Int J App Pharm, Vol 15, Issue 6, 2023, 53-59Review Article

FELODIPINE-REVIEW OF ANALYTICAL METHODS DEVELOPED FOR PHARMACEUTICAL DOSAGE FORMS AND BIOLOGICAL FLUIDS

KIRAN MALLI1, LALIT KUMAR2, RUCHI VERMA1*

1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Udupi, Karnataka, India. 2Department of Pharmaceutics, National Institute of Pharmaceutical Education, Hajipur-844102, Vaishali, Bihar, India
*Email: ruchiverma.pharma@gmail.com

Received: 23 Aug 2023, Revised and Accepted: 09 Oct 2023

ABSTRAC

Felodipine (FDP) is a vascular selective L-type calcium channel blocker, in hypertension patients FDP significantly lowers systolic and diastolic blood pressure (BP). It is a lipophilic drug molecule that contains a dihydropyridine ring responsible to show pharmacological activity, it is mainly used to control and prevent essential hypertension. This review article provides a summary of various analytical techniques for determining felodipine in pure form, pharmaceutical formulations, and biological fluids. Various analytical techniques are developed and validated, such as ultraviolet/visible spectrophotometry, high-performance liquid chromatography (HPLC), high-performance thin layer chromatography (HPTLC), and bioanalytical techniques. Estimated validation parameters such as linearity, LOD (Limit of Detection), and LOQ (Limit of Quantification) are discussed for each method. The wavelength of detection (λmax), mobile phase, columns, flow rate, retention time (Rt) and sample preparation techniques are all important quality elements for calculating Felodipine via analytical procedures.

Keywords: Felodipine, Analytical methods, Pharmaceutical dosage forms, Biological fluids

© 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2023v15i6.49211. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Hypertension is one of the main risk factors for atherosclerosis and other life-threatening cardiovascular diseases. Calcium channel blockers are categorised chemically into three groups: benzothiazepines, dihydropyridines, and phenylalkylamines [1]. Chemically FDP is ethyl methyl (4RS)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5 dicarboxylate produces antihypertensive activity due to the presence of dihydropyridine ring [2]. Belongs to the class of dihydropyridine and is chemically similar to nifedipine, nimodipine, nisoldipine, nicardipine and nitrendipine. FDP suppresses contractile responses to calcium in potassium-depolarized tissue in cardiac and smooth muscle at therapeutic doses. Contraction of cardiac muscles takes place by binding of calcium to calmodulin protein, which results in the activation of myosin light-chain kinase (MLCK), which causes heart muscle contraction. Myosin light chain is phosphorylated by activated MLCK, causing myosin head attachment to act in, which causes smooth muscle contraction and vasoconstriction. FDP acts by binding to calmodulin protein, hence prevents calcium-calmodulin interaction [3]. Dilation of peripheral arterioles is the primary effect of FDP. In vitro researches revealed that selectivity is more for vascular smooth muscle than myocardial muscle when compared to nifedipine or verapamil [4]. Felodipine does not cause orthostatic hypotension because it has no effect on venous smooth muscle in clinical doses [5]. FDP also have natriuretic and diuretic property as it has direct action on tubular reabsorption and thus prevents retention of salt and water and hence lowers blood pressure and increased cardiac output [6]. FDP does not appear to have a significant effect on glomerular filtration rate (GFR), creatinine clearance, glucose tolerance, or plasma lipoprotein concentrations in hypertensive patients [3].

Felodipine (FDP) belongs to the class of dihydropyridine calcium antagonist and it is lipophilic in nature. According to research, once-daily use of an extended-release (ER) formulation is equivalent to twice-daily administration of conventional tablets in terms of antihypertensive efficacy. At the therapeutic dose, in patients with congestive heart failure (CHF), FDP seemed to have no negative inotropic effect but it might slightly increase myocardial contractility [3, 4]. FDP gets absorbed in GI tract rapidly and completely when given as an oral solution and reaches peak plasma concentration after 15-90 min (tmax) of administration. It Takes 1h to 2h when administered as plain tablet. It takes 3h to 5h to attain peak plasma concentration when administered as an extended-release tablet. Only about 15% of the drug reaches systemic circulation due to first-pass metabolism. FDP is highly distributed to extravascular tissue. FDP has a volume of distribution of about 10.3L/Kg, which signifies that less than 1% of the drug is concentrated in the blood. Plasma protein binding was found to be 99.64% [7]. FDP gets metabolized in the liver by Cytochrome P-450-dependent oxidation to its pyridine analogue [8]. Small amount of the drug gets excreted in the urine in its unchanged form. The elimination phase of FDP plasma drug concentration-time curve, which begins 8 to 10 h after administration, reflects the drug's elimination [9]. FDP is an orally administered drug, available as extended-release tablets with the strength 2.5 mg 5 mg and 10 mg in the market. FDP can be estimated using a wide range of analytical techniques in formulations and biological samples.

Fig. 1: Structure of felodipine

Molecular formula C18H19Cl2 NO4 and molecular weight t 384.254 g/mol [2]. Felodipine USP is a crystalline powder that is light yellow to yellow in colour. It is insoluble in water but freely soluble in dichloromethane and ethanol. FDP is a highly lipophilic neutral molecule within normal pH range. The partition coefficient of FDP is about 30000 between toluene and water.

Fig. 2: Number of publications from 1991 to 2021 for quantification of FDP
Database sources: Scopus, Springer, Web of Science

Fig. 2 shows the number of papers published from the year 1991 to 2020. The literature was obtained from various databases i.e. science direct, scopus, taylorand francis, web of sciences, Elsevier, springer, pubmed. The data collected was from 1991-2021. Among all these, year’s highest number of papers were published in the year 2010 and 2018.

Fig. 3: An outlook of various analytical methods proposed for estimation of FDP

Fig. 3 is the statistical pie diagram representing various analytical techniques proposed for the estimation of LAC. It shows that HPLC and LC/MS/MS, GC/MS are the most widely used chromatographic technique for the estimation of FDP in API, formulations and in biological fluids, respectively.

Spectroscopic techniques

Ultra-violet visible spectrophotometric technique

UV/vis spectrophotometry is a quick, easy, and sensitive approach for detecting and quantifying FDP based on UV absorption and chemical interactions. This method is cost-saving, accurate and precise for the routine analysis of the FDP in tablet dosage form. Table 1 represents the various spectrophotometric methods for determining and estimating FDP in pharmaceuticals, formulations, bulk pharmaceuticals as a whole and in combination with other drugs.

Spectrofluorimetric methods

The spectrofluorimetric methods are also used to estimate FDP in tablet dosage forms, in addition to the UV-visible spectrophotometric techniques. The spectrofluorimetric techniques are used because they are highly selective, sensitive, simple to operate, and cost-effective. Mohamed AM and his colleagues developed micelle-enhanced spectrofluorimetric techniques to determine FDP and Nimodipine in formulations and human plasma, and the sample was treated with 2% Tween-80 solution. Using tween-80, fluorescence intensity was measured at 423 nm after getting excited at 385 nm. In the range of 0.05-4.0 g/ml, the standard fluorescence–concentration curve was found to be linear. For the reported linearity range LOD and LOQ were found to be 2-0.02µg/ml and 2-0.05µg/ml respectively [10]. Table 1 represents the spectrofluorimetric methods for determining and estimating FDP in pharmaceuticals, formulations and in biological matrix.

Chromatographic methods

HPTLC

For the quantitative determination of felodipine in solid dosage form and in bulk, simple, precise, and sensitive HPTLC and RP-HPTLC methods have been developed and were validated as per ICH. These techniques can be used to analyse Felodipine in bulk and pharmaceutical preparations on a regular basis [21, 22]. Table 2 represents the HPTLC methods for determining and estimating FDP in pharmaceuticals, formulations.

Table 1: Spectrofluorimetric and spectrofluorometric methods for determining and estimating FDP in pharmaceuticals, formulations and in biological matrix

Method Drug Matrix Diluent Wavelength (nm) Linearity (µg/ml) LOD LOQ Ref.
Spectrophotometric FDP Tablet Ethanol 363.5 5-50 NA NA [11]
Spectrofluorometric FDP Tablet/Plasma Method 1-Methanol (MeOH), Method 2-2% Tween-80 and distilled water λem Method 1-426 nm, Method 2-423 nm λex Method 1and2-385 nm Method 1-0.2–3.0µg/ml, Method 2-0.05-4.0 µg/ml Method 1-0.04µg/ml, Method 2-0.02µg/ml Method 1-0.12µg/ml, Method 2-0.05µg/ml [10]
Spectrofluorometric FDP Tablet Methanol 375 nm 0.2-2 μg/ml 0.02 μg/ml 0.06 μg/ml [12]
Spectrophotometric FDP Tablet Water 760 nm 1.5-5.0 μg/ml NA NA [13]
Spectrophotometric FDP Tablet Solvent A-acetonitrile (ACN)-distilled water (70: 30), Solvent B-0.1 N HCl, phosphate buffer pH 6.8 and water-ACN (70: 30 v/v) 268 nm, 245 nm 2 to 12 μg/ml NA NA [14]
Spectrophotometric FDP Tablet Methanol and 0.1N HCl in 1:9 ratio 366.5 nm 3 to 10 μg/ml NA NA [15]
Spectrophotometric FDP API and Formulation MeOH 237 nm 2-18 µg/ml 0.265 0.8835 [16]
Spectrophotometric FDP Tablet MeOH BTB-420 nm, BCP-415 nm BTB: 5.0-25.0µg/ml, BCP: 4.0-20.0µg/ml NA NA [17]
Spectrophotometric FDP Tablet MeOH 234 nm and 360 nm 4-24µg/ml and 8-60µg/ml 2µg/ml and 2.5µg/ml 1µg/ml and 5µg/ml [18]
Spectrophotometric FDP API and tablet MeOH 326.4 nm 10-100 µg/ml NA NA [19]
Spectrophotometric FDP API and tablet Method B (Methyl Orange)-Water, Method C (Indigo Carmine)-Water Method B-520 nm, Method C-610 nm Method B: 0.12–0.87µg/ml, Method C: 0.5–6.0µg/ml Method B: 0.013µg/ml, Method C: 0.09µg/ml Method B: 0.044µg/ml, Method C: 0.32µg/ml [20]

FDP: Felodipine, NA: Not available, MeOH: Methanol, ACN: Acetonitrile, HCl: Hydrochloric acid

Table 2: HPTLC methods for determining and estimating FDP in API and tablets

Method Drug Matrix Stationary phase Mobile phase Rf Wavelength Linearity LOD and LOQ Ref.
HPTLC FDP Tablet Precoated aluminium plates with silica gel 60 F254 n-hexane: ethyl acetate 6: 4 (v/v) 0.53±0.027 366 nm NA 23.54ng/spot and 71.33 ng/spot [21]
HPTLC FDP API and formulation Pre-coated aluminium plates with 250 μm layer of Silica gel 60 F254(NP), Silica gel 60 RP-18 TLC
F254S(RP)		 Toluene: Methanol (8:2 v/v) (NP), acetonitrile: water: glacial acetic acid (8:2:1 v/v/v)(RP) 0.40(RP), 0.53(RP) 237 nm 300-1800 and 500-3000 ng/band 11.51(NP), 34.90(RP) and 29.90(NP), 90.61(RP) [22]

FDP: Felodipine, NA: Not available, RP: Reverse phase, NP: Normal phase

High-performance liquid chromatography

HPLC is a simple and sensitive method for estimating and measuring FDP in the presence of impurities, employing a simple mobile phase and minimal amounts of samples, and it has been validated in terms of accuracy, precision, stability, sensitivity, specificity, and robustness.

Ultra-performance liquid chromatography

Ultra-high-performance liquid chromatography (UPLC) is a more efficient and effective method for determining FDP. To identify and quantify FDP, its impurities, and degradation products, simple and accurate RP-UPLC methods are developed. Table 3 represents the HPLC/UPLC methods for the determination and estimation FDP in pharmaceutical, formulations.

Biological matrices

For the determination and quantification of FDP in biological matrices, various bioanalytical methods have been developed. Bioanalytical methods are useful for identifying and quantifying drugs and their metabolites in biological matrices, which helps in drug evaluation of bioequivalence, pharmacokinetics, and pharmacodynamic studies [23]. Various analytical approaches have been developed, including hyphenated techniques for estimating FDP as a single entity and in combination, which requires less time. Table 4 represents various analytical methods for determining and estimating FDP in biological matrix (serum and plasma).

Table 3: HPLC methods for determining and estimating FDP in API and pharmaceutical formulations

Method Drug Matrix Sample preparation Mobile phase Flow rate Column Detection Linearity LOD and LOQ Rt (min) Ref.
SFC/UV, LC/UV FDP Tablet NA 6% (v/v) MeOH-modified CO2, CAN-MeOH0.05 M Potassium phosphate buffer (40:20:40, v/v/v) 2 ml/min Hypersil Silica (25 cm * 4.6 mm * 5 µm) 254 nm NA NA <6 min [24]
HPLC-fluorescence detection FDP Tablet Pulverisation 25 mmol of sodium dihydrogen phosphate and 85 mmol of sodium dodecylsulfate with 6.5% v/v pentanol 1.5 ml/min CLC-C18 (250 mm * 4.6 mm * 5 µm) 240 nm (excitation)
440 nm (emission)		 0.05–15 mg/ml 0.011 mg/ml and 0.032 mg/ml NA [25]
HPLC FDP Tablet Trituration Methanol–potassium dihydrogen orthophosphate (75:25, v/v). 1.5 ml/min LiChroCART (250 mm * 4 mm * 5.0 µm) 238 nm 1–7 µg/ml 150ng/ml and 500ng/ml NA [26]
HPLC FDP Tablet Trituration Potassium di-hydrogen phosphate: MeOH: ACN 15:15:70 (v/v/v) 1.5 ml/min Hyperchom C18 (250 × 4.6 mm, 5.0 μm) 210 nm 5-80 μg/ml 1.21 µg/ml NA [27]
HPLC FDP Tablet NA Buffer: ACN: MeOH (2:2:1 v/v) 1 ml/min Inertsil ODS _2 C_18 (100 × 4.6 mm, 3.0 μm) 238 nm NA 1.71μg/ml NA [28]
HPLC FDP Tablet NA ACN: water (70:30 v/v) 1 ml/min KYA TECH HiQ Sil C18HS (250 mm x 4.6 mm, 5.0 µm) 238 nm 5-30 µg/ml 0.12µg/ml and 0.36µg/ml 11.46 min [29]
HPLC FDP API and tablet NA ACN: water(70:3v/v) 1 ml/min PhenomenexC-18 (150 mm x 4.6 mm, 5.0 μm) 238 nm 2-10 µg/ml 0.000665µg/ml and 0.002014µg/ml 8.29 min [30]
HPLC FDP Tablet Dilution ACN–0.01 M KH2 PO4 1.5 ml/min JASCO-metaphase ODS (25034.0 mm) 5.0 µm column 250 nm 25–3200 ng/ml NA 12.20 min [31]
HPLC FDP API NA Acetonitrile: Methanol: Phosphate buffer (40:20:30v/v) 1.0 ml/min Lichrocart C18 (150 ×4.6 mm, 5.0 µm) 326 nm NA 4.5ng/ml NA [32]
HPLC FDP Tablet NA ACN: Water (80:20 V/V) 1.0 ml/min ODS C18 (4.6 x 150 mm, 5.0 µm) 305 nm 15-75 μg/ml 0.19µg/ml and 0.6µg/ml NA [33]
HPLC FDP Tablet NA ACN: water (80:20 v/v) 1.0 ml/min Symmetry C18 (25 cm × 4.5 mm, 5.0 μm) 234 nm 25 to 200 μg/ml 0.125 ng/ml and 1.25 ng/ml NA [34]
HPLC FDP API NA Methanol: acetonitrile: water (50:15:35%, v/v/v) 1.0 ml/min C18 (5μm, 250 ×4.6 mm) 238 nm 5.05-40.4μg/ml 1ng and 4ng 6.5 min [35]
HPLC FDP Tablet Trituration Phosphate buffer: acetonitrile (20:80v/v) 1.2 ml/min C18 Zorbax (250 mm × 4.6 mm, 5.0 µm) 234 nm 0.1–150 µg/ml 0.0279µg/ml and 0.0852 µg/ml 2.51 min [36]
HPLC FDP Tablet Trituration Acetonitrile-20 mmol aqueous ammonium acetate (80:20v/v) 1.0 ml/min RP C18 (250x4.6 mm i. d) 236 nm 2.49 to 99.60 μg/ml 0.6µg/ml and 1.60µg/ml NA [37]
HPLC FDP Tablet Trituration MeOH-0.055M phosphate buffer (83:17 v/v) 0.7 ml/min Luna C18 (250x4.6 mm, 5µ) 275 nm 2-20µg/ml 0.4µg/ml and 1µg/ml 12.52 min [18]
HPLC FDP Agglomerates NA MeOH 0.055 M phosphate buffer (83:17v/v) 0.8 ml/min HIQ Sil C 18 HS 4.6 mm×250 mm 232 nm 10-60µg/ml 0.8891µg/ml and 1.42758µg/ml NA [38]
HPLC FDP Tablet NA 0.02 mmol Ammonium acetate and acetonitrile (55:45, v/v) 0.7 ml/min Phenomenex Gemini C18 (150 × 2.0 mm, 5.0 µm) 240 nm 0.2-8.0 μg/ml 0.05µg/ml and 0.15 µg/ml NA [2]

Table 4: Various methods for determining and estimating FDP in biological matrix (serum and plasma)

Method Drug Matrix Sample preparation Mobile phase Flow rate Column Detection Linearity LOD and LOQ Rt (min) Ref.
HPLC FDP Plasma Ultrasound assisted dispersive liquid-liquid micro extraction 10 mmol phosphate buffer pH= 3.0, ACN (50:50; v/v) 1.0 ml/min Thermo BDS Hypersil C18 column (4.6 mm × 150 mm, 5.0 µm) NA 0.05–2µg/ml 0.013-0.031 µg/ml and 0.043-
0.103 µg/ml		 13 min [39]
HPLC, GC/MS FDP Plasma Frozen n-hexane: isopropanol (5:l v/v), Helium NA Chiralcel OJ column (4.6 mm x 250 mm), JEOL JMS-Dx-300, Hewlett Packard 0.20 mm x 12.5 m, UI 240 nm, mlz 238 0.05-10.00 ng/ml 0.05ng/ml NA [40]
GC/MS FDP Plasma Liquid-liquid extraction Helium, n-hexane-isopropanol (88:12 v/v) 0.365 ml/min GC column (30 m* 0.2 mm0.5 µm)
Chiralcel OJ (250 x 4.6 mm 10 µm)		 240 nm NA 0.1 ng/ml 13 min [41]
LC–ESI–MS–MS FDP Plasma Liquid–Liquid Extraction 1 mmol ammonium acetate–ACN, 20:80 (v/v) 200 µl/min C8 Capcell Pak (2.0 mm150 mm5.0 µm) NA NA 0.05 ng/ml NA [42]
LC/MS FDP Plasma Solid phase extraction Solvent A (0.1% Formic acid with 1 mmol Ammonium formate) solvent B (ACN/0.1% formic acid with 1 mmol ammonium formate, (95:5v/v) Luna RP-C18 (15 mm * 3.2 mm, 3.0 µm) NA NA <1 ng/ml NA [43]
HPLC/MS FDP Plasma Liquid liquid extraction ACN: water (80:20v/v, 10 mmol of formic acid) 0.80 ml/min C8 (100 mm × 4.6 mm, 3 µm) NA 0.02 to 10 ng/ml 20pg/ml NA [1]
HPLC-MS/MS FDP Plasma Frozen ACN and 0.1 % formic acid (75:25, v/v) 0.25 ml/min C18 (3.0 mm, 150 mm; 3.5 µm) NA 0.1 to 20 ng/ml 0.1ng/ml NA [44]
LC-ESI-MS FDP Plasma Toluene 2-propanol–iso-hexane (11:89, v/v) 1 ml/min Chiralcel OJ-R (150 mm×4.5 mm, 5.0 µm) NA NA 0.10ng/ml NA [45]
HPLC-MS/MS FDP Plasma Solid phase extraction 0.1% formic acid-methanol 1 ml/min Zorbax Eclipse XDB-C18 (150 mm 4.6 mm3.5 µm) NA 0.1 to 5 ng/ml 0.1ng/ml NA [46]
LC-ESI-MS/MS FDP Plasma Liquid–liquid extraction 0.2% formic acid in water–acetonitrile
(25:75, v/v)		 Atlantis C18 (50* 4.6 mm 3 µm) NA 0.59–1148ng/ml NA 1.05 min [47]
HPLC-MS/MS FDP Plasma Liquid–liquid extraction MeOH-10 mmol/l ammonium acetate (80: 20v/v) 0.70 ml/min Nucleosil C (50 mm x 4.6 mm5 µm) NA 0.05-10.00 ng/ml 0.05ng/ml NA [48]
GC-ECD/GCMS FDP Plasma Solid phase extraction Helium 40 ml/min GC-ECD ULBON HR-52 (25 m x 0.32 mm.) GCMS-Hewlett-Packard HP-1 (12 m x 0.20 mm.) NA 0.2-20ng/ml (M-1, M-2), 2-150 ng/ml (M-3,M-4,M-5) 0.02ng/ml (M-1, M-2) 2ng/ml(M-3,M-4,M-5) NA [49]
HPLC FDP Plasma Liquid–liquid extraction and Solid phase extraction Methanol in phosphate buffer (0.05 M) 1.15 ml/min LiChrospher 60 RP-select B (250 mm x 4 mm 5.0 µm) 220 nm NA 20 nmol/l NA [50]
HPLC FDP Plasma Protein precipitation 5 mmol Phosphate Buffer: acetonitrile (25:75: v/v) 1.0 ml/min C8 DD S5 (4.6 mm × 250 mm, 5 µm) 360 nm 0.25-20.00 µg/ml 0.055µg/ml and 0.210µg/ml <3 min [51]
LC/MS FDP Plasma Protein precipitation ACN: 2 mmol
ammonium acetate 80:20%		 0.8 ml/min Princeton SPHER C18 (150 x 4.6 mm, 5 µm) NA 0.8-13.0ng/ml. 0.10 ng/ml and 0.50 ng/ml NA [52]
HPLC FDP Serum Evaporation ACN and 50 mmol ammonium acetate buffer pH-5 at a ratio of 67:33 v/v 1 ml/min C18 (25 cm, 4.6 mm, 5 μm) 240 nm 1-4000 ng/ml 0.75 ng/ml and 1ng/ml 10.53 min [53]

DISCUSSION

FDP is calcium channel antagonist [54, 55] which belongs to the class of dihydropyridine anti-hypertensive agents, and it was approved by FDA in 1991. In vitro studies have revealed that FDP is highly vascular selective, and it does not cause orthostatic hypotension as they don’t have any effect on venous smooth muscles in clinical dose. FDP is a lipophilic molecule that is soluble in methanol and is used as a solvent for UV-Visible spectroscopy to determine FDP concentrations in bulk and tablets. Spectrofluorometric method is highly selective, sensitive, simple to operate, cost-effective and doesn’t require any derivatization. The developed HPTLC method is easy and inexpensive, and it can be used for routine analysis. The HPLC methods were used to determine FDP, and the results with the UV detector showed greater sensitivity, specificity, and accuracy. The separation is accomplished using a UPLC approach that does not require the use of an ion-pair reagent in the mobile phase. Gas chromatography methods for the determination of FDP is also developed where helium was used as carrier gas. To determine FDP and evaluate pharmacokinetic parameters and toxicological properties, several bioanalytical procedures like HPLC, UPLC, LC–MS/MS, LC–ESI–MS/MS, LC-Tandem MS have been developed. Biological matrices like plasma and serum as a single drug alone and also in association with other drugs have been used for the studies. All these methods utilized derivatization, protein precipitation, Liquid-Liquid extraction, and solid-phase extraction methods that are used for sample preparation in biological matrices.

Future developments in hyphenated methods may widen the path for analysing FDP in biological fluids and finished products, which could be more useful for FDP therapeutic monitoring. HPLC is the most extensively used analytical technique since it is cost-effective, has good sensitivity, and accurate and robust results are obtained hence it is used in routine analysis.

CONCLUSION

The present review examines the several analytical methodologies for estimating FDP that are available. For the estimation of FDP various analytical methods such as spectrophotometry, spectrofluorimetric, HPTLC, HPLC, UPLC are employed. HPLC, UPLC, LC–MS/MS, LC–ESI-MS/MS, LC-Tandem-MS, GCMS are the various bioanalytical techniques developed for the estimation of FDP in biological fluids. Since it is relatively easy, economical, and sensitive, HPLC is the most extensively used technique for the determination and quantification of FDP in bulk, formulations, and biological fluids. LC–MS/MS, LC–ESI-MS/MS, LC-Tandem-MS, GCMS are the hyphenated techniques for estimation of FDP. Analysts and skilled formulators should work together in the foreseeable future to develop more environmentally safe techniques for estimating FDP that use less toxic solvents. More HPLC approaches can help with FDP evaluation in biological fluids and bulk formulations. Further developments in UV spectrophotometric methods might help to estimate FDP in the future, as they are reliable and can be employed on regular basis.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All the authors have contributed equally.

CONFLICT OF INTERESTS

Declared none

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