present in the kidneys, is inhibited by ertugliflozin. When glucose is removed from glomerular filtrate and returned to circulation, the main transporter, SGLT2, is responsible. Ertugliflozin blocks this particular transporter's role in the reabsorption of glucose, increasing renal excretion of glucose, and assisting in lowering blood glucose levels18.
An inhibitor of the protease dipeptidyl peptidase-4 (DPP-4), which breaks down the incretin GLP-1. GLP-1 levels that are elevated or sustained can enhance the pancreas' ability to secrete insulin by blocking DPP-4. Sitagliptin reduces hepatic glucose overproduction while increasing insulin production. In order to address decreased insulin levels brought on by beta-cell malfunction and the liver's unchecked synthesis of glucose, sitagliptin only functions when blood sugar levels are raised 19-20.
Metformin lowers blood sugar levels by reducing hepatic glucose synthesis (also known as gluconeogenesis), intestinal glucose absorption, and insulin sensitivity while increasing peripheral glucose uptake and utilization. Metformin's ability to decrease mitochondrial complex I activity has long been known, and it is now widely believed that this is how it exerts its strong anti-diabetic effects21.
Analytical methods used for estimation of ertuglifozin in combination in Sitagliptin and Metformin:
1. Spectrophotometric Methods:
By measuring the intensity of light as a beam of light travels through a sample solution, a technique called spectrophotometry may determine how much light a chemical component absorbs. It is also possible to use this measurement to determine how much of a certain chemical is present22.
Table 3: Analytical method development and validation of Spectrophotometric method for Ertugliflozin in combination with Sitagliptin:
|
Sr. No |
Drug and Sample |
Analytical Method |
Description |
Reference |
|
1. |
Ertugliflozin And Sitagliptin
|
Simple UV Spectrophotometric Method
|
Solvent: Water and Acetonitrile Taken in The Ratio 1:1 V/V Wavelength: 210 Nm And 221nm Linearity: 7.0-42𝜇g/ml and 4.2- 6.3μg/ml at 210 nm and 221 nm Respectively With 100.34-99.95% Respectively LOD: 0.070µg/ml and 0.0105µg/ml LOQ: 0.21µg/ml and 0.0315µg/ml |
23 |
2. HPLC Methods:
In analytical chemistry and biochemistry, a process known as high-performance liquid chromatography (HPLC) is used to separate mixtures of substances in order to identify, measure, or purify the mixture's constituent components. Reversed-phase The separation method most frequently employed is HPLC. It allows for the dynamic preservation of substances with hydrophobic and organic properties. Retention of these compounds via reversed-phase reactions is made possible by a mix of hydrophobic and van der Waals-type interactions between all of the target compounds and both the stationary and mobile phases24.
Table 3: Analytical method development and validation of HPLC method for Ertugliflozin in combination Sitagliptin and Metformin:
|
Sr. No |
Drug |
Analytical Method |
Description |
Reference |
|
2. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Zorbax C18(4.6x150mm,5µm) Mobile phase: Buffer 0.01N Na2HPO4: Acetonitrile taken in the ratio 55:45 Retention time: Sitagliptin and ertugliflozin were found to be 2.156 min and 3.057 mins. Wavelength: 265nm Flow rate: 1ml/min Run time: 6 mins LOD: 1.55µg/ml,0.04 µg/ml LOQ: 4.71µg/ml,0.12 µg/ml |
25 |
|
3. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Std Discovery C18150 x 4.6 mm, 5m Mobile phase: Buffer 0.1% OPA (2.2ph): Acetonitrile taken in the ratio 60:40 Retention time: Ertugliflozin and Sitagliptin were and found to be 0.4 and 0.7 respectively. Wavelength: 218nm Flow rate: 1ml/min LOD: 0.20µg/ml, 0.46 µg/ml LOQ: 0.61µg/ml, 1.40 µg/ml |
26 |
|
4. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Discovery C18(250mm x 4.6 mm, 5mm) Mobile phase: Phosphate buffer and acetonitrile (45:55 v/v) Retention time: Sitagliptin and Ertugliflozin were found to be 2.381 min and 3.429 min, respectively Wavelength: 260nm Flow rate: 1.0ml/min LOD: 0.523µg/ml, 0.442µg/ml LOQ: 1.586µg/m, 1.340µg/ml |
27 |
|
5. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Inertsil ODS C185mm (4.6 x 250mm) Mobile phase: Phosphate buffer and Acetonitrile in the ratio of 30:70 Retention time: Sitagliptin and Ertugliflozin were found to be 2.395min and 3.906min Wavelength: 235nm. Flow rate: 1ml/min LOD: 2.94µg/ml and 3.03µg/ml LOQ: s 9.87 µg/ml and 10.1µg/ml |
28 |
|
6. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: water’s C18 column capacitate (250X4.6 mm, 5 µm particle size), Mobile phase: 0.5mm potassium dihydrogen ortho phosphate buffer: Methanol taken in the ratio of 55:45 v/v Retention time: Ertugliflozin and Sitagliptin were found to be 2.39 and 4.60 min Wavelength: 215 nm Flow rate: 1mL/min Run time: 6 min. LOD: 12.71µg/m, 8.59µg/ml LOQ: 42.37µg/ml, 28.65µg/ml |
29 |
|
7. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Std Ascentis C18 150 x 4.6 mm, 2.7m Mobile phase: Buffer 0.01N Ammonium acetate: Acetonitrile taken in the ratio 60:40 Retention time: Sitagliptin and Ertugliflozin were found to be 2.151min and 2.722min. Wavelength: 220nm Flow rate: 0.9ml/min Run time: 8 min LOD: 0.69µg/ml, 0.05 µg/ml LOQ: 2.10µg/ml, 0.15 µg/ml |
30 |
|
8. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Cosmicsil C8 column (250 mm × 4.6 mm I.D., 5 μm size particle) Mobile phase: 0.1 Molar dipotassium hydrogen phosphate and methanol taken in the ratio 65:35 v/v Retention time: Ertugliflozin and Sitagliptin are 3.035 min and 1.799 min, respectively Wavelength: 225nm Flow rate: 1ml/min Run time: 7min LOD: 0.087 and 0.071μg/ml LOQ: 0.291μg/ml and 0.237 μg/ml
|
31 |
|
9. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Standard Azilent (4.6 x 150mm, 5µm particle size) Mobile phase: Buffer (Potassium di hydrogen Ortho Phosphate): Acetonitrile taken in the ratio 70:30 V/V Retention time: 3.203min (Ertugliflozin), 2.106min (Sitagliptin) Wavelength: 240 nm Flow rate: 1.0 ml/min LOD: 0.43ug/ml, 0.43ug/ml LOQ: 0.74ug/ml, 2.24ug/ml |
32 |
|
10. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: Phenomenex Luna C18 (4.6mm×150mm, 5µm) Mobile phase: Methanol: Buffer taken in the ratio 35:65% v/v Retention time: ertugliflozin and sitagliptin were found to be 2.256, 5.427respectively Wavelength: 261nm Flow rate: 1.0 ml/min Run time: 10 min LOD: 2.63µg/ml, 3.02µg/ml LOQ: 7.92µg/ml, 9.06 µg/ml |
33 |
|
11. |
Ertugliflozin and Sitagliptin
|
RP-HPLC |
Column: column used as Xbridge C18(50 x 2.1 mm, 1.7m) Mobile phase: Buffer: Acetonitrile took in the ratio 50:50 Retention time: Ertugliflozin and Sitagliptin were found to be 0.883 min and 1.465 min Wavelength: 240 nm Flow rate: 1 ml/min LOD: 0.139 µg/ml and 0.18µg/ml LOQ: 0.421 and 0.56µg/ml |
34 |
|
12. |
Ertugliflozin and Metformin
|
HPLC |
Column: Kromasil C18 column (250 mm×4.6 mm) Mobile phase: 0.1 M sodium dihydrogen phosphate and methanol taken in the ratio 50:50 v/v Retention time: MET – 2.481 min and ERT – 4.140 min Wavelength: 238 nm Flow rate: 1.0 ml/min Run time: 8 min LOD: 0.563 µg/ml and 0.038 µg/ml LOQ: 1.878 µg/ml and 0.127µg/ml |
35 |
|
13. |
Ertugliflozin and Metformin
|
HPLC |
Column: Inertrsil C18 (250 × 4.6 mm) Mobile phase: Buffer (pH 4.0): Methanol taken in the ratio 65:35 Retention time: Ertugliflozin and Sitagliptin were found to be 7.357 and 4.053 min Wavelength: 220 nm Flow rate: 1.0 mL/min Run time: 6 min LOD: 1.04 μg/mL and 0.0007 μg/mL LOQ: 9.61 μg/mL and 0.006 μg/mL |
36 |
|
14. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: Denali C18 (150 x 4.6 mm, 5 μm) Mobile phase:0.01 N KH2 PO4: acetonitrile taken in the ratio 60:40 V/V Retention time: Metformin and Ertugliflozin were found to be 2.357 min and 3.209 min Wavelength: 224 nm Flow rate: 1 mL/min Run time: 6 min LOD: Metformin and Ertugliflozin were found to be 0.72 μg/mL and 0.01 μg/mL respectively LOQ: Metformin and Ertugliflozin were found to be 2.18 μg/mL and 0.04 μg/mL respectively |
37 |
|
15. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: Phenomenex C18 column (150 mm × 4.6 mm, 5 μm) Mobile phase: Acetonitrile and 0.1% OPA buffer, with a proportion of 40: 60% v/v Retention time: Ertugliflozin and Metformin were 2.226 min and 2.955 min Wavelength: 220.0 nm Flow rate: 1 ml/min Run time: 10 min LOD: Metformin 0.10 μg/ml and Ertugliflozin 0.2 μg/ml LOQ: Metformin 0.03 μg/ml and Ertugliflozin 0.09 μg/ml |
38 |
|
16. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: BDS C18 (4.6 x 150mm, 5µm) Mobile phase: 55% 0.1% OPA buffer: 45% Acetonitrile Retention time: Metformin and Ertugliflozin were 2.565min and 3.221min. Wavelength: 230.0 nm Flow rate: 1ml/min Run time: 6min LOD: Metformin 0.36 μg/ml and Ertugliflozin 0.01 μg/ml LOQ: Metformin 1.08 μg/ml and Ertugliflozin 0.03 μg/ml |
39 |
|
17. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: Kromasil C18 (5 µm), 250 mm x 4.6 mm Mobile phase: Buffer (0.1 % v/v Phosphoric acid in water) and Acetonitrile (ACN) in the ratio 60: 40 v/v Retention time: 1.8 min for Metformin Hydrochloride and 3.8 min for Ertugliflozin Wavelength: 235 nm Flow rate: 1 mL/min Run time: 20 min LOD: 0.0003 and 0.0009 μg/ml for Metformin Hydrochloride and Ertugliflozin, LOQ: 0.0037 and 0.0112 μg/ml for Metformin Hydrochloride and Ertugliflozin |
40 |
|
18. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: ACE Column C18, (150 mm x 4.6 mm i.d, 5μm) Mobile phase: Buffer (Potassium dihydrogen Ortho Phosphate): Acetonitrile taken in the ratio 70:30 v/v Retention time: 3.203 min and 2.106 min Wavelength: 240 nm Flow rate: 1ml/min Run time: LOD: 0.43μg/mL and 0.74 μg/mL LOQ: 1.30μg/mL and 2.24μg/mL |
41 |
|
19. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: BDS C8 column (150 mm × 4.6 mm, 5 µm) Mobile phase: Buffer: acetonitrile taken in the ratio 55:45 v/v Retention time: 2.338 min for MET and 3.143 min for ERT Wavelength: 224 nm. Flow rate: 1.0 ml/min Run time: 6 min LOD: 1.70 µg/ml for MET and 0.07 µg/ml for ERT LOQ: 5.16 µg/ml for MET and 0.21 µg/ml for ERT |
42 |
|
20. |
Ertugliflozin and Metformin |
RP-HPLC |
Column: Kromasil C18 column (150 mm × 4.6 mm, 5 μm) Mobile phase: 0.1% ortho-phosphoric acid buffer (pH 2.7): acetonitrile taken in the ratio 65:35% v/v Retention time: Metformin HCl at 2.170 min and ertugliflozin pidolate at 2.929 min Wavelength: 224 nm Flow rate: 1 ml/min Run time: 5.0 min. LOD: Ertugliflozin pidolate and metformin HCl were 0.025 μg/ml and 0.87 μg/ml LOQ: Ertugliflozin pidolate and metformin HCl were 0.076 μg/ml and 2.63 μg/ml |
43 |
3. LC-MS/MS Method:
Combining tandem mass spectrometry (LC-MS-MS), a very effective analytical technology, with liquid chromatography's separation power and triple quadrupole mass spectrometry's highly sensitive and selective mass analysis capabilities44.
Table 4: Analytical method development and validation of LC-MS/MS method for Ertugliflozin in combination with Sitagliptin and Metformin:
|
Sr. No |
Drug |
Analytical Method |
Description |
Reference |
|
1. |
Ertugliflozin and Sitagliptin
|
LC-MS/MS method |
Column: Phenomenex Gemini, C18, (150 × 4.6 mm,5 μm) Mobile phase: 0.1% formic acid: acetonitrile taken in the ratio 10:90 v/v Flow rate: 0.6 mL/minute Linearity range: 15 to 450 ng/mL and 100–3000 ng/mL for Ertugliflozin and Sitagliptin respectively LOD: 568.50 ng/mL and3796.35 ng/mL for Ertugliflozin and Sitagliptin respectively. LOQ: 5685.24 ng/mL and 37963.54 ng/mL for Ertugliflozin and Sitagliptin respectively. |
45 |
|
2. |
Ertugliflozin and Metformin |
LC-MS/MS Method
|
Column: s XBridge C18 3.5 μ (150×4.6 mm) Mobile phase: 0.1% Orthophosphoric Acid and Acetonitrile in the ratio of 80: 20 v/v Flow rate: 1.0 ml/min. Linearity range: 10–150 ng/ml and 0.1–1.5 ng/ml for MET and ERT, respectively |
46 |
4. UPLC Method:
The underlying principle behind UPLC, a form of HPLC, is that efficiency and, consequently, accuracy improve when column packing particle sizes decrease. The primary distinction is in the design of the column material's smaller-than-2-micron-sized particle size. High-resolution chromatograms and quick analysis times enable UPLC analysis to perform more analytical work with meaningful, trustworthy, and authentic results47.
Table 5: Analytical method development and validation of UPLC method for Ertugliflozin in combination with Sitagliptin:
|
Sr. No |
Drug |
Analytical Method |
Description |
Reference |
|
1. |
Ertugliflozin and Sitagliptin
|
RP-UPLC method |
Column: Waters Hibar C8 [100×2.1mm, 2μ] Mobile phase: Acetonitrile: Water (pH 3.5) taken in the ratio 50:50% v/v Flow rate: 0.2ml/min Wavelength: 218nm Linearity: 3 25–125μg/ml and 3.75– 22.5μg/ml for sitagliptin and ertugliflozin, respectively r2=0.999 LOD: 0 0.11μg/ml ERT and 0.48μg/ml SIT LOQ: 0.33μg/ml ERT and 0.33μg/ml SIT |
48 |
|
2. |
Ertugliflozin and Sitagliptin
|
UPLC Method |
Column: X-bridge c18 50 x 2.1 mm, 1.7m Mobile phase: Buffer: Acetonitrile taken in the ratio 50:50 Flow rate: 1 ml/min Wavelength: 240 nm Retention time: EGZ and SGP were found to be 0.883 min and 1.465 min. Linearity: 3.25–12.5μg/ml and 3.75– 22.5μg/ml for sitagliptin and ertugliflozin, respectively r2=0.999 LOD: 0.139 μg/ml ERT and 0.18 μg/ml SIT LOQ: 0.421 μg/ml ERT and 0.56μg/ml SIT |
49 |
CONCLUSIONS:
SGLT2 inhibitors, such as ertugliflozin alone or in combination with sitagliptin and metformin, are available to treat diabetes, as demonstrated by a thorough assessment of the literature. Ertugliflozin concentrations can be determined using a number of different techniques. According to an article, pharmacological dose forms of ertugliflozin, either alone or in combination with sitagliptin and metformin, were estimated using RP-HPLC testing techniques. UV techniques are also documented. Research studies on LC-MS/MS and UPLC that used ertugliflozin alone or in combination with metformin and sitagliptin in bulk and formulation are also reported. Therefore, all of these procedures have been proven to be straightforward, reliable, cost-effective, exact, and repeatable. Because these approaches provide the best accessibility, dependability, repeatability, and analysis time, compassion.
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Received on 19.04.2023 Modified on 11.06.2023
Accepted on 26.07.2023 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Ana. 2023; 13(3):222-228.
DOI: 10.52711/2231-5675.2023.00036