Startseite Canagliflozin: A review with specific focus on analytical methods in biological matrices and pharmaceuticals
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Canagliflozin: A review with specific focus on analytical methods in biological matrices and pharmaceuticals

  • Ajitha Azhakesan ORCID logo und Sujatha Kuppusamy ORCID logo EMAIL logo
Veröffentlicht/Copyright: 2. Dezember 2022
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Reviews in Analytical Chemistry
Aus der Zeitschrift Reviews in Analytical Chemistry Band 41 Heft 1

Abstract

Sodium-glucose transporter 2 inhibitor emerges as the latest group of oral hypoglycemic agents, which shows insulin-independent pathology and provides an upper hand to enhance renal glucose elimination. Canagliflozin (CGN) was the number one drug, approved by FDA on 29th March 2013 for the treatment of type 2 diabetes mellitus. By totting up to its glucose-lowering effects, it exhibits beneficial effects on the heart and potentially on the kidneys. The study aims to summarize various analytical techniques, such as chromatography, spectrophotometry, and hyphenated techniques, such as Liquid chromatography with tandem mass spectrometry (LC-MS/MS) and Ultra performance liquid chromatography with tandem mass spectrometer (UPLC-MS) for the analysis of CGN. In the proposed work, we have reviewed various analytical methods reported for the estimation of CGN in biological matrices and Pharmaceuticals from various databases like ScienceDirect, Springer, PubMed, Scopus, Taylor & Francis, and Web of Science for the estimation of CGN. Various analytical methods adapted were high-performance liquid chromatography, UPLC, LC-MS/MS, high-performance thin-layer liquid chromatography, Fourier-transform infrared spectroscopy, spectrofluorimetry, and UV spectrophotometry. This current review presented the determination of CGN using various analytical techniques and biological matrices either in single or in combination with other hypoglycemic agents, as per International Conference on Harmonization guidelines. Further, some future trends that can be integrated were also suggested.

Keywords: canagliflozin; type 2 diabetes; analytical methods; validation; ICH guidelines; LC-MS/MS

Abbreviations

CGN

canagliflozin

DAD

diode array detector

DGN

dapagliflozin

EGN

empagliflozin

HPLC

high performance liquid chromatography

ICH

International Conference on Harmonization

LC-MS/MS

liquid chromatography with tandem mass spectrometry

LNG

linagliptin

LLE

liquid–liquid extraction

LOD

limit of detection

LOQ

limit of quantitation

MFN

metformin

PDA

photo diode array

PPE

protein precipitation extraction

SGLT2

sodium glucose transporter 2

SPE

solid-phase extraction

T2DM

type 2 diabetes mellitus

TLC

thin layer chromatography

UPLC

ultra performance liquid chromatography

UV-Vis

ultra violet-visible spectroscopy

VWD

variable wavelength detector

1 Introduction

Type 2 diabetes mellitus (T2DM) resumes being a major non-communicable ailment with a universal burden of 366 million. India is considered the epicenter of diabetes with 77 million and is supposed to be 134 million by the year 2045. Sodium-glucose transporter 2 (SGLT2) inhibitor are the latest group of anti-diabetic medicines available in the market for the treatment of T2DM, preventing re-absorption of glucose from the blood, which is filtered through the kidneys and hence facilitating the excretion of glucose in urine. Canagliflozin (CGN) is the first approved member of the SGLT2 inhibitor class by the USFDA in March 2013 applicable to patients with T2DM as an adjunct to exercise and diet to enhance glycemic control [1]. SGLT2 inhibitors get inhibited in the proximal renal tubules by the action of CGN, lowering the urinary glucose threshold, which further enhances urinary glucose excretion. Cardiopathy is considered as a frequently developed etiology along with T2DM to cause morbidity and mortality among people with T2DM [2,3]. CGN was approved in the year 2018 to treat cardiovascular diseases, which includes blood pressure, body weight, and urinary function. CGN has superiority of SGLT2 inhibitors and cardiovascular treatment compared with other anti-diabetic drugs used to treat T2DM. CGN is chemically1-(beta-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate (Figure 1) with chemical formula C24H25FO5S·1/2H2O and molecular weight of 453.52 g·mol−1. It is freely soluble in methanol. It is yet to be monographed in any pharmacopoeias [4].

Figure 1 Structure of canagliflozin hemihydrate.
Figure 1

Structure of canagliflozin hemihydrate.

The threat of disease, access to medicine for the poor, and rising costs of medicine are the big challenges for the people of the world. For making affordable drugs available for people of the world that are extremely poor and prone to large epidemics, it is important to bring down the costs of research and development and thereby the production process and quality control. Simple, rapid (to reduce analytical down time in turn revenue), and cost-effective analytical method development is a thirst area of importance in the pharmaceutical industry. In view of the significance of CGN to the universal population, sensitive quality control methods are required for their analysis. Analytical methods have a major task in ensuring and assuring the quality of pharmaceuticals. Hence, currently, there is a need for the collection of the reported analytical methods of CGN. The main objective of the review is to summarize the multiple approaches available to estimate CGN in API, dosage form and biological matrix separately and drug combinations. The analytical methods were classified into four main methods: (1) UV-visible (UV-Vis) spectroscopy, (2) chromatography (Ultra performance liquid chromatography (UPLC), high-performance liquid chromatography (HPLC), high-performance thin-layer liquid chromatography (HPTLC)), and (3) bio-analytical. Figure 2 represents an overview of various analytical methods for the determination of CGN from various databases like ScienceDirect, Springer, PubMed, Scopus, Taylor & Francis, and Web of Science for the estimation of CGN.

Figure 2 Analytical methods for the estimation of CGN.
Figure 2

Analytical methods for the estimation of CGN.

Figure 3 provides the graphical representation of the number of articles published for the quantification of CGN from 2014 to 2022.

Figure 3 Number of analytical methods reported during 2014–2021. Database sources: ScienceDirect, Springer, PubMed, Scopus, Taylor & Francis, and Web of Science.
Figure 3

Number of analytical methods reported during 2014–2021. Database sources: ScienceDirect, Springer, PubMed, Scopus, Taylor & Francis, and Web of Science.

2 Spectroscopic methods

2.1 UV-Vis spectroscopic methods

UV-Vis spectroscopy methods are employed in pharmaceutical product estimation for their simplicity, versatility, accuracy, speed, and cost-effectiveness. Over a 40 years period, it has become the most important analytical instrument where expensive instruments like HPLC, Gas chromatography, Liquid chromatography with tandem mass spectrometry (LC-MS/MS) are not available. Singh et al. [5] developed a UV spectroscopic method using methanol as a diluent and measured the absorbance at 280 nm with a linearity of 5–50 µg·mL−1. Chinta et al. [6] reported a UV spectroscopic method using phosphate buffer as diluent at an absorbance wavelength of 289 nm and attained 99% purity with a linearity of 1–6 µg·mL−1. Ishpreet et al. [7] developed a UV spectroscopic method with a linearity of 5–10 µg·mL−1 at an absorbance of 290 nm and recovery within 80.00–120.00%. Vichare et al. [8] have reported two simultaneous methods, one based on absorbance correction UV spectroscopy (absorbance measurement at wavelengths 233 nm (λ max of metformin (MFN)) and 291 nm (λ max of CGN) and another based on first order derivative spectroscopy overlain spectra wavelengths 243 nm (zero absorbance of CGN) and 318 nm (zero absorbance of MFN) with a linearity of 0.75–4.5 µg·mL−1 for CGN and 2.5–15 µg·mL−1 for MFN, respectively. The percentage drug contents were found to be 98.48% ± 0.83% and 100.76% ± 1.29% for method A and 97.94 ± 0.96 and 97.22 ± 1.15 for CGN and MFN, respectively. The spectroscopic method existing for the determination of CGN as a single entity or in combination with other drugs [5,6,7,8] and the results (solvent, wavelength measured, linearity, accuracy, limit of detection (LOD), and limit of quantitation (LOQ)) obtained are represented in Table 1.

Table 1

Overview of published UV-Vis spectroscopic methods

Drug Dosage form Accuracy LOD (µg·mL−1) LOQ (µg·mL−1) Reference
CGN Bulk, tablets 99.46–100.31% 0.00945 2.8638 Singh et al. [5]
CGN Bulk, tablets 80–120% NA NA Chinta et al. [6]
CGN Bulk, tablets 80–120% 0.084 0.255 Ishpreet et al. [7]
CGN and MFN Bulk, tablets CGN: 98.48% and MFN: 100.76% NA NA Vichare et al. [8]
CGN: 97.94% and MFN: 97.22% NA NA

2.2 Spectrofluorimetry method

Spectrofluorimetry is a highly sensitive analytical method for the detection and determination of fluorescent compounds at ng or lower level. Nirav et al. [9] reported a specific, accurate, precise and robust spectrofluorometric method using methanol as the solvent, which emit excitation λ max at 293 nm and emission λ max at 349 nm. The method was linear over the range of 100–500 ng·mL−1 with a percentage recovery of 99.42–99.81%. The LOD and LOQ for the developed method were found to be 13.58 and 41.15 ng·mL−1, respectively. The method was novel, sensitive, and can be applied for the routine analysis of CGN by spectrofluorimetry [9].

3 Chromatographic methods

3.1 HPLC

HPLC is the most versatile and dominant separation technique in modern pharmaceutical and biomedical analysis due to its highly efficient separation and enhanced detection sensitivity. Most of the drugs are analyzed by HPLC method due to its accuracy, ease of automation, rapidity, specificity, and accuracy. Vymyslicky et al. [10] reported a new stability indicating HPLC method using electrochemical detection which significantly saves time and reduces the consumption of active ingredients and solvents, thereby minimizing the costs of forced degradation. Using ammonium phosphate buffer with methanol in a 50/50 volume ratio as a working electrolyte, the authors electrochemically oxidized samples and analyzed them by HPLC. Oxidation with hydrogen peroxide required 7 days, whereas electrochemical oxidation was completed in 3 h. Reddy et al. [11] reported a HPLC method which eluted CGN at a longer retention of 7.3 min using acetonitrile:water (50:50) as the mobile phase. The method was found to be sensitive over the other reported methods. Sadasivuni and Gundoju [12], using C18 column and acetonitrile:pH 2.5 with orthophosphoric acid (50:50) as the mobile phase, had developed an accurate method but did not mentioned the retention time (Rt). Mounika et al. [13] had developed a cost-effective, accurate, and sensitive method compared to other methods using a cost-effective mobile phase and eluted CGN at a Rt of 3.3 min. Another author had used methanol:water (90:10) and eluted CGN at 4.4 min (Sushil et al. [14]). Singh et al. [5] reported an accurate, precise, and linear method using acetonitrile:orthophosphoric acid (0.01 M) (50:50) and C18 column and eluted CGN at 4.7 min. Bhatt et al. [15] used acetonitrile:ammonium acetate buffer (pH 4.5) (70%:30% v/v) to elute CGN at 4.5 min. Parida et al. [16] reported a method using methanol:phosphate buffer with pH 4 (65:35) as mobile phase and C18 column using variable wavelength detector (VWD) at 293 nm and eluted CGN at 2.9 min. The Rt was comparatively less than the other methods. Sreenivasulu et al. [17] had reported a novel method using ion pair reagent, acetonitrile:1-octane sulphonic acid buffer (70:30) as the mobile phase and Rt of CGN was found at 3.4 min. The authors had achieved a good retention by using an ion pair reagent. Another author reported a method using orthophosphoric acid (0.1%):acetonitrile (60:40) which had a longer Rt at 8.7 min (Rahul et al. [18]) compared to the other reported methods. Vijaya et al. [19] developed a sensitive, selective method using 0.02% formic acid:acetonitrile (40:60) as the mobile phase and C18 column and achieved separation at 4.4 min. Goutam et al. [20] separated CGN from its process and degradation related substances using Ascentis Express RP-amide (150 mm × 4.6 mm, amide groups chemically bonded to porous silica particles of 2.7 µm) column, and ammonium acetate buffer:acetonitrile as the mobile phase at 290 nm. This method can be used to estimate the related substances of CGN. Triveni et al. [21], Ishpreet et al. [22], and Ladva et al. [23] have reported rapid, sensitive, accurate, and linear method using C18 as the stationary phase and various ratios of buffers (formic acid in water (0.1% v/v), ortho phosphoric acid, and 0.1% ammonium acetate:organic solvent (acetonitrile, methanol) as the mobile phase. The detectors used for the estimation were UV and PDA detectors. Suma et al. [24] had developed a cost effective, accurate method which eluted CGN at 2.8 min using HPLC grade water:acetonitrile (55:45 v/v) as the mobile phase. Al-Shdefat et al. [25] developed a simple, easy, and precise stability indicating HPLC method with diode array detector (DAD) for the simultaneous determination of CGN and MFN in a combined dosage formulation using a triple combination of mobile phase 0.05 M H3PO4, acetonitrile, and methanol in the 45:45:10 (v/v). The Rt for MFN and CGN were obtained at 8 and 9.45 min, respectively, which was a longer Rt compared to the other reported methods and found to be linear over the range of 5–100 g·mL−1. Authors Sunitha et al. [26], Bangaruthalli et al. [27], and Gandla et al. [28] performed simultaneous estimation of CGN and MFN using C18 as the stationary phase and wide choice of mobile phases. The methods were validated as per ICH guidelines. Moussa et al. [29] reported a simple and precise HPLC method for the quantitative estimation of CGN, empagliflozin (EGN), linagliptin (LNG), and MFN in their pharmaceutical formulation using a systematic and practical experimental design approach with minimum experimental trials. Authors selected three factors affecting the peaks significantly and determined using Plackett–Burman design. This method was found to be in good agreement with the observed value approving that design of experiment was simple methodology which was easy to instrument and chromatographically dependable in analyzing the single and multi-component drugs. Khalil et al., [30] developed the first reverse phase HPLC (RP-HPLC) method for simultaneous determination of CGN, dapagliflozin (DGN), EGN, and MFN on C18 column (250 mm × 4.6 mm, 5 µm p.s) Inertsil ODS through isocratic elution using acetonitrile and 0.05 M potassium dihydrogen phosphate buffer pH 4 in a ratio of 65:35, v/v as a mobile phase at flow rate of 1 mL·min−1. The method showed good linearity, accuracy, precision, and was successfully applied for determination of the four drugs in laboratory prepared mixtures and in the seven pharmaceutical dosage forms. Jyothi and Umadevi [31], Wafaa Zaghary et al. [32], Vinutha et al. [33], Kommineni et al. [34], Sonia et al. [35], and Panigrahy and Reddy [36] performed simultaneous estimation of CGN and MFN using C18 as the stationary phase and wide choice of mobile phases. The authors had developed RP-HPLC method for the estimation of CGN in single and in combined dosage forms by varying the chromatographic conditions and achieved better retention. The various HPLC methods (method, matrix, sample preparation, internal standard, column/mobile phase) available for quantification of CGN in pharmaceutical dosage forms as single and in combination [5,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] and the results (Rt, detection, and linearity) obtained are presented in Table 2.

Table 2

Summary of the reported HPLC methods for the determination of CGN in bulk and its dosage forms

Drug Column (dimension) Mobile phase Detector, detection wavelength (nm) Flow rate (mL·min−1) Rt (min) Linearity (µg·mL−1) Accuracy (%) LOD (µg·mL−1) LOQ (µg·mL−1) Reference
CGN NA Ammonium phosphate buffer:methanol (50:50) Electrochemical detection 0.1 mL·h−1 NA NA NA NA NA Vymyslicky et al. [10]
CGN C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:water (50:50) UV: 290 1 7.3 From 98 ng·mL−1 to 50 µg·mL−1 98.9–99.8 0.048 0.098 Reddy et al. [11]
CGN C18 (100 mm × 4.6 mm, 5 µm) Acetonitrile: orthophosphoric acid with pH 2.5 (50:50) UV: 235 1 NA 10–200 NA NA NA Sadasivuni and Gundoju [12]
CGN C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:0.1% sodium acetate (pH 4.6) (20:80) 291 1 3.3 2–14 99.98 NA NA Mounika et al. [13]
CGN Grace C18 (4.6 mm × 250 mm, 5 µm) Methanol:water (90:10) UV: 290 0.9 4.4 1–5 99.95–106.18 0.7212 2.1854 Sushil Patil et al. [14]
CGN NA Acetonitrile:orthophosphoric acid (0.01 M) (50:50) 280 0.9 4.732 2–40 91.70–102.03 NA NA Singh et al. [5]
CGN C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:ammonium acetate buffer (pH 4.5) (70:30%, v/v) UV: 252 1 4.5 5–30 98–101 0.01 0.04 Bhatt et al. [15]
CGN C18 (4.6 mm × 250 mm, 5 µm) Methanol: phosphate buffer (pH 4) (65:35) VWD: 293 1 2.9 10–125 99.33–99.92 0.9 2.7 Parida et al. [16]
CGN C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:1-octane sulphonic acid (70:30) PDA: 245 1 3.4 10–100 98–102 0.017 0.1705 Sreenivasulu et al. [17]
CGN X-bridge C18 (4.6 mm × 150 mm, 5 µm) Orthophosphoric acid (0.1%):acetonitrile (60:40) 230 1 8.7 25–75 99.6–99.8 3.58 10.85 Rahul et al. [18]
CGN C18 (4.6 mm × 250 mm, 5 µm) 0.02% formic acid:acetonitrile (40:60) UV: 230 1.2 4.4 10–50 98.44–100.31 0.00136 0.00414 Vijayalakshmi et al. [19]
CGN, RS-1,2,3,4 RP-amide (4.6 mm × 150 mm, 2.7 µm) Ammonium acetate:acetonitrile (50:50) UV: 290 0.7 23 0.055–1.177 NA 0.0005 0.015 Goutam et al. [20]
CGN C18 (4.6 mm × 150 mm, 5 µm) Methanol:formic acid in water (0.1% v/v) (90:10) UV: 220 1 2.4 100–300 99.9–100.8 0.0009 0.029 Triveni et al. [21]
CGN C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:ortho phosphoric acid (55:45) PDA: 290 1 6.29 1–6 99.6–99.8 0.41 1.24 Ishpreet et al. [22]
CGN C18 (4.6 mm × 250 mm, 5 µm) Methanol:acetonitrile:0.1% ammonium acetate (40:40:20) UV: 290 1.1 4.1 100–300 98.04–100.27 3.538 10.72 Ladva et al. [23]
CGN ODS (150 × 4.6 mm, 5 µm) Water:acetonitrile (55:45, v/v) PDA: 214 1 2.8 25–150 NA 0.037 0.112 Suma et al. [24]
CGN C18 (4.6 mm × 250 mm, 5 µm) 0.05 M H3PO4:acetonitrile:methanol (45:45:10 (v/v)) DAD: 238 1 CGN: 8.00 5–100 98–102 CGN: 0.653 CGN: 2.167 MFN: 0.874 Al-Shdefat et al. [25]
MFN MFN: 9.45 MFN: 0.261
CGN Spolar C18 (4.6 mm × 250 mm, 5 µm) pH 6 phosphate buffer:acetonitrile (55:45) UV: 254 0.8 CGN: 10.77 CGN: 5–30 NA NA NA Sunitha et al. [26]
MFN MFN: 3.24 MFN: 50–300
CGN Kromasil C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:phosphate buffer (pH 4.2):methanol (52:38:10) 254 1 CGN: 3.223 CGN: 5–30 NA NA NA Bangaruthalli et al. [27]
MFN MFN: 2.216 MFN: 50–300
CGN Primesil C18 (4.6 mm × 250 mm, 5 µm) Methanol:phosphate buffer (70:30) PDA: 220 1 CGN: 3.47 CGN: 50–250 CGN: 99.38–99.53 CGN: 4.13 CGN: 0.112 Gandla et al. [28]
MFN MFN: 2.413 MFN: 5–25 MFN: 99.18–99.91 MFN: 2.1 MFN: 0.0372
CGN C8 (250 mm × 4.6 mm, 5 μm) pH 6 phosphate buffer (0.05 M):acetonitrile:methanol (50:25:25, v/v/v) UV 1.5 CGN: 8.3 50–350 98–102 12.96 39.29 Moussa et al. [29]
EGN MFN: 2.2 500–3,500 57.51 174.29
LNG CGN/EMG: 3.6 10–70 1.1 3.33
MFN EMG: 6.0 20–140 1.73 5.24
LNG/MFN: 3.6 1.25–8.75 0.11 0.32
CGN Inertsil, ODS C18 (250 mm × 4.6 mm, 5 µm) Acetonitrile:0.05 M potassium dihydrogen phosphate (pH 4) (65:35) UV: 212 1 CGN: 4.414 CGN: 7.5–225   CGN: 2.1 CGN: 6.5 Khalil et al. [30]
DGN DGN: 3.560 DGN: 5–150 DGN: 0.7 DGN: 2.2
EGN EGN: 3.004 EGN: 6.5–187.5 EGN: 1.4 EGN: 2.3
MFN MFN: 1.898 MFN: 10–1,000 MFN: 3.2 MFN: 9.6
CGN Inertsil ODS 3 VC18 (250 mm × 4.6 mm, 5 µm) TFA in water (0.1% v/v):acetonitrile (20:80) UV: 254 1 CGN: 4.20 CGN: 20–40 NA NA NA Jyothi and Umadevi [31]
MFN MFN: 2.32 MFN: 200–600
CGN C18 (100 mm × 4.6 mm, 5 µm) Methanol:0.03 M phosphate buffer (75:25) 240 1.3 CGN: 0.9 CGN: 1–50 CGN: 99.81 ± 0.73 CGN: 0.7154 CGN: 2.1075 Wafaa et al. [32]
MFN MFN: 0.5 MFN: 0.5–90 MFN: 99.37 ± 0.54 MFN: 0.9327 MFN: 2.8263
CGN Kromasil C18 (4.6 mm × 250 mm, 5 µm) 0.1% OPA (pH 2.8):acetonitrile (45:55) PDA: 254 1 CGN: 2.671 CGN: 2.5–15 98.2–101.4 CGN: 0.01 CGN: 0.50 Vinutha et al. [33]
MFN MFN: 2.112 MFN: 25–15 MFN: 0.17 MFN: 2.20
CGN Kromasil C18 (4.6 mm × 250 mm, 5 µm) 0.1% orthophosphoric acid (pH 2.8):acetonitrile (45:55) UV: 254 1 CGN: 2.671 CGN: 2.5–15 98.22–101.54 CGN: 0.01 CGN: 0.50 Kommineni et al. [34]
MFN MFN: 2.112 MFN: 25–150 MFN: 0.17 MFN: 2.20
CGN Gracesmart C18 (4.6 mm × 250 mm, 5 µm) Acetonitrile:ammonium acetate (pH 4.5) (45:55) PDA: 252 1 CGN: 5.76 1–80 CGN: 99.19–100.57 CGN: 0.124 CGN: 0.376 Sonia et al. [35]
MFN MFN: 4.00 MFN: 98.65–100.87 MFN: 0.134 MFN: 0.406
CGN Kromasil C18 (4.6 mm × 250 mm, 5 µm) 0.01 M (pH 3.5) ammonium acetate:acetonitrile (65:55) PDA: 254 1 CGN: 3.713 CGN: 5–30 CGN: 99.45–100.65 MFN: 99.95–100.74 NA NA Panigrahy and Reddy [36]
MFN MFN: 2.440 MFN: 50–300

3.2 UPLC technique

UPLC is a recent separation technique which reduces the cost and increases the rapidity and efficiency of analysis required for developing and validating the method. Wafaa et al. [32] validated an UPLC method for the determination of MFN and CGN in tablets using Hypersil Gold (50 mm × 3 mm, 1.9 µm) as the stationary phase and methanol:0.03 M phosphate buffer (80:20) considered as the mobile phase at 0.4 mL·min−1 flow rate. The Rt of CGN and MFN was 1 and 0.5 min using a detection wavelength of 240 nm. Accuracy of CGN and MFN was 99.47% ± 1.03% and 99.73% ± 0.89% with a linearity of 0.1–50 and 0.25–100 µg·mL−1 for CGN and MFN, respectively. LOD and LOQ were 0.463 and 1.406 µg·mL−1 for CGN and 0.614 and 1.862 µg·mL−1 for MFN, respectively [32].

3.3 HPTLC technique

HPTLC is a powerful technique for qualitative and quantitative analysis. It contains chromatographic layers with the highest separation efficiency, the possibility to use multiple detection methods on the same sample and plate. Accurate quantitative measurements and high resolution makes HPTLC to meet all quality requirements for today’s analytical labs.

Vichare et al. [37] reported a novel HPTLC method for the simultaneous estimation of CGN and MFN using toluene:methanol:triethyl amine:glacial acetic acid (7:2.6:0.2:0.2, v/v/v/v) as a mobile phase. The detection was done at 254 nm with an excellent resolution of retardation factor (R f) values 0.21 ± 0.02 and 0.50 ± 0.03 for MFN and CGN, respectively. Detection and quantitation limits were found to be 8.01 and 24.28 ng/band for MFN and 8.27 and 25.07 ng per band for CGN, respectively. The proposed method was applied to marketed formulation, the % drug contents were found to be 98.20% ± 0.24% and 99.33% ± 1.80% w/w for MFN and CGN, respectively. This HPTLC method was novel and found to be more linear, accurate, precise, and sensitive compared to the other reported methods [37].

Ishpreet et al. [38] validated a HPTLC method using toluene:ethyl acetate:methanol (2:2:1) as the mobile phase and silica gel 60 F254 as the stationary phase for the estimation of CGN in tablet dosage form. The densitometric detection was at 290 nm. The recovery was 99.04–99.82% with a linearity of 10–500 ng per spot. LOD and LOQ were 0.39 ng/spot and 119 ng/spot, respectively. The % assay of CGN tablets was found to be 99.8%. Forced degradation studies of CGN showed stability in acidic, alkaline, photolytic, and oxidation [38].

Bhole et al. [39] developed a combination of CGN and MFN using silica gel 60 F 254 (10 × 10 cm, 250 µm) as the stationary phase and toluene:ethyl acetate:methanol:ammonia (4:4:2:0.1) as mobile phase at a wavelength of 254 nm. The Rf of MFN and CGN was found to be 0.15 and 0.50 ng/band, respectively. The linearity of MFN and CGN was found to be 0.5–3 and 50–300 ng/band, respectively. The proposed HPTLC method selectively quantitated MFN and CGN in the presence of the degradation products [39].

4 Bioanalytical methods

Bio-analytical techniques are used for the quantitative determination of drugs and their metabolites in biological fluids, which plays a major role in the evaluation and interpretation of bioequivalence, pharmacokinetic, and toxicokinetic studies. Hence, the development of selective, sensitive, and reliable bio-analytical methods for the quantitative evaluation of drugs and their metabolites in biological matrices is important. An analytical method for the quantification of CGN in human plasma has been developed, validated, and enforced for the analysis of samples. The analytical method consists of extraction of the drug by protein precipitation method, the internal standard DGN was added to the plasma sample and extracted using protein denaturant acetonitrile followed by centrifugation. The supernatant was dried and reconstituted using the mobile phase and injected into the HPLC (Ajitha et al. [40]). Another method employed extraction of sample by liquid extraction using tertiary butyl methyl ether in human Plasma. In liquid–liquid extraction (LLE) the plasma was spiked with internal standard and tert-butyl methyl ether followed by centrifugation. The supernatant was dried and reconstituted with a solvent and then injected into the HPLC/LC-MS/MS. Determination was done using Zorbax XDB phenyl (7.5 × 4.6 mm, 3.5 mm) column and methanol:acetate (80:20) as the mobile phase by LC-MS/MS. The method used a deuterium labeled CGN as internal standard and eluted at 1.15 min with a linearity of 10–7,505 ng·mL−1 (Deepan et al. [41]). Udhayavani et al. [42] employed a LC-MS method to quantify CGN in human plasma using solid phase extraction. In solid-phase extraction (SPE), the plasma sample was spiked with ammonium acetate and internal standard into the SPE cartridge followed by conditioning and washing to extract CGN and injected into the HPLC/LC-MS/MS. Another author also followed a similar method but showed variation by using C18 (100 × 4.6 mm, 5 µm) as the stationary phase and 2 mM ammonium acetate:methanol (15:85) as the mobile phase (Somarouthu et al. [43]). Darshan et al. [44] estimated CGN by LC-MS/MS from rabbit plasma using EGN as internal standard. The author extracted CGN using LLE with tertiary butyl methyl ether using C18 (50 × 4.6 mm, 5 µm) column and 0.01 M ammonium acetate:methanol (30:70) as the mobile phase. CGN was extracted from rat plasma by LLE using LC-MS/MS (Kobuchi et al. [45]). Nalawade et al. [46] developed a simultaneous method and successfully applied for the determination of pharmacokinetics of MFN and CGN by using 100 μL of rat plasma. Mohamed et al. [47] performed the simultaneous estimation of CGN and MFN in biological samples (rat plasma) by protein precipitation extraction (PPE; acetonitrile) and LLE (ethyl acetate) using valsartan, CGN d4, MFN d6, tadalafil, and propranolol as the internal standard using LC-MS/MS. The authors estimated the plasma concentrations of the studied drugs in a pharmacokinetic study involving Egyptian health volunteers. Ramisetti et al. [48] reported a simple, rapid, and sensitive LC-MS/MS method for the simultaneous quantification of CGN and MFN. The authors used a one-step PPE for samples preparation and obtained highest recovery for the analytes. This method was successfully used for the in vivo plasma concentrations obtained from a pharmacokinetic study. Syeda et al. [49] used HPLC to estimate CGN and MFN in human plasma using PPE (2% v/v acetic acid in acetonitrile) with pioglitazone as the internal standard. The method was simple, accurate, precise, and can be applied in bioequivalence, pharmacokinetic, and toxicokinetic studies with desired precision and accuracy along with high-throughput. Another author also reported a sensitive, novel HPLC method using SPE as the extraction method (Deepan et al. [50]).The bio-analytical methods published for the quantitative analysis of CGN separately and in drug combination (40–50) and the results (method, matrix, sample preparation, internal standard, column/mobile phase, Rt, detection technique, and linearity) are represented in Table 3.

Table 3

Summary of bio-analytical methods for the quantification of CGN alone and in combination with other drugs

Drug Matrix Sample preparation Internal standard Column/mobile phase Rt (min) Detection Linearity (ng·mL−1) Ref.
CGN Human plasma PPE DGN Phenomenex Luna C18 (150 × 4.6 mm, 5 µm)/0.01 M phosphate buffer (pH 3.5):acetonirile (45:55) 8.7 UV: 222 nm 60–2,400 Ajitha et al. [40]
CGN Human plasma Tertiary butyl methyl ether CGN d4 Zorbax XDB Phenyl (7.5 mm × 4.6 mm, 3.5 mm) 1.15 m/z: 462.2–267.10 for CGN 10–7,505 Deepan et al. [41]
Methanol: acetate (80:20) m/z: 466–267.2 for IS
CGN Human plasma SPE with ammonium acetate CGN d4 Zodiac C18 (100 mm × 4.6 mm, 5 µm) 1.5 MS/MS 10.253–6019.311 Udhayavani et al. [42]
Methanol:2 mM ammonium acetate (90:10)
CGN Human plasma SPE with ammonium acetate CGN d4 C18 (100 mm × 4.6 mm, 5 µm) 1.5 m/z: 462.2–267.10 for CGN 10.3–6,019 Somarouthu et al. [43]
2 mM ammonium acetate:methanol (15:85) m/z: 466–267.1 for IS
CGN Rabbit plasma Tertiary butyl methyl ether EGN C18 (50 mm × 4.6 mm, 5 µm) 2 m/z: 462.1–267.10 for CGN 5 × 105 to 600 Darshan et al. [44]
0.01 M ammonium acetate:methanol (30:70) m/z: 451.2–71.10 for IS
CGN Rat plasma LLE with tertiary butyl methyl ether EGN Quicksorb ODS (150 mm × 2.1 mm, 5 µm) NA m/z: 462.1–191 for CGN NA Kobuchi et al. [45]
Acetonitrile:0.1% formic acid (90:10) m/z: 451.2–71.0 for IS
CGN Rat plasma NA Valsartan Methanol:0.1% formic acid (65:35) CGN: 8.2 MS/MS 200–8,000 for CGN Vivek et al. [46]
MFN MFN: 1.83 100–4,000 for MFN
  IS: 6.2  
CGN NA Protein precipitation Internal standard 1-CGN d4 Hypersil BDS C18 (100 mm × 4.6 mm, 5 µm) 5 mM ammonium acetate 0.01% formic acid:methanol (15:85) CGN: 1.5 MS/MS 10–6,028 for CGN Muralikrishna et al. [47]
MFN Internal standard 2-MFN d6 MFN: 1.8 10–3,027 for MFN
CGN Human plasma PPE with acetonitrile CGN-Tadalafil C18 (50 mm × 4.6 mm, 5 µm) CGN: 4.5 m/z: 130.2–60.1 for MFN 50–5,000 for MFN Ramisetti et al. [48]
MFN LLE with ethyl acetate MFN-propranolol 0.1% formic acid:acetonitrile MFN: 0.9 462.3–191.0 for CGN 10–1,000 for CGN
260.2–183.0 for propranolol
390.2–268.8 for tadalafil
CGN NA Protein precipitation Pioglitazone Spursil (Dikma) ODS C18 (4.6 mm × 250 mm, 5 µm) CGN: 8.352 NA 250–1,250 for MFN Syeda et al. [49]
MFN 2% v/v acetic acid in acetonitrile Acetonitrile:phosphate buffer (pH 3.0) (15:85% v/v) MFN: 4.738 25–125 for CGN
Pioglitazone: 10.995
CGN Human plasma SPE Pioglitazone Inertsil ODS C18 (4.6 mm × 250 mm, 5 µm) CGN: 8.10 NA 5,000–25,000 for MFN Deepan et al. [50]
MFN (pH 3 with sodium hydroxide) phosphate buffer:acetonitrile (85:15) MFN: 4.6 500,000–1,250,000 for CGN
Pioglitazone: 10.64

5 Multiple spectroscopic methods

Elnadi et al. [51] reported three novel, simple, accurate, and sensitive methods for the determination of CGN using FTIR, spectrofluorimetry, a stability-indicating UV-Vis spectroscopic method for the simultaneous estimation of CGN and MET. Method A is a green FTIR method using KBr disc for CGN determination measuring alkyl halide C–F peak area centered on 1,230 cm−1. Method B is a spectrofluorimetry method using Δλ = 50 nm synchronous mode at a peak maximum of 291.8 nm for CGN determination using methanol as diluent. Method C is a stability-indicating MCRS method measuring the peak amplitude of CGN and MET at 306.2 and 246.6 nm, respectively, in their mixture with complete CGN oxidation degradation. All the three spectroscopic methods can be used efficiently for routine analysis in QC laboratories [51].

6 Discussion

CGN is considered as a primary member in the gliflozins family, which has a considerable contribution since 2013. Authors Singh et al. [5], Ishpreet et al. [7], and Vichare et al. [8] used methanol as the diluent to develop an accurate and linear method for the estimation of CGN separately and in combined dosage forms by UV-Vis spectroscopic technique. Vichare et al. [8] reported two analytical methods for the simultaneous estimation of CGN and MFN using methanol as the diluent. Both the methods showed good recovery with a linearity of 0.75–4.5 and 2.5–15 µg·mL−1 for CGN and MFN, respectively. Whereas Chinta et al. [6] developed a cost effective, sensitive method using phosphate buffer as the diluent which is a better method. HPLC method is utilized for the estimation of CGN separately and in combination with other drugs in bulk and pharmaceutical formulations. Rahul et al. [18] reported a cost-effective method for the estimation of CGN using X-Bridge C18 (4.6 × 150 mm, 5 µm) as stationary phase and orthophosphoric acid (0.1%):acetonitrile (60:40) as the mobile phase. Rt of CGN is about 8.7 min with a linearity of 25–75 µg·mL−1 and recovery of 99.6–99.8% at detection wavelength of 230 nm. This method had a higher Rt of 8.7 min compared to all the other reported methods. The authors would have tried by varying the mobile phase composition for a better method. Another author Reddy et al. [11] reported a HPLC method in which CGN eluted at 7.3 min, but achieved a linearity in the range from 98 ng·mL−1 to 50 µg·mL−1 indicating the sensitiveness of the method. Mounika et al. [13] developed a method which was cost effective method using ecofriendly solvents compared to the other reported methods. Panigrahy et al. [36] reported a cost-effective method for the simultaneous estimation of CGN and MFN using kromasil C18 (4.6 × 250 mm, 5 µm) as the stationary phase and 0.01 M (pH 3.5) ammonium acetate:acetonitrile (65:55) as the mobile phase at a detection wavelength of 254 nm. CGN eluted at 3.713 min with % recovery of 99.45–100.65%. MFN eluted at 2.44 min with % recovery of 99.85–100.74%. This method was validated as per ICH guidelines and found to be sensitive, accurate, and precise. Many bio-analytical methods using LC-MS/MS and a few HPLC methods were reported for CGN separately and in combination with other drugs. Deepan et al. [41] reported a LC-MS/MS method for the estimation of CGN using Zorbax XDB phenyl (7.5 × 4.6 mm, 3.5 mm) as the stationary phase and methanol:acetate (80:20) as the mobile phase with CGN d4 as the internal standard. LLE was performed by using tert butyl methyl ether as the extraction solvent. CGN eluted at 1.15 min with an m/z: 462.2–267.10 for CGN and m/z: 466–267.2 for CGN d4 and a linearity of 10–7505 ng·mL−1. The method was selective and sensitive compared to all the reported methods. Deepan et al. [50] reported a simultaneous method for the estimation of CGN and MFN by HPLC in human plasma using Inertsil ODS C18 (4.6 × 250 mm, 5 µm) as the stationary phase and (pH 3 with sodium hydroxide) phosphate buffer:acetonitrile (85:15) as the mobile phase. CGN eluted at 8.10 min and MFN eluted at 4.6 min with a linearity of 5–25 µg·mL−1 for MFN and 500–1,250 µg·mL−1 for CGN, respectively. Bio-analytical method using HPLC is always cost effective compared to the sophisticated LC-MS/MS techniques. But LC-MS/MS methods are sensitive and selective compared to the HPLC methods. All reviewed methods were validated as per ICH guidelines.

7 Conclusion

This detailed review explains the existing methods for the determination of CGN in pharmaceutical formulations and in biological fluids using spectroscopy, UPLC, HPLC, HPTLC, and LC-MS/MS. This review has presented the complete review of the methods reported right from the drug approval time to up-to-date. In future, researchers can take efforts to develop more methods using eco-friendly solvents for the determination of CGN in pharmaceutical dosage forms and employ sample extraction methods using green analytical techniques (single-drop micro-extraction, liquid-phase micro-extraction, liquid–liquid–liquid micro-extraction, single short column, solid-phase micro-extraction, stir-bar-sorptive extraction, matrix solid-phase dispersion, supercritical-fluid extraction, pressurized-liquid extraction, subcritical-water extraction, microwave-assisted extraction, sonication-assisted solvent extraction). More methods based on LC-MS/MS can pave the way for the toxicokinetic studies and therapeutic monitoring of CGN.

Acknowledgments

The authors are privileged to thank the Management of Sri Ramachandra Institute of Higher Education and Research (Deemed to be University) for helping us to carry out this work.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: Ajitha Azhakesan: writing – original draft, writing – review and editing, methodology, and formal analysis; Sujatha Kuppusamy: writing – original draft and formal analysis.

  3. Conflict of interest: Authors state no conflict of interest.

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Received: 2022-04-01
Revised: 2022-09-25
Accepted: 2022-09-27
Published Online: 2022-12-02

© 2022 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  10. Purification and characterisation of phytochemicals extracted from Rhizophora mucronata: Their efficacy against Pseudomonas aeruginosa infection in Catla catla
  11. Review Articles
  12. Recent applications of quantitative analytical FTIR spectroscopy in pharmaceutical, biomedical, and clinical fields: A brief review
  13. Review of characteristics and analytical methods for determination of indomethacin
  14. A review of the application of comprehensive two-dimensional gas chromatography MS-based techniques for the analysis of persistent organic pollutants and ultra-trace level of organic pollutants in environmental samples
  15. Enrichment and analysis of glycated proteins
  16. Round robin tests of secondary raw materials: A systematic review of performance parameters
  17. Paper-based microfluidic devices: Fabrication, detection, and significant applications in various fields
  18. Applications of headspace solid-phase microextraction in human biological matrix analysis
  19. Chemometrics and infrared spectroscopy – A winning team for the analysis of illicit drug products
  20. Canagliflozin: A review with specific focus on analytical methods in biological matrices and pharmaceuticals
  21. RNA-based isothermal amplification technology and its clinical application in pathogen infection
  22. Detection of diarrheal shellfish toxins
  23. Special Issue: Nanomaterials with mimetic enzymatic properties for label-free sensors and biosensors (Guest Editors: Gang Wei and Zhiqiang Su)
  24. Preparation of cuprous oxide-supported silver-modified reduced graphene oxide nanocomposites for non-enzymatic electrochemical sensor
  25. Recent advances in matrix metalloproteinases-responsive nanoprobes for cancer diagnosis and therapy
  26. A simple salicylaldehyde-bearing pyrazine as a turn-on fluorescent chemosensor for Al3+ and Zn2+ recognition and its applications
  27. Preparation of silver nanosheet-assembled film as a surface-enhanced Raman scattering substrate
  28. Synthesis of group I–III–VI semiconductor quantum dots and its application in food safety testing
https://doi.org/10.1515/revac-2022-0049
Schlagwörter für diesen Artikel
canagliflozin; type 2 diabetes; analytical methods; validation; ICH guidelines; LC-MS/MS
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Abnormal retention of s-triazine herbicides on porous graphitic carbon
  3. One-factor-at-a-time method combined with ICP-MS for determining 11 elements in soy sauce and their migration from the containing glass bottles
  4. Analysis of initiator content of prepreg by near-infrared spectroscopy
  5. Simultaneous MEKC-DAD and smart spectrophotometric assays of thiocolchicoside and etoricoxib in challenging concentration ratio mixtures
  6. Alternative analytical methods for ibrutinib quantification in pharmaceutical formulation: A statistical comparison
  7. Chemometric determination of common cold infection drugs in human urine
  8. An effective, novel, and cheap carbon paste electrode for naproxen estimation
  9. Fabrication of ultra-sensitive carbon paste electrode with nanocomposite CdS modification for electroanalysis of rafoxanide in dosage form and biological fluids
  10. Purification and characterisation of phytochemicals extracted from Rhizophora mucronata: Their efficacy against Pseudomonas aeruginosa infection in Catla catla
  11. Review Articles
  12. Recent applications of quantitative analytical FTIR spectroscopy in pharmaceutical, biomedical, and clinical fields: A brief review
  13. Review of characteristics and analytical methods for determination of indomethacin
  14. A review of the application of comprehensive two-dimensional gas chromatography MS-based techniques for the analysis of persistent organic pollutants and ultra-trace level of organic pollutants in environmental samples
  15. Enrichment and analysis of glycated proteins
  16. Round robin tests of secondary raw materials: A systematic review of performance parameters
  17. Paper-based microfluidic devices: Fabrication, detection, and significant applications in various fields
  18. Applications of headspace solid-phase microextraction in human biological matrix analysis
  19. Chemometrics and infrared spectroscopy – A winning team for the analysis of illicit drug products
  20. Canagliflozin: A review with specific focus on analytical methods in biological matrices and pharmaceuticals
  21. RNA-based isothermal amplification technology and its clinical application in pathogen infection
  22. Detection of diarrheal shellfish toxins
  23. Special Issue: Nanomaterials with mimetic enzymatic properties for label-free sensors and biosensors (Guest Editors: Gang Wei and Zhiqiang Su)
  24. Preparation of cuprous oxide-supported silver-modified reduced graphene oxide nanocomposites for non-enzymatic electrochemical sensor
  25. Recent advances in matrix metalloproteinases-responsive nanoprobes for cancer diagnosis and therapy
  26. A simple salicylaldehyde-bearing pyrazine as a turn-on fluorescent chemosensor for Al3+ and Zn2+ recognition and its applications
  27. Preparation of silver nanosheet-assembled film as a surface-enhanced Raman scattering substrate
  28. Synthesis of group I–III–VI semiconductor quantum dots and its application in food safety testing
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