1. INTRODUCTION:

Hypertension is common disorder, mostly past middle age. It's not disease in itself, but main hazard factor for cardiovascular mortality and morbidity [1]. It is defined normally as sustained rise in blood pressure with systolic and diastolic ranges being 140/90 mm Hg and higher [2]. High arterial pressure results in changes in the left ventricle's vasculature and hypertrophy. Hypertension is therefore major cause of stroke and is a significant hazard coronary artery disease factor and its complications myocardial infarction and sudden heart attack are major contributor to cardiac failure, kidney failure, and aortic aneurysm dissection. [3]. When used alone to treat hypertension is mild to moderate, all Ca2 + channel blockers are effective; however, this class of drug is not currently viewed appropriate for monotherapy of hypertension [4].

Ca2 + channel blockers are an important group of medicines for hypertension treatment. The term ' calcium antagonist ' is used for drugs that block Ca2 + cell entry via calcium channels [5]. This 1,4-dihydropyridine derivative acts on smooth vascular muscles by alter voltage-gated L-channels of calcium type. Calcium antagonists of therapeutic importance act on channels of the type L.L - type calcium antagonists are 3 classes of chemically different: phenylalkylamine (for example, verapamil), dihydropyridine (for example, nifedipine, amlodipine) and benzothiazepine (for example, diltiazem [6].

1.1 Chemical Properties and uses of Nifedipine:

Nifedipine is the dihydropyridine derivative with fast action beginning and short duration time. The drug was discovered in 1969 and approved for use in the US in 1981.It is chemically known as 2,6-Dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydropyridine(Figure1). It has molecular formula is C₁₇H₁₈CN₂₀₆and molecular weight is 346.335 g/mole [7]. Nifedipine is completely soluble in acetone and chloroform, is sparsely ethanol soluble and is virtually water soluble [8]. The mNIF's melting point is 172 - 174 °C and is photolabile in nature. It is used to manage angina, high BP and premature labor. NIF is taken by mouth route and is a slow formulation. The common unwanted effects are lightheadedness, headache, feeling tired, leg swelling, cough, and shortness of breath. Significant aftereffect include low BP and heart failure. It is a calcium channel blocker of the dihydropyridine type [8,9].

Figure 1: Chemical structure of Nifedipine

1.2 Pharmacokinetics of Nifedipine:

NIF is available both as an immediately release and as an extended-release product. Bioavailability For both formulations, it is similar, approximately 52-56% [10]. The immediate-release product if used should be taken without food due to possible reduced peak plasma concentrations and prolonged drug action time when administered with meals. Nifedipine is 90-96% protein bound, which gets reduced slightly [92-93%] in renal/hepatic impairment. Interestingly, extensive nifedipine is also distributed to Placenta transfer and placental transfer takes place in some patients [11]. The half-life for the immediate release capsules is 1.7-3.4 h, while the half life for the biphasic extended released tablet is 3.7-4.3 h. The drug undergoes significant hepatic metabolism by cytochrome P450 (CYP) 3A4 enzyme system, with the greater part oxidized to a free acid and a smaller fraction converted to a lactone. 20 to 30% of the drug is removed from the portal blood supply by the liver due to first-pass metabolism [12].

1.3 Pharmacodynamics of Nifedipine:

Nifedipine inhibits the slow innermost current of calcium in normal cardiac tissues and its most important effects being on Sino and atrio - ventricular nodes. When compared to the verapamil or diltiazem, NIF in-vivo has null effect on atrioventricular nodal transmission [13]. It also reduces atrioventricular functional refractory periods and cycle lengths of the atrioventricular nodal wenckebach and diltiazem or verapamil may be preferableIn patients with symptomatic ischaemic heart disease and nodal depression. The NIF effects on heart rateare governed by the rate of input into the body. Oral capsule administration was not associated with significant heart rate increases, While administration is Intravenous and intracoronary sublinguals increased increased heart rate by up to 28 %. [14]. Other effects of nifedipine includes increased blood flow peripheral and reduced platelet aggregation inhibition of peripheral vascular resistance, decrease lowers Esophageal sphincter pressure and peristalsis inhibition [15].

1.4 Metabolic Pathway of Nifedipine:

Nifedipine is a slow calcium channel blocker, which undergoes wide first pass metabolism. The pharmacodynamic property of the nifedipine was intimately related to its plasma concentration [16]. Nifedipine initially gets metabolized to dihydropyridine by oxidation process. It is converted into carboxylic acid derivative that is the major metabolite measured in the urine. [17]. A minor fraction of hydroxyl metabolite is also formed (interconvertible to lactone) which is not measurable. The water soluble acid metabolite accounts for 60-80% dose excreted in urinewhile the rest minor metabolite get excreated via biliary excretion [18]. The drug gets metabolized via Cytochrome P-450 3A4 system; Figure 2, representsthe metabolism of nifedipine on oral administration of drug.

Figure 2: Metabolic pathway of Nifedipine

2. Analytical methods for estimation of Nifedipine:

The extensive literature survey comprised of several analytical techniques such as (Table-1) UV/Visible- Spectrophotometry, HPLC, HPTLC, GC, Voltametric method And lc ms for nifedipine determination in bulk and pharmaceutical formulations. The methods reported describe nifedipine estimation as a single constituent in different dosage forms and in conjunction with atenolol varapamil amlodipine, lignocaine-HCl, lidocaine, nicardipine, lovastatin, atorvastatin, enalapril etc [19-22].

Table-1: Various analytical methods used for estimation of Nifedipine

Sr. No	Methods
1	UV-Visible Spectrophotometry Method
2	Gas Chromatography
3	HPLC
4	HPTLC
5	Voltametric Method
6	LC-MS/MS
7	Bioanalytical Methods

2.1 Ultraviolet-visible absorption Spectrophotometry:

The commonly used technique of ultraviolet visible spectrophotometry in pharmaceutical analytical methods. This includes the measurement of the quantity of UV or absorbed visible radiation in the solution by the substance. The absorption of the light in both the UV and visible region There is a visible area of the spectrum of electromagnetics when the energy of the light matches that required to induce in the molecule an electronic transition along with transitions of vibration and rotation [23-25].

2.2 Gas-Chromatography:

Gas-chromatography is common chromatographic technique used in chemical analysis for separation and Analysing of compounds can vaporized without breaking down.It has been efficiently used for purity testing of substance or separating various compounds of a mixture [26]. GC is a method of selection of volatile organic, thermally stable and inorganic compounds [27].

2.3 High-Performance Liquid-Chromatography:

This analytical chemistry technique that separates the Identifying and quantifying each mixture component. Hplc used pumps to pass through a liquid under pressure and sample mixture an adsorbent - filled column to separate the sample components [28]. The principle advantages of HPLC compared to classical column chromatography are improved resolution of the separated substances, faster separation times and the increased accuracy, precision and Sensitivity to quantify the separate substances [29].

2.4 High Performance Thin Layer Chromatography:

HPTLC is an improvised form of thin-layer chromatography (TLC). There can be a number of improvements done to the basic thin-layer chromatography method automate the various Steps to enhance the achieved resolution and enable more accurate quantitative measurements[30]. Thin-layer Chromatography is undoubtedly most multipurpose and popular and widely used chromatography separation methods in chromatography[31].

2.5 Voltammetric Technique:

This technique is used to study the solution composition through current-potential relationship in electrochemical cell and with the current response time a microelectrode at a controlled potential. Its fast speed of determination is major advantage and makes it potent analytical tool. Its foremost advantage is sensitivity [32]. Voltammetry based on current measurement develops in electrochemical cells when there is polarization of concentration [33].

2.6 LC-MS:

The LC-MS is hyphenated analytical technique which is combination of Liquid-Chromatography (LC) and Mass Spectrometry (MS). HPLC (LC) separate the components of mixtures by passing through chromatographic column. Generally, the separated components cannot be positively identified by LC alone. Thus, LC-MS is used for rapid purification of specific substance from mixture [34]. Figure 3, represents the statistical data that use in different analytical methods used for the estimation of NIF during year 1980-2018.

Figure 3: Statistical analysis of analytical methods developed for estimation of Nifedipine during year 1980-2018

Table 2: Bioanalytical and Analytical Methods developed for NIF using UV spectrophotometry

Sr No.	Analyte(s)	Method and Wavelength (nm)	Dosage form	Solvent or Reagent	Linearity/LOQ/LOD	References
1	Nifedipine	UV-Spectroscopic method 350 nm	Tablet form	MeOH	Linearity- 20-100 µg/ml LOD- 1.2833 µg/ml LOQ- 3.888 µg/ml	37
2	Amlodipine and Nifedipin simultaneous	UV-Spectroscopic method	Pure form	Ethanol (95%): Water	Linearity- AML- 1.0-20.0 and NIF- 3.0-19.0 µg ml	38
3	Atenolol and Nifidipine simultaneous	UV-Spectroscopic method 245.63 nm 218.7 nm resp.	Combined tablet form	Water : Acetonitrile	Linearity- Atenolol- 50-150 µg/ml Nefidipine- 20-60 µg/ml LOD- Atenolol-5.214 µg/ml, NIF-0.52 µg/ml LOQ-Atenolol-15.18 µg/ml, NIF -1.58 µg/ml	39
4	Nefidipine	UV-Spectroscopic method 430 nm 830 nm resp.	Pure form	MeOH and DMSO	Linearity- Method A- 5.0-50.0 µg/ml Method B- 2.5-45.0 µg/ml LOD- 0.155 µg/ml, 0.059 µg/ml LOQ- 0.470 µg/ml, 0.179 µg/ml	40
5	Nefidipine and Atenolol simultaneous	UV-Spectroscopic method 341 nm 273.8 nm resp	Combined tablet form	MeOH	Linearity- NIF- 2-10 µg/ml Atenolol- 5-25 µg/ml LOD- 3.3 µg/ml LOQ- 10µg/ml	41
6	Nifedipine and Metoprolol Succinate simultaneous	UV-Spectroscopic method 283.80 nm 242.60 nm resp.	Synthetic mixture	MeOH	Linearity- NIF- 5-25 µg/ml MET- 25-125 µg/ml LOD- NIF- 0.032 µg/ml MET-0.831 µg/ml LOQ- NIF- 0.098 µg/ml MET-2.520 µg/ml	42
7	Nifedipine	UV- Spectroscopic method 235.5 nm 235 nm	Tablet	Ethanol and Water	Linearity- 2-10 µg/ml LOD- 0.5614 µg/ml LOQ- 1.7014 µg/ml	43
8	Nifedipine and Atenolol simultaneous	UV- Spectroscopic method (200nm-400nm) 341.2 nm 273.8 nm resp.	Tablet	MeOH and Water	Linearity-NIF- 2-10 µg/ml ATN- 5-25 µg/ml	44
9	Atrovastatin calcium and Nifedipine HCL	UV- Spectroscopic method (200nm-400nm) 337 nm 297 nm resp.	Bulk and Tablet Form	MeOH	Linearity-NIF- 6-10 µg/ml LOD- Atrovastatin calcium -0.1028 µg/ml Nifedipine-0.1214 µg/ml LOQ- Atrovastatin calcium-4.464 µg/ml Nifedipine-0.3678 µg/ml	45
10	Nifedipine Simultaneous	Visible spectrophotometry (400nm-800nm)	Pure and dosage form	Chloroform ethanol	Linearity- 5-175 µg/ml	46
11	Nifedipine	Visible spectrophotometry (400nm-800nm)	Tablet Form	MeOH	5.0-32.5, 6.5-33.0, 4.0-37.5, 4.5-22.5 µg/ml	47
12	Nifedipine	UV/Visible spectrophotometry (240-800)	Pure form		Linearity-2.9 to 4.4 µg/ml	48
13	Nicardipine, Nifedipine and Isradipine simultaneous	UV-Spectroscopic method 460/364 nm 450/393 nm 446/360 nm resp.	Tablet form	MeOH	Linearity- nicardipine-0.6-6.0 nifedipine-0.2-4.0 isradipine-0.1-9.0	49
14	Nifedipine	UV-Spectroscopic method 685 nm 546 nm	Tablet	Distilled Water	Linearity-1-19 µg/ml, 4-18 µg/ml LOD- 0.210 µg/ml LOQ- 0.70 µg/ml	50

NIF= Nifedipine, ACN= Acetonitrile, MeOH= Methanol, LOD=Limit of Detection, LOQ= Limit of Quantification, µg/ml- micro gram per mili litre

Table 3: HPLC Methods developed for Estimation of NIF alone

Sr No	Analyte	Dosage form	Stationary phase/Column	Mobile phase	Detector	Linearity	Accuracy and Precision	RT (min)	Ref
1	NIF	Pure form	LiChrosphere 100 RP-18 (250x4.6mm; 5µm) column	chloroform: MeOH (9:1, v/v )	UV-Spectrophotometer	1 – 16 µg/ml	Accuracy -100.01%	0.17	51
2	NIF	Capsule form	Reversed phase C-18 (100 X 8 mm) column	ACN: MeOH: Water (25:25:50, v/v)	UV-Spectrophotometer	0.05-0.10 µg/ml	-	12.2	52
3	NIF	Bulk form	Acquity shield RP18 (50×3.0 mm,1.7 µm)	Ammonium phosphate: MeOH	Photodiode array	0.25-1.5 µg/ml	-	11	33
4	NIF	Tablet form	Shim-Pack CLC, ODS (C- 18), 250×4.6mm, 5 µ	MeOH: Water (70:30, v/v)	UV-Spectrophotometer	5-40 µg/ml	Accuracy 98.85-100.89%	3.401	54
5	NIF	Bulk drug and Tablet form	ODS C-18 250 x 4.6 mm) column	ACN: Tea (78:22,v/v)	UV-Spectrophotometer	625-10000 ng/ml	Accuracy 104.20%,102.57%,106.13%,101.33% Precision -100.80%,108.00%	3.783	55
6	NIF	Loaded Polymeric Nano-capsules	RP Phenomenex Luna® C18 column (250 × 4.6 mm id) with a particle size of 5 μm	MeOH: water (70:30,v/v)	UV/Vis-Spectrophotometer	10-100 µg/ml	Accuracy and precision 1.40 μg/ml	-	56
7	NIF	Tablet form	Bondapack C18 (250×4.6 mm) column	MeOH: water (60:40, v/v)	uv/vis absorbance detector	12.5-150 µg/ml	-	15	57
8	NIF	Tablet form	ODS-5 Column (150 X 4.6 mm) i.d. column packed with a particle size of 5 μm	Hydrogen phosphate: MeOH (45:55, v/v)	Ultraviolet detector	0.5-5 µg/ml	-		58
9	NIF	Capsule form	C-18 column	Orthophosphte buffer: octane: SDS: Butanol (87.1:0.8:4.5:7.6)	UV-Spectrophotometer	1-60 µg/ml	Accuracy 99.11-101.64%	-	59
10	NIF	Pure form	C18 reversed-phase column (Novapack; 150×3.9 mm. i.d.) packed with 4μm particles	MeOH: Amminiumacetate: ACN: Triethylamine (2:2:1:0.04 v/v)	UV absorbance detector	1-1000 µg/ml	Accuracy 93.7,95.8,99.3% Precision 0.71,0.90,0.42%	Less than 11 min	60
11	NIF	Bulk form	Reversed phase ODS C-18 column (250 mm × 4.6 mm i.d., 5-μm particle)	MeOH:Water:Phosphate buffer:Sodium heptanesulfonate (65:35:3:0.13,v/v)	UV absorbance detector	3-50 µg/ml	-	>20	61
12	NIF	Pure form and human plasma	Reversed phase-HPLC ODS Column(150 x 4.6mm, 5 μm)	Acetronitile: MeOH: tetrahydrofuran:0.01 M phosphate buffer (17:20:1.5:61.5,v/v)	UV-Spectrophotometer	10.0-200.0 µg/ml	Accuracy 100.50-100.63% Precision- 1.75-8.82%	-	62
13	NIF	Tablet form and Human plasma	Reversed phase-HPLC ODS Column(20 x 4.0 mm)	MeOH:Acetate buffer (75:25,v/v)	UV-Spectrophotometer	2.5-50 µg/ml	Accuracy 6.4% and 11.8% 0.6% and 4.1%	10-30	63
14	NIF	Table form and dog plasma	BST ODS Hypersil pre-column (5 µm, 20×4.0 mm)	MeOH:Acetate buffer (75:25,v/v)	UV-Spectrophotometer	1-50 µg/ml	-	-	64
15	NIF	Pure form and rat plasma	Phenomenex® C18 (Phenomenex, CA, USA), 250 mm × 4.6 mm, 5 μm particle size and guard column (C18, 4.0 X 2.0mm	ACN:Phosphate buffer(40:60,v/v)	UV-Spectrophotometer	1-10 µg/ml	Accuracy between 85.45-112.87% Pre-below-15%	3.025	65
16	NIF	Sustain release tablet and human plasma	Acquity UPLC BEH C18 column (50 mm×2.1mm;1.7 µm)	n-hexane:diethyl ether (1:3,v/v)	UV-Spectrophotometer	0.104-52.0 µg/ml	-	1.4	66
17	NIF	Tablet form and human plasma	Acquity UPLC BEH C18(50×2.1mm,1.7 µm)	Ammonium acetate:Acetonitrie (15:85,v/v)	UV-Spectrophotometer	0.050-150 µg/ml	-	1.2	67
18	NIF	Tablet form and human plasma	µ-Porasil column	n- hexane:Chloroform: MeOH (80:17:3) v/v	UV-Spectrophotometer	Upto-120 μg/ml	-	7.82	68
19	NIF	Tablet form dog plasma	C-8 column	ACN: Water:Formic acid (60:40:0.2, v/v/v)	Ultra triple quadrapole mass spectrometer with APCI	0.20-50.0 µg/ml	Accuracy 74.5-84.1% Precision 4.1-8.8 and 6.7-7.4%	-	69
20	NIF	Pure form plasma	Analytical C-18 column	Hexane: isopropanol:ACN (90:12:2,v/v)	UV absorbance detector	10-300 µg/ml	Accuracy 81.9% ±2.9% Precision less than 5%	3.2	70
21	NIF	Sustained released formulation and human plasma	C18 column	MeOH:ACN:disodium hydrogen phosphate buffer (40:23:27 v/v)	UV/Vis absorbance detector	6-200 µg/ml	-	7.8	71
22	NIF	Pure form and human plasma	gold C18 column	formic acid buffer: ACN (30:70 v/v)	Triple quadrupole tandem mass spectrometer	0.5-100 µg/ml	-	less than 2.5 min	72
23	NIF	Slow release t Tablet plasma	C18 column	ACN:Water (48:52% v/v)	UV absorbance detector	1-10 µg/ml	Accuracy 98.81%-101.33% Precision 3.32-7.17	7.2	73
24	NIF	Sustained release tablet and human plasma	RP C18 column	ACN:Ammonium acetate solution (60:40 v/v)	UV absorbance detectors	10-200 µg/ml	Accuracy 3.92-7.31 % Precision less than 15%	5	74
25	NIF	Pure form and human plasma	Reversed phase C-18 column	Potassium dihydrogen phosphate:ACN (42:58 v/v)	UV-Spectrophotometer at 240 nm	5.0-200.0 µg/ml	-	-	75
26	NIF	Table form and human plasma	Partisil ODS-3 analytical column	ACN: water (60:40, v/v)	ISCO V-4 variable wave- length uv-vis detector	5.0-400 µg/ml	Accuracy 94.5 to 98.0,93.1 to 98.0% Precision 1.4 to 4.2, 3.9 5.6%		76
27	NIF	Bulk form	C-18 column	ACN:Phosphate buffer (65:35 v/v)	UV absorbance detector	30 µg/ml	Accuracy 4.759510.087 Precision 4.171-7.584%	NIF-3.12± 0.04	77

NIF= Nifedipine, RT= Retention time, ACN= Acetonitrile, MeOH= Methanol, µg/ml- micro gram per mili litre

Table 4: HPLC Methods for Simultaneous Analysis of NIF in combination with other drugs

Sr No	Analyte (s)	Dosage form	Stationary Phase/ column	Mobile phase	Detector	Linearity	Accuracy/ Precision	RT (min)	Ref
1	Atenolol and NIF	Tablet form	C18 column (Agilent ODS 5 column, 250mm x 4.6mm)	ACN:MeOH:phosphate buffer (60:20:20,v/v)	UV-Spectrophotometer	ATN-5-25 µg/ml NIF-2-10 µg/ml	Accuracy ATN-99.38-100.56% and NIF- 99.16-99.17%	ATE-2.80 NIF-4.40	78
2	NIF and ATE	Capsule form	C18 stationary phase column Intersil® ODS-3 (5 μm, 4.6 x 150 mm)	ACN:Sodium percholate (5:95,v/v)	UV-Spectrophotometer	2-50 µg/ml	Accuracy ATN 100.40±0.85% NIF-100.30±1.10%	ATE-6.05±0.02 NIF-14.50±0.04	79
3	NIF, Nateglinide and Lovastatin	bulk and combined dosage forms	C-18 column (125 × 4.6 mm id, 5-µm particle)	ACN: phosphatebuffer (60:40, v/v)	UV-Spectrophotometer	NIF-0.125-8.0 µg/ml NG-0.25-16 µg/ml NT-0.25-16 µg/ml	Accuracy NIF-99.99% NG-99.25% LT-98.93%	NIF-3.12 NG-4.45 LT-7.23	80
4	NIF and ATE	Bulk drug	HiQSil C8- 250×4.6 mm column	phosphate buffer solution: MeOH (75:25,v/v)	UV/Vis detector	10-100 µg/ml	Accuracy - 9NIF and ATN-9.32–100.02 and 99.10–100.4	NIF-4.1 ATE-3.03	81
5	NIF and Lignocaine HCl	Cream form	LC- 20 AT C18 hypersil BDS column	Sodium hydrogen phosphate:MeOH (50:50,v/v)	UV-Spectrophotometer	NIF-1.5-4.5 μg/ml and for Lignocaine HCl 7.5-22.5 μg/ml.	-	Lignocaine-4.170 NIF-6.530	82
6	NIF and ATE	Capsule form	Shimpack CLC phenyl column (6.0 mm x 15 cm)	MeOH:Orthophosphoric acid (75:25,v/v)	UV absorbance detector	NIF-2.5-50 μg/ml, ATN-5-50 μg/ml.	NIF-99.97% ATN-99.2%	NIF-1.55 ATN-5.7	83
7	NIF and ATE	Capsule form	RP Hypersil BDS C18 column Column (4.6 × 150 mm, 5 µm)	ACN:phosphate buffer (53.2:46.8% v/v)	Diode array detector	0.1-10 µg ml-1	Accuracy NFD-98.4-100.5% ATN-99.7-101.3% Precision - NIF-1.08-1.74 ATN-0.83-1.52		84
8	NIF and ATE	Capsule form	YMC-pack pro C18 ODSA (250 mm x 4.6 mm, 5 μm) column	ACN:Phosphate buffer (62.5:37.5,v/v)	UV-Spectrophotometer	NIF-5-15 µg/mL and ATN-20-30 µg/ml	NIF-99.77 ± 0.560, ATN-100.90 ± 1.23)	NIF-1.78 ATE-1.70	85
9	NIF and Lidocaine	Cream form	HPLC ODS C18 G (250 × 4.6 mm, 5 µm) column	Ammonium acetate buffer: ACN (65:35,v/v)	UV absorbance detector	NIF-75-225 µg/ml and LIDO-15-45 µg/ml	Accuracy - NIF-100.7-100.3% LIDO-100.4-100.1% Precision NIF-0.7,0.02-0.25,0.02-0.62 LIDO-0.9,0.02-0.17,0.01-0.23	Lidocain 2.751 min NIF-7.769 min	86
10	NIF and ATE	Capsule form	C18 column	MeOH: ACN:phosphate buffer (60 :20 :20,v/v)	UV absorbance detector	10-100 µg/ml for both	Accuracy NIF-99.32-100.02 ATN-99.10-100.4 Preci- Less than 2%	ATN-3.8 NIF-14.1	87
11	NIF and Enalapril	Capsule form and human plasma	Reversed phase C-18 column	ACN:Water:Formic Acid (5:95:0.1 v/v)	UV-Spectrophotometer	2-200 µg/ml	Accuracy 99.0-99.6% Prec-2.24-2.36%	NIF-2.5 min Enalapril-2.09 min	88
12	NIF and Lidocaine	Pure form and human plasma	YMC-Triart C18 column	MeOH:Water (60:40 v/v)	ion trap mass spectrometer	0.5-50 µg/ml	Accuracy and Precision for OQ-below 20% For QC-below 15%	NIF-3.5 min LID-1.4 min	89
13	NIF and Virapamil	Tablet form and Rat plasma	C18 column	ACN:MeOH:Phosphate buffer (55:35:30 v/v)	UV absorbance detector	Nif-0.2-1 µg/ml Virapamil-0.4-2 µg/ml	Accuracy	NIF-6.4 min, VER-9.8 min, Nicardipine-4 min	90

NIF= Nifedipine, ATE= Atenolol, RT= Retention time, ACN= Acetonitrile, MeOH= Methanol, µg/ml- micro gram per mili litre

Table 5: Bioanalytical and Analytical Methods for Analysis of NIF alone and in combination using LC-MS/MS

Sr no.	Analyte(s)	Dosage form	Extraction method	Stationary phase/ Column	Mobile Phase	RT (min)	Linearity	Flow rate (ml/min)	Ref
1	NIF	Human plasma and amniotic fluid	At pH 13 dicholoromethane: n pentane (3:7,v/v)	RP C18 column	Water:ACN:Glacial acetic acid (30:70:0.5,v/v)	1.61 and 1.85 resp.	0.1-100 µg/ml-in plasma 0.1-10.0 µg/ml-in amniotic fluid	1	91
2	NIF	Human plasma	Diethyether containing diazepam as internal std	RP C18 column	ACN:MeOH:Water (35:17:48)	0.60	10-200 µg/ml	1.2	92
3	NIF	Serum and Urine	-	RP C18 column	0.125 M SDS:3% Pentanol buffer	19.2,10.8,6.7,7.4,4.4 resp.	1-100 µg/ml	1	93
4	NIF	Canine plasma	Liq-Liq extraction,Carbamazepine was used as int std.	Hypersil BDS C18 column	Water:MeOH (45:55,v/v)	11 and 8 resp.	1-200 µg/ml	1	94
5	NIF and ATE	Human plasma	Liq-Liq extraction,Carbamazepine was used as int std.	C18 column	Ammonium acetate:ACN (15:85,v/v)	0.779, 1.04	NIF-1.02-101 ng/ml ATN-5.05-503 ng/ml	1	95
6	NIF	Human plasma	Extraction by precipitation method	C18 column	Ammonium acetate:MeOH (30:70,v/v)	2.80	1.558-360.561 ng/ml	1.0	96
7	NIF	Human plasma	Using diethyether with dimethoxamate.	Hypersil BDS C18 column	MeOH:Water (66:34,v/v)	3.6	1-100 µg/ml	0.8	97
8	NIF	Plasma and Urine	dichloromethane-pentane (3:7)	RP C18 column	Acetate buffer:ACN	0.96 and 2.41 resp.	5-400 µg/ml	4.0	98
9	NIF, Gliclazide, Monte-lukast	Biological fluid	Protein ppt with ACN using Zaferolukast as an internal std	RP C18 column	ACN:Formic acid (84:16,v/v)	NIF-1.433 GLI-1.496 MO-2.255	NIF-10.0-800.0 µg/ml 10.0-5000 µg/ml 10.0-600.0 µg/ml resp.	0.6	99
10	NIF	Controlled release form	-	RP C18 column	MeOH:Water (65:35)	20	5-30 µg/ml	0.9	100
11	NIF and Dehydro NIF	Tablet form	One step liquid extraction	Hypersil BDS C18 column	MeOH:Water (80:20)	-	0.5-100 µg/ml	200 *	101
12	NIF	Pure form	-	RP-Phenomenex lona C18 column	MeOH:Water (70:30)	4.5	0.2-1.0 µg/ml	1.2	102

NIF= Nifedipine, ATE= Atenolol, RT= Retention time, ACN= Acetonitrile, MeOH= Methanol, *= µl/ml, µg/ml- micro gram per mili litre

Table 6: Analysis of NIF using Voltammetry

Sr No	Analyte(s)	Dosage form	Working Electrodes	Linearity	LOD	Technique	Ref
1	Nifedipine	Pure from (reagent grade purity)	Mercury Drop Electrode and a Mercury Meniscus Modified Silver Amalgam Electrode	0.2-20.0 µg/ml	0.12 µmol/L (HMDE) and 1.2 µmol/L	Differntial pulse voltametry	103
2	Nifedipine	Pure form	-Cyclodextrin modiﬁed multi-walled carbon nanotube paste electrode	4.77 × 10µg/ml to 2.00 × 10.0 µg/ml	LOD-1.48 µg/ml	Differential pulse adsorptive stripping voltammetry	104
3	Nifedipine and Nimodipine	Serum and in urine sample	Carbon‐Paste Electrode	3.9-10 µg/ml	NIF-3.9 µg/ml Nimodipine-4.8 µg/ml	Differential pulse voltammetry	105
4	Nifedipineand Atenolol	Human fluids	MgO-nanoplates modified screen-printed electrodes	0.2-104.41 µg/ml	NIF-0.032 µM ATN-1.76 µM	Differential pulse voltammetry	106
5	Nifedipine	Huamn plasma	Hanging mercury drop electrode (HMDE)	1.00-125.01 µg/ml	LOD-0.42µg/ml LOQ- 1.00 µg/ml	Square wave adsorptive stripping voltammetry	107

NIF= Nifedipine, ATE= Atenolol, LOD= Limit of Detection, LOQ= Limit of Quantification, µg/ml- micro gram per mililitre, HMDE=Hanging Mercury Drop Electrode

Table 7: HPTLC method for analysis of NIF alone and in combination

Sr No	Analyte(s)	Dosage form	Stationary phase	Mobile phase	Detection limit	Linearity	Rf	Ref
1	Nifedipine	Sustained release solid and liquid hard gelatin capsules	-	Chloroform:ethylacetate: cyclohexane(19:2:2,v/v)	238 nm	180-720 µg/ml	0.3	108
2	Nifedipine and alsartan	Tablet and Capsule form	Precoated silica gel 60 F 254	Toluene:ACN:Formic acid(8:2:0.2,v/v)	227 nm	300-2100 µg/ml	Nif-0.25 Val-0.49	109
3	Nifedipine	Tablet form	Silica gel 60 F 254	n-hexane:ethyl acetate: acetone (6:3:2 v/v)	335 nm	0.025-0.150 µg/ml	45	110
4	Nifedipine and Atenolol	Tablet	Kieselghur 60,GF254	Cyclohexane:MeOH:ethylacetate: ammonia (5:1.5:3:0.5 v/v)	230 nm	5.7-18.9 µg/ml	NIF-0.69 ATN-0.07	111
5	Nifedipine	Human serum and extended- release tablet	silica gel F 254	Chloroform:ethylacetate: cyclohexane (19:2:2,v/v)	238 nm	0.02-0.25 µg/ml	0.31	112

NIF= Nifedipine, ATE= Atenolol, RT= Retention time, Val= Valsaratn, ACN= Acetonitrile, Rf= Retention Factor, MeOH= Methanol, µg/ml- micro gram per mililitre

Table 8: GC Methods:

Sr No.	Analyte(s)	Linearity	Dosage form	Column	Detector	Gas used	Ref
1	Nifedipine	2-300 µg/ml	Human plasma	Methylsilica fused-silica column	Nitrogen-phosphorous ionization detector	Helium gas-20ml/min Hydrogen gas-3.5 ml/min	113
2	Nifedipine	0.5-500 µg/ml	Plasma	Capillary column OV1	Pulse Ni electron capture detector	Argon:Methane (95:5) 20ml/min	114
3	Nifedipine	10-200 µg/ml	Human serum	Packed column OV-17 or OV-1	Pulsed 63-Ni electron capture detector (ECD)	Argon:Methane (95:5) 30ml/min	115
4	Nifedipine and Atenolol	ATN-5-70 µg/ml NIF-4-50 µg/ml	Capsules	Phenylmethyl silicon fused silica wide boore column	Flame ionization detector	Nitrogen gas is used as carrier gas with pressure 180Kpa	116

µg/ml- micro gram per mili litre, ml/min= mili litre per minute, NIF= Nifedipine, ACN= Acetonitrile.

Gas chromatography is the analytical method for separation and analyzing the compounds. This method is used for organic compounds thermally stable and volatile. Table 8 [113-116] shows the analytical and bioanalytical methods developed for the gas chromatography in pharmaceutical preparations and biological fluids/matrices. The range of linearity was reported to be 2-300 µg/ml in plasma. The GC was performed at a helium flow of 6 ml / min on 12 m approx. 0.31 mm methyl silicone cross - link fused silica column. Detector were set at helium gas 20 ml/min; hydrogen 3.5 ml and air 75 ml/min [113] C. Le Guellec, H. Bun, M. Giocanti and A. Durand et al., reported the GC method fitted with pulsed Ni electron capture detector. The carrier gas used were argon:methane (95:5) with flow rate 20 ml/min; helium make up gas flowed at 10 ml/min and RT was 3.90 min [114] Lawrence J. Lesko and Ann K. Miller et al., also reported the GC method for the estimation of NIF where the GC with pulsed 63-Ni electron capture detector was used. The flow rate of argon: methane (95:5) carrier gas was 30 ml/min. Mass spectra was recorded with an impact on the electron analyser, with ionizing energy of 70 electron volt connected to a data system [115] M. Veronico et al., also reported the GC with UV spectrophotometry simultaneous method assay of ATN and NIF. For UV the mixture is in ethanol with ATN and NIF concentration was 5 to 70 µg/ml and from 4 to 50 µg/ml respectively. The GC standard mix in ethanol was prepared with ATN and NIF between 0.1 to 1.0 mg/ml. The UV wavelength ranged from 190-400 nm with scanning speed 60nm/s.

5. CONCLUSION:

The review presented here deals with a comprehensive data of various analytical and bioanalytical methods developed for Nifedipine alone and in combination during the period of last 38 years. The method along with their details with respect to mobile phase, stationery phase, retention time etc have been enlisted. This data will be of great help to researchers working in analysis and bio - analysis field of nifedipine in pharmaceutical and biological formulations. It presents an opportunity to gather information on what has already been done and what new methods and changes can be inculcated to get better estimation.

6. ACKNOWLEDGEMENTS:

Authors are thankful to R.C. Patel Institute of Pharmaceutical Education and Research Shirpur, Dist: Dhule (MS) 425 405 for providing necessary library facilities.

7. CONFLICT OF INTEREST:

The authors declares that no conflict of Interest.

8. ABBREVATIONS:

µg/ml- micro gram per mililitre

ACN- Acetonitrile

ATE- Atenolol

BP- British Pharmacopoeia

DPH- Dihydropyridine

GC- Gas chromatography

HMDE- Hanging mercury drop electrode

HPLC- High performance liquid chromatography

HPTLC- High performance thin layer chromatography

IP- Indian Pharmacopoeia

LC- Liquid chromatography

LC-MS/MS- liquid chromatography mass spectroscopy-mass spectroscopy

MeOH- Methanol

MFE- Mercury drop Electrode

NIF- Nifedipine

nm- nano meter

ODS- Octadecylsilyl

RT- Retention time

TLC-Thin layer chromatography

UV/VIS- Ultra violet/Visible spectroscopy

VAL- Valsartan

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Received on 14.03.2019 Accepted on 10.04.2019

Asian J. Pharm. Ana. 2019; 9(3):177-190.

DOI: 10.5958/2231-5675.2019.00031.0