Analytical Methods of Dihydropyridines Based Calcium Channel Blockers - Amlodipine, Lacidipine, Isradipine, Nifedipine, Felodipine, Cilnidipine and its related formulations: A Review

 

Pankaj Kisan Chatki1*, Sana Tabassum2

1Analytical Research and Development Department, Neuheit Pharma Technologies Private Limited,

Hyderabad, Telangana-500 072 India.

2Department of Pharmaceutical Analysis, Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological Unversity, Hyderabad, Telangana-500 085 India.

*Corresponding Author E-mail: pankajchatki22@gmail.com

 

ABSTRACT:

Objectives: Various analytical techniques are applied in pharmaceutical field to estimate the quality of active pharmaceutical ingredients, amount of drug in biological fluids and in formulations. The aim of this review article is to provide utmost existing analytical methods for analysis of dihydropyridines based calcium channel blockers for estimation of Amlodipine, Lacidipine, Isradipine, Nifedipine, Felodipine, and Cilnidipine in pure form, biological fluids (like Human Plasma, Human Serum, Human Urine etc.,) and its related formulations including novel formulations. Dihydropyridines based Calcium Channel blockers is a major chemical class of drugs used in the treatment of hypertension and various coronary artery diseases. Evidence acquisition: Current analytical techniques available for active pharmaceutical ingredients and its related formulations are tabulated with extensive method conditions which can be used in analysis of dihydropyridines based calcium channel blockers drugs outlined from official pharmacopoeias and other relevant research articles. Conclusion: Various analytical techniques such as HPLC, HPTLC, UPLC, GC, LC-MS, and GC-MS are involved. This review assists in appropriate selection of analytical technique, solvent, mobile phase, column, detector based on available analytical instruments and chemicals, by referring tabulated extensive method conditions. It can be implemented in quality control and quality assurance department for quality assessment of diverse pharmaceutical formulations.

 

KEYWORDS: Analytical techniques, Dihydropyridines, Calcium channel blockers, Hypertension, Coronary artery diseases.

 

 

INTRODUCTION:

Analytical techniques include titrimetric techniques, chromatographic techniques, and spectroscopic techniques. Chromatographic techniques include TLC, HPLC, GC. Spectroscopic techniques include Spectrophotometry, Infra red spectroscopy, Fluorimtery, Phosphorimetry, Electrochemical methods, Electrophoretic methods1. HPLC or LC is a powerful separation technique2,3. HPLC can be coupled with various spectroscopic techniques by the means of selection of the detector. HPLC hyphenated techniques are Ultra-violet Visible detector (UV), HPLC-MS Mass Spectrometer, HPLC-FTIR (Fourier-transform Infra-red Spectroscopy), HPLC-NMR (Nuclear Magnetic Resonance Spectrophotometer), HPLC-RI (Refractive Index detector) 3-5. Electrochemical techniques have found widespread application as sensors for continuous analysis as well as for low resolution chromatograph 6. UPLC is a novel technique of Liquid chromatography. UPLC is more selective and sensitive with high resolution performance and faster resolving power. With UPLC increased resolution in shorter run times can generate more information faster without sacrifices. Higher sample throughput with more information per sample may decrease the time to market, an important driving force in today’s pharmaceutical industry 7, 8. UPLC is equipped with detectors such as Tunable Ultraviolet detector, Photodiode array detector, Fluorescence detector, Refractive index detector and mass detector9, 10.

 

Dihydropyridines are the most potent type of CCBs. Voltage sensitive channels, located on smooth muscles are blocked by the CCBs 11. CCBs have been used extensively in various cardiovascular conditions including ischemic heart diseases, supraventricular arrhythmias, systemic hypertension, pulmonary hypertension, congestive heart failure and hypertrophic cardiomyopathy. They may have a role in many non-cardiac diseases like bronchial asthma, esophageal spasm, migraine, Reynaud’s phenomena and premature labor 12. The movement of calcium ions is essential for the function of all types of muscle, including cardiac muscle and vascular smooth muscle. For both cardiac and smooth muscle, the flow of calcium ions into the muscle cells through specific channels allows muscle contraction to occur. When calcium flow is reduced, this results in weakening of muscle contraction and relaxation of muscle tissue 13. CCBs inhibit the flow of extracellular calcium through ion-specific voltage gated channels that span the cell wall 14. CCBs or calcium antagonists are widely used drugs in treatment of hypertension and angina. CCBs exhibits its action by promoting vasodilator activity (and reduce blood pressure) by reducing calcium influx into vascular smooth muscle cells by interfering with voltage-operated calcium channels (and to a lesser extent receptor-operated channels) in the cell membrane15. There are two major classes of CCBs dihydropyridines, which are similar in chemical structure, and non-dihydropyridines, which are a structurally miscellaneous group. Widely used non-dihydropyridines CCBs are Verapamil and Diltiazem. Dihydropyridines derivatives have pronounced peripheral vasodilator properties and intense reflex cardiac stimulation overcomes any direct cardiac effects. Verapamil and Diltiazem are also vasodilators but the balance of actions is such that these drugs have noticeable cardiac effects including reduced heart rate13, 15, 16. Various dihydropyridines based calcium channel blocker drugs are Amlodipine, Nifedipine, Felodipine, Clevidipine, Nimodipine, Isradipine, Nicardipine, Lercanidipine, Benidipine, Aranidipine, Azelnidipine, Barnidipine, Cilnidipine, Efonidipine, Manidipine, Lacidipine, Nicardipine, Nitrendipine, Nilvadipine, Nisoldipine, Pranidipine. Drugs have different binding sites to exhibit its action. CCBs have similar efficacy in terms of blood pressure lowering effects CCBs differ in tolerability profiles 17-21.

 

MAIN TEXT:

AMLODIPINE:

Amlodipine besylate is the besylate salt of Amlodipine, a long-acting CCB. Amlodipine besylate is a white crystalline powder. It is slightly soluble in water, freely soluble in methanol and sparingly soluble in ethanol. Its Molecular formula is C20H25ClN2O5•C6H6O3S. Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1, 4-dihydro-6-methyl-3, 5 pyridine dicarboxylate, monobenzenesulphonate. Molecular weight of Amlodipine besylate is 567.1. Amlodipine is an official drug in United States Pharmacopoeia and British Pharmacopoeia. It is used as racemic mixture, only S-(-) enantiomer is pharmacologically active whereas R (+)-enantiomer is thousand-fold less active 22-25. Analytical methods described in literature and pharmacopoeias for determination of Amlodipine besylate in pure form (API), biological fluids and its related formulations are listed in table 1.


 

Table 1- Analytical Methods for Amlodipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·       Column-L1 or C-18 (150 mm × 3.9-mm)

·       MP-pH 3.0 triethylamine Buffer, methanol, and acetonitrile (50:35:15%V/V)

·       Flow rate-1.0 mL/min.

λ- 237 nm

API and tablets

[26]

HPLC

·       Column-C-18 (25mm ×4mm, 5µm)

·       MP-2.3 g/L solution of ammonium acetate R, methanol R (30:70 % V/V).

·       Flow rate-1.5 mL/min.

·       Column temperature-30ºC

λ- 237 nm

API

[27]

HPLC

·       Column- Kinetex C-18 (100 mm×4.6 mm, 2.6µm)

·       MP-

MP-A: pH 3.0 Potassium dihydrogen orthophosphate (0.03 M) and Methanol (45:55 % V/V).

MP-B: pH 3.0 Potassium dihydrogen orthophosphate (0.03 M) and Methanol (30:70 % V/V). Gradient mode of elution.

·       Flow rate: 0.6 mL/min.

λ- 238 nm

Tablets and oral solution

[27]

HPLC

·       Column-C-18 (150 mm × 3.9 mm, 5 µm)

·       MP-pH 3.0 triethylamine Buffer, methanol, and acetonitrile (50:35:15%V/V)

·       Flow rate-1.0 mL/min.

λ- 237 nm

API

and Tablets

[28]

HPLC

·       Column-WATERS C-18 (250 mm × 4.6 mm, 5 µm)

·       MP-Acetonitrile, pH 3.0 Potassium dihydrogen orthophosphate and Methanol (50:35:15 % V/V)

·       Flow rate-1.0 mL/min.

λ- 240 nm

Tablets

[29]

LC-MS

·       Column-ZORBAX SB C-18 (50 mm × 4.6 mm, 3.5 µm)

·       MP- 5 mM ammonium acetate in 0.1 % formic acid, Methanol and Acetonitrile (30:30:40 % V/V)

·       Flow rate-0.7 mL/min.

-

Human Plasma

[30]

HPLC

·       Column- Phenomenex Luna C-18 (150 mm × 4.6 mm, 5 µm)

·       MP- Acetonitrile and Acetate buffer (50:50 % V/V) pH mobile phase set as 5.

·       Flow rate-1.0 mL/min.

λ- 232 nm

UV detector

API

and Tablets

[31]

HPLC

·       Column-WATERS C-18 (250 mm × 4.6 mm, 5 µm)

·       MP- pH 6.4 Potassium dihydrogen phosphate buffer (10 mM), Acetonitrile and Methanol (20:70:10 % V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-28ºC

λ- 360 nm

Human Plasma

[32]

HPLC

·       Column- C-18 (250 mm × 4.6 mm, 5 µm)

·       MP- 0.05 M Potassium dihydrogen orthophosphate buffer and Acetonitrile (45:55 % V/V)

·       Flow rate-1.5 mL/min.

·       Column temperature-40ºC

λ- 465 nm,

Photodiode array detector,

Sodium 1, 2-naphthoquinone-4-sulfonate (NQS) reagent is used

API

 

[33]

HPLC

·       Column-Zodiac C-18 (250 mm × 4.6 mm, 5 µm)

·       MP- Methanol, Acetonitrile and pH 5.8 0.01M orthophosphoric acid solution. (75:23:2 % V/V)

·       Flow rate-1.0 mL/min.

λ- 236 nm

API

and Tablets

[34]

HPLC

·       Column-Hypersil BDS C8 (150 mm × 4.6 mm, 5 µm)

·       MP- pH phosphate buffer and Acetonitrile (65:25 % V/V)

·       Flow rate-1.5 mL/min.

λ- 237 nm

Tablets

[35]

LC-MS

·       Column-WATERS C-18 (250 mm × 4.6 mm, 5 µm)

·       MP- Methanol and pH 5.0 Phosphate buffer with gradient mode of elution.

·       Flow rate-1.0 mL/min.

λ- 240 nm

UV Visible detector

API

[36]

UV

·       Solvent-Ammonium acetate, potassium acetate and nicotinamide solution, hydrotropic Solubilization technique used

λ- 243 nm

API

[37]

UV

·       Solvent- 0.01 % orthophosphoric acid solution and further dilution with water.

λ- 366 nm

Tablets

[38]

HPLC

·       Column-Zorbex Eclipse C-18 (150 mm × 4.6 mm, 5 µm) MP- pH 3.0 Orthophosphoric acid buffer and Methanol (40:60 % V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-30ºC

λ- 239 nm

UV Visible detector

Oral films

[39]

HPLC

·       Column-Ascentis C-18 (150 mm × 4.6 mm, 5 µm)

·       MP- Acetonitrile and 0.1 % Trifluoroacetic acid Solution (40:60 % V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-30ºC

λ- 237 nm

UV Visible detector

Tablets

[40]

 Spectro-fluorimetric

·       Solvent-Ethanol

Fluorescence Detector, Excitation λ- 360 nm and emission λ- 440 nm

Plasma

 

[41]

Tandem LC-MS

·       Column-Hypurity C-18 (50 mm × 2.1 mm, 5 µm) MP- Acetonitrile and 0.1 % Formic acid Solution (90:10 % V/V)

·       Column temperature-40ºC

Positive ionization detector

Human Plasma

[42]

LC-MS

·       Column- Phenomenex Luna C-18 (150 mm × 4.6 mm, 5 µm)

·       MP- 10 mM ammonium formate, Methanol and Acetonitrile (30:50:20 % V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-30ºC

 

 

Electron spray Ionization

Human Plasma

[43]

LC-MS

·       Column- Diamond C-18 (150 mm × 4.6 mm, 5 µm)

·       MP- methanol mixed with 10 mM ammonium acetate solution, with gradient flow rates and varied ratio of mobile phase

·       Column temperature-30ºC

·       Gas temperature -350°C

·       Spray gas pressure -350 Pascals

·       Capillary voltage -4000 V

·       Nebulizer pressure (45 psi)

Triple Quadrupole mass spectrometer equipped with an Electrospray ionization source

Human Plasma

[44]

LC-MS

·       Column- Princeton SPHER C-18 (100 mm × 4.6 mm, 5 µm)

·       MP- Acetonitrile and 10 mM Ammonium acetate (90:10 % V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-30ºC

·       Turbo ion spray source temperature - 37.5°C

·       Turbo ion spray voltage was set at 5500 V.

Electron spray Ionization

Human Plasma

[45]

 

Table 2: Analytical Methods for Lacidipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·       Column- Cyanosilyl silica gel, Spherisorb CN

(250 mm × 4.6 mm, 5 µm)

·       MP-Absolute ethanol and n-Hexane (3 : 97 %V/V)

·       Flow rate-2.0 mL/min.

λ- 240 nm

API and tablets

[27]

LC-MS

·       Column- Zorbex SB C-18 (50 mm × 4.6 mm, 5 µm)

·       MP- 5 mM Ammonium acetate buffer and Acetonitrile (15:85 % V/V)

·       Flow rate-0.6 mL/min.

·       Column temperature-40ºC

·       Turbo ion spray source temperature - 450°C

·       Nebulizer gas pressure-35 psi.

Electron spray Ionization-Turbo ion spray

Human Plasma

[48]

HPLC

·       Column- Thermo Hypersil BDS C-18 (75 mm × 3.5 mm, 3 µm)

·       MP-pH 6.5 Ammonium acetate buffer and Methanol (30 : 70 %V/V)

·       Flow rate-1.2 mL/min.

·       Column temperature-40ºC

λ- 242 nm

Photodiode array detector

Tablets

[49]

HPLC

·       Column- X-Bridge C-18 (150 mm × 4.6 mm, 3 µm)

·       MP-Acetonitrile and 5 mM Ammonium acetate buffer (95 : 5 %V/V)

·       Flow rate-1.0 mL/min.

·       Column temperature-30ºC

λ- 240 nm

Photodiode array detector

API and Tablets

[50]

UV

·       Solvent- Methanol

λ- 218 nm

Tablets

[51]

HPTLC

·       Stationary Phase-TLC aluminium plate precoated with silica gel 60F254.

·       MP- Toluene and Ethyl acetate

(65 : 35 %V/V)

-

Urine

[52]

HPLC

·       Column- Phenomenex Luna C-18 (250 mm × 4.6 mm, 5 µm)

·       MP-pH4.5 Ammonium acetate buffer and Methanol (30 : 70 %V/V)

·       Flow rate-1.2 mL/min.

·       Column temperature-40ºC

λ- 240 nm

Photodiode array detector

Tablets

[53]

UPLC

·       Column- Waters Acquity BEH C-18 (100 mm × 2.1 mm, 1.7 µm)

·       MP- pH4.5 Ammonium acetate buffer and Methanol (70 : 30 %V/V)

·       Flow rate-0.25 mL/min.

·       Column temperature-40ºC

λ- 240 nm

 

Tablets

[54, 55]

HPLC

·       Column- RP Shim Pack GWS C-18 (250 mm × 4.6 mm, 5 µm)

·       MP-Acetonitrile and Water, pH adjusted to 3.5 with orthophosphoric acid (85 : 15 %V/V)

·       Flow rate-1.2 mL/min.

λ- 239 nm

Photodiode array detector

API

[56]

HPLC

·       Column- Lichrospher C-18 (250 mm × 4.6 mm, 5 µm)

·       MP-Acetonitrile and 5 mM Ammonium acetate (85 : 15 %V/V)

·       Flow rate-1.0 mL/min.

λ- 240 nm

 

Niosomal gel in rat plasma

[57]

UV

·       Solvent- Methanol

Zero order λ- 284 nm and first order λ- 277 nm

API and Tablets

[58]

UPLC-MS

·       Column- Thermo C-18 (50 mm × 2.1 mm, 2.6 µm)

·       MP- Acetonitrile and Water containing 0.1 % Formic acid (83 : 17 %V/V)

·       Flow rate-0.2 mL/min.

Waters Tandem Qudrapole detector

 

Dog Plasma

[59]

HPLC

·       Column- Grace Vydac RP C-18 (250 mm × 4.6 mm, 5 µm)

·       MP-Acetonitrile and pH 0.1 Triethylamine (90 : 10 %V/V)

·       Flow rate-0.8 mL/min.

λ- 240 nm

 

Nanoform-ulations

[60]

 

 

LACIDIPINE:

Lacidipine is a lipophilic dihydropyridine calcium antagonist. Lacidipine is an orally administered CCB which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action 46, 47. Lacidipine is a white to pale yellow crystalline powder. It is freely soluble in acetone, sparingly soluble in absolute ethanol and practically insoluble in water. Its Molecular formula is C26H33NO6. Lacidipine is chemically described as diethyl (E)-4-{2-[(tert-butoxycarbonyl) vinyl] phenyl}-1, 4-dihydro-2, 6-dimethylpyridine-3, 5-dicarboxylate. Molecular weight of Lacidipine is 455.6. Lacidipine is an official drug in British Pharmacopoeia27. Analytical methods described in literature and pharmacopoeias for determination of Lacidipine in pure form (API), biological fluids and its related formulations are listed in table 2.

 

 

Table 3: Analytical Methods for Isradipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·  Column-L1 or C-18 (100 mm × 4.6 mm)

·  MP-Methanol, Tetrahydrofuran and Water (40:10:50 %V/V/V)

·  Flow rate-1.7 mL/min.

λ- 326 nm

API and tablets

[26]

HPLC

·  Column-L1 or C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Methanol, Tetrahydrofuran and Water (42:20:38 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 240 nm

Compounded oral solution

[26]

HPLC

·  Column-L1 or C-18 (100 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Tetrahydrofuran and Water (12.5:27:62.5 %V/V)

·  Flow rate-1.2 mL/min.

λ- 326 nm

API and tablets

[27]

HPLC

·  Column-Bondapak C-18

·  MP-Methanol, Acetonitrile and pH 2.8 acetate buffer (60:30:10 %V/V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-40ºC

λ- 290 nm

Capsules

[63]

HPLC

·  Column- Agilent Zorbex C-18 (150 mm × 4.6 mm, 5 µm)

·  MP-Methanol, Acetonitrile and 0.1 % Orthophosphoric acid solution (55:35:10 %V/V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-30ºC

λ- 326 nm

Tablets

[64]

HPLC

·  Column- Kromasil C-18 (100 mm × 4.6 mm, 5 µm)

·  MP-Water, Methanol and Tetrahydrofuran (50:40:10 %V/V/V)

·  Flow rate-1.4 mL/min.

λ- 330 nm

Tablets

[65]

HPLC

·  Column- Bondapak C-18 (5 µm)

·  MP- Methanol and Water (70:30 %V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-40ºC

λ- 290 nm

Capsules

[66]

UV

·  Solvent- Methanol : Chloroform(70:30 %V/V)

λ- 327 nm

Solid Lipid Nano-particles

[67]

UPLC-MS

·  Column- Waters Acquity BEH C-18 (50 mm × 2.1 mm, 1.7 µm)

·  MP- Acetonitrile, Water and Formic Acid (80:20:0.3 % V/V/V)

·  Flow rate-0.2 mL/min.

·  Column temperature-30ºC

·  Ion source temperature - 500°C

·  Nebulizer gas pressure-50 psi.

Triple Quadrupole Tandem Mass Spectrometer

Dog Plasma

[68]

HPLC

·  Column- Chiralpak AD

·  MP- Heaxane, 2-Propanol and Ethanol (94:4:2 %V/V/V)

·  Flow rate-1.5 mL/min.

λ- 325 nm

HF-LPME

[69]

HPLC

 

·  Column- Aluspher RP- Select B

(250 mm × 4.6 mm, 5 µm)

·  MP-0.1 M Britton–Robinson Buffer (pH 11.8), Acetonitrile and Methanol (60:30:10 % V/V/V)

·   Flow rate-1.0 mL/min.

λ- 330 nm

(Electro-chemical detection)

Human Serum

[70]

LC-MS

·  Column- XTerra MS C-18

(100 mm × 3 mm, 5 µm)

·  MP- 0.1 % Formic acid and (Mixture of 75 parts of Acetonitrile an 25 parts of Methanol) (42:58 % V/V)

·   Flow rate-0.5 mL/min.

Turbo-ion spray detection

Human Plasma

[71]

 

ISRADIPINE:

Isradipine, a dihydropyridine calcium antagonist has high affinity for voltage-operated calcium channels 61. Isradipine is a yellow crystalline powder. It is soluble in methanol, freely soluble in acetone and practically insoluble in water. Its Molecular formula is C12H21N3O5. Isradipine is chemically described as Methyl 1-methylethyl (4RS)-4-(2, 1, 3-benzoxadiazol-4-yl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate. Molecular weight of Isradipine is 371.4. Isradipine is an official drug in United States Pharmacopoeia and British Pharmacopoeia26,27. Isradipine binds to calcium channels with a very high affinity and excellent specificity 62. Intravenous Isradipine is effective in controlling hypertension following coronary artery bypass graft surgery and that it appears useful in the treatment of intraoperative hypertension and hypertensive crisis and in hypertensive disorders in pregnancy, when administered orally or intravenously 61. Analytical methods described in literature and pharmacopoeias for determination of Isradipine in pure form (API), biological fluids and its related formulations are listed in table 3.

 

FELODIPINE:

Felodipine, a dihydropyridine calcium antagonist reversibly competes with Nitrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent calcium channels72, 73. Felodipine is a white or light-yellow crystalline powder. It is freely soluble in acetone, in anhydrous ethanol, in methanol and in methylene chloride and practically insoluble in water. Its Molecular formula is C18H19Cl2NO4. Felodipine is chemically described as 3, 5-Pyridinedicarboxylic acid 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-, ethyl methyl ester. Molecular weight of Felodipine is 384.25. Felodipine is an official drug in United States Pharmacopoeia and British Pharmacopoeia26, 27. In-vitro studies show that the effects of Felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle without altering calcium level in serum. Negative ionotropic effects can be detected in-vitro, but such effects have not been seen in intact animals. The effect of Felodipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance in man, with a modest reflex increase in heart rate72, 73. Analytical methods described in literature and pharmacopoeias for determination of Felodipine in pure form (API), biological fluids and its related formulations are listed in table 4.

 

Table 4: Analytical Methods for Felodipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·  Column-L1 or C-18 (150 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Methanol, and pH 3.0 Monobasic sodium phosphate buffer (40:20:40 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 254 nm

API

[26, 27]

HPLC

·  Column-L1 or C-18 (150 mm × 4.6 mm, 4 µm)

·  MP-Acetonitrile, Methanol, and pH 3.0 Monobasic sodium phosphate buffer (40:20:40 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 362 nm

Extended Release tablets

[26]

Titration

·  Redox Titration

·  Titrant- 0.1 M Cerium Sulfate.

·  Solvent for analyte (0.16g) 25:25 mixture of 2-methyl-2-propanol and perchloric acid solution.

·  Indicator-Ferroin solution.

·  1 mL Cerium Sulfate is equivalent to 19.21 mg of Felodipine.

End point –Pink to colorless.

API(Assay)

[27, 28]

HPLC

·  Column-Waters Novapak C-18 (150 mm × 3.9 mm, 4 µm)

·  MP-(pH 3.0, 0.08% w/v of orthophosphoric acid R and 0.8% w/v of sodium dihydrogen orthophosphate), Methanol and Acetonitrile (40:20:40 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 254 nm

Prolonged Release tablets

[27]

HPLC

·  Column-Zorbex C-18

·  MP-Sodium acetate buffer and Acetonitrile (30:70 %V/V)

·  Flow rate-1.2 mL/min.

λ- 237 nm

Extended Release tablets

[74]

HPLC

·  Column-Waters Symmetry C-18 (250 mm × 4.5 mm, 5 µm)

·  MP- Acetonitrile and Water (80:20 %V/V)

·  Flow rate-1.0 mL/min.

λ- 234 nm

API

[75]

UV

·  Solvent –Ethanol(green solvent)

λ- 363.5 nm

API and Tablets

[76]

HPLC

·  Column-ODS C-18 (150 mm × 4.6 mm, 5 µm)

·  MP- Acetonitrile and Water (80:20 %V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-35ºC

λ- 305 nm

API and Tablets

[77]

HPLC

·  Column- HIQ Sil C 18 HS (250 mm × 4.6 mm, 5 µm)

·  MP- Methanol and pH 3.0 phosphate buffer (83:17 %V/V/V)

·  Flow rate-0.8 mL/min.

λ- 232 nm

API and Agglomerates

[78]

 

 

LC-MS

·  Column-Zorbax SB C-18 (50 mm × 4.6 mm, 3.5 µm)

·  MP- pH 4.0 Ammonium acetate buffer and Methanol(30:70 %V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-50ºC

Atmospheric Pressure Chemical Ionization source

Human Plasma

[79]

HPLC

·  Column-Inertsil ODS C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- pH 4.5 phosphate buffer Acetonitrile and Methanol (40:40:20 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 362 nm

API and Capsules

[80]

HPTLC

·  Stationary Phase for Normal HPTLC-200 × 100 mm pre-coated aluminum plates with 250 μm layer of silica gel 60 F254.

·  Stationary Phase for Reverse Phase HPTLC- 200 × 100 mm pre-coated aluminum plates with 250 μm layer of Silica gel 60 RP-18 TLC F254S

·  MP for Normal HPTLC-Toluene and Methanol (80:20 % v/v)

·  MP-for Reverse Phase HPTLC-Acetonitrile, Water and Glacial acetic acid (80:20:10 %V/VV)

λ- 237 nm

Densitometry

 

API and Tablets

[81]

HPLC

·  Column-Inertsil ODS C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- pH 7.0 phosphate buffer and Acetonitrile (20:80 %V/V)

·  Flow rate-1.2 mL/min.

λ- 234 nm

Tablets

[82]

LC-MS

·  Column- Princeton SPHER C-18 (150 mm × 4.6 mm, 5 µm)

·  MP- Acetonitrile and 2mM ammonium acetate (80:20 %V/V)

·  Flow rate-0.8 mL/min.

·  Gas temperature-250ºC

Electron Spray Ionization

Human Plasma

[83]

HPLC

·  Column-Kromasil C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- Methanol, Acetonitrile and Water (50:15:35 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 238 nm

Tablets

[84]

HPLC

·  Column- C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- 10 mM Tetra butyl ammonium hydrogen sulphate and Acetonitrile (18:82 %V/V)

·  Flow rate-1.2 mL/min.

λ- 237 nm

Tablets

[85]

HPLC

·  Column-Waters Symmetry C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- Acetonitrile and Water (80:20 %V/V)

·  Flow rate-1.0 mL/min.

λ- 243 nm

API

[86]

HPLC

·  Column-Luna C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- pH 3.0 phosphate buffer and Methanol (83:17 %V/V)

·  Flow rate-1.0 mL/min.

λ- 275 nm

API and Tablets

[87]

Micellar HPLC

·  Column- C-18

·  MP- Micellar mobile phase 85 mM sodium dodecyl sulphate, 25 mM phosphate buffer and 6.5% pentanol at pH 7.

·  Flow rate-1.0 mL/min.

Fluorescence Detector, Excitation λ- 240 nm and emission λ- 440 nm

Human Plasma

[88]

 

NIFEDIPINE:

Nifedipine, a dihydropyridine calcium antagonist inhibits the entry of calcium ions by blocking voltage-dependent L-type calcium channels in vascular smooth muscle and myocardial cells. The reduced intra-cellular calcium, results in reduction of peripheral arterial vascular resistance and dilation of coronary arteries, leading to a reduction in systemic blood pressure and increased myocardial oxygen delivery89. Nifedipine is a yellow crystalline powder. It is freely soluble in acetone, sparingly soluble in ethanol and practically insoluble in water. Its Molecular formula is C17H18N2O6. Nifedipine is chemically described a 3, 5-Pyridinedicarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester. Molecular weight of Nifedipine is 346.3. When exposed to daylight and to artificial light of certain wavelengths, it readily converts to a nitroso-phenyl pyridine derivative. Exposure to ultraviolet light leads to the formation of a nitro-phenyl pyridine derivative. Nifedipine is an official drug in United States Pharmacopoeia and British Pharmacopoeia26, 27. Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of Nifedipine in Vasospastic (Prinzmetal’s or variant) angina 90. Analytical methods described in literature and pharmacopoeias for determination of Nifedipine in pure form (API), biological fluids and its related formulations are listed in table 5.


 

Table 5: Analytical Methods for Nifedipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·  Column-L1 or C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Methanol, and Water (25:25:50 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 235 nm

API and Extended Release tablets

[26]

HPLC

·  Column-L1 or C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Methanol, and Water (25:25:50 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 265 nm

Capsules

[26]

Titration

·  Redox Titration

·  Titrant- 0.1 M Cerium Sulfate.

·  Solvent for analyte (0.13g) 25:25 mixture of 2-methyl-2-propanol and perchloric acid solution.

·  Indicator-Ferroin solution.

·  1 mL Cerium Sulfate is equivalent to 17.32 mg of Felodipine.

End point –Pink to colorless.

API

[27]

HPLC

·  Column-Lichrosorb C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Methanol, and Water (9:36:55 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 235 nm

Prolonged Release tablets

[27]

HPLC

·  Column-Hypersil C-18 (100 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile and 0.03 % Orthophosphoric acid solution. (40:60 %V/V)

·  Flow rate-1.0 mL/min.

λ- 235 nm

Capsules

[27]

HPLC

·  Column-L1 or C-18 (150 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile, Methanol, and Water (9:36:55 %V/V/V)

·  Flow rate-1.0 mL/min.

λ- 235 nm

Prolonged Release Capsules

[27]

UPLC

·  Column-Sunniest C-18 HT (50 mm × 2.1 mm, 2 µm)

·  MP-Mobile phase-A (Water: Acetonitrile, 95:5 %V/V) and Mobile Phase-B 0.5 mL of Formic acid in 1 liter of Acetonitrile, with gradient mode of elution.

·  Flow rate-0.7 mL/min.

·  Column temperature-40ºC

λ- 335 nm

API

[91]

HPLC

·  Column- Phenomena Luna C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- Acetonitrile and pH 7.4 0.1 % Triethylamine (78:22 %V/V)

·  Flow rate-1.0 mL/min.

λ- 326 nm

Novel Proniosomes

[92]

HPLC

·  Column- Nucleosil C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- pH 3.0 disodium hydrogen phosphate, Methanol and Acetonitrile (37:40:23 %V/V/V)

·  Flow rate-0.8 mL/min.

λ- 238 nm

API, Plasma and Sustained Release Tablets

[93]

HPLC

·  Column- Purospher Star C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- Acetonitirle and pH 3.0 phosphate Buffer (40:60 %V/V)

·  Flow rate-1.0 mL/min.

UV Visible

Tablets, Human milk and Urine

[94]

UPLC-MS

·  Column- Phenomenex C-18 (50 mm × 4.6 mm, 3 µm)

·  MP- Acetonitrile and pH 3.5 Ammonium formate buffer, 5 mM (60:40 %V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-35ºC

Electron Spray ionization

Human Plasma

[95]

UV

(Oxidative coupling)

·  Solvent-Methanol

·  MBTH reagent (3- methyl-2-benzothiazolinone hydrazone)

Visible

λ- 685 nm (green color)

API, tablet, Serum, Urine

[96]

·  Brucine sodium iodated solution

λ- 546 nm (violet color)

HPLC

·  Column- Phenomenex Luna C-18 (250 mm × 4.6 mm, 5 µm)

·  MP- 0.01 M Ammonium formate solution, Methanol and Acetonitrile (55:43:2 %V/V/V) and pH was adjusted to 4.9 with formic acid.

·  Flow rate-0.8 mL/min.

·  Column temperature-37ºC

λ- 235 nm

Rat Plasma

[97]

LC-MS

·  Column- Hypersil Gold C-18 (50 mm × 4.6 mm, 5 µm)

·  MP- 0.1 % Formic Acid buffer and Acetonitrile (30:70 % V/V)

·  Flow rate-0.6 mL/min.

·  Column temperature-40ºC

·  Gas temperature-450ºC

Triple Qudrapole mass detector

Human Plasma

[98]

LC-MS

·  Column- Zorbex SB C-8 (100 mm × 4.6 mm, 3.5 µm)

·  MP- pH 4.0 10mM Ammonium Acetate solution and Methanol (30:70 % V/V)

·  Flow rate-1.0 mL/min.

·  Column temperature-40ºC

·  Gas temperature-300ºC

 

Multiple reaction monitoring mode

Human Plasma

[99]

LC-MS

·  Column- Agilent Eclipse Plus C-18 (100 mm × 2.1 mm, 3.5 µm)

·  MP- 0.1 % Formic Acid buffer and Acetonitrile with gradient mode of elution.

·  Flow rate-0.3 mL/min.

·  Column temperature-30ºC

·  Gas temperature-320ºC

Electron Spray Ionization by Multiple reaction monitoring mode

Injection- Rat plasma

[100]

Visible Spectro-phometry

·  Absorbance spectra of was analysed using Non-Destructive Visible Spectrophotometry Technique, using tungsten halogen lamp as source.

·  Analysed by placing film in sample holder.

Scanned from 400 nm to 800 nm.

Transdermal Drug Delivery System.

[101]

HPTLC

·  Stationary Phase –Pre-coated silica gel 60- F254 on aluminium sheet (100 × 100 mm, 0.2 mm thickness) TLC plates.

·  MP – Acetonitrile, Methanol, n-Butanol and Acetic acid

(6:2:2:1:0.1 V/VV/V)

λ- 230 nm

Densitometry

 

API

[102]

LC-MS

·  Column- Lichrocrat C-18 (125 mm × 4 mm, 5 µm)

·  MP- Water, Acetonitrile and Glacial acetic acid (30:70:0.5 V/V/V)

·  Flow rate-1.0 mL/min.

Tandem Mass Spectrometer

Human Plasma and Amniotic fluid

[103]

LC-MS

·  Column- Supelco C-18 (150 mm × 4.6 mm, 5 µm)

·  MP- Acetonitrile, Methanol and Water (35:17:48% V/V/V)

·  Flow rate-1.2 mL/min.

Tandem Mass Spectrometer

Human Plasma

[104]

Micellar

HPLC

·  Column- C-18

·  Micellar MP- 0.125 M Sodiumdodecylsulfate and 3% Pentanol, pH adjusted to 3.

λ- 235 nm

 

Serum and Urine

[105]

Differential Pulse Voltametry

·  Buffer- pH 8 Britton Robinson Buffer.

·  Reference Electrode-Hanging Mercury Drop Electrode.

·  Working Electrode-Mercury Meniscus Modified Silver Solid Amalgam Electrode.

Polarograph

API

[106]

GC

·  Column-Methyl silica fused-silica column.

·  Gas-Helium gas-20ml/min.

Hydrogen gas-3.5 ml/min.

Nitrogen-phosphorous ionization detector

Human Plasma

[107]

GC

·  Column- Packed column OV-17 or OV-1

·  Gas-Argon and Methane (95:5 % V/V) 30ml/min.

Pulsed 63-Ni electron capture detector (ECD)

Human Serum

[108]

 

CILNIDIPINE:

Cilnidipine is a promising fourth generation dual L/N type dihydropyridine calcium antagonist109. Cilnidipine is a pale yellow powder. It is sparingly soluble in chloroform and methanol. Its Molecular formula is C27H28N2O7. Cilnidipine is chemically described a 1, 4-Dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylic Acid 2-Methoxyethyl (2E)-3-Phenyl-2-propenyl Ester. Molecular weight of Cilnidipine is 492.52110, 111. An N-/L-type calcium channel blocker, Cilnidipine, suppresses autonomic, electrical, and structural remodeling associated with atrial fibrillation. The blockade of N-type calcium channels results in neuro-hormonal regulation in the cardiovascular system. This results in favorable effects in the prevention of number of complications of hypertension, prevention of progression of proteinuria and renal disease. Based on study on hypertensive patients with respect to tolerability, it concluded that Cilnidipine is better than Amlodipine109, 112, 113. Both Amlodipine and Cilnidipine have equal efficacy in reducing blood pressure in hypertensive individuals. But Cilnidipine being N-type and L-type calcium channel blocker, associated with lower incidence of pedal edema compared to only L-type channel blocked by Amlodipine114. Major side effect upon long term usage of Cilnidipine is gingival overgrowth115. Analytical methods described in literature for determination of in pure form (API), biological fluids and its related formulations are listed in table 6.


 

Table 6: Analytical Methods for Cilnidipine in pure form (API), biological fluids and its related formulations

Technique

Extensive Method Conditions

Detection outline

Form

References

HPLC

·  Column-Princeton Spher C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile and pH 4.5, 0.05 M Potassium dihydrogen Orthophosphate buffer. (60:40 %V/V)

·  Flow rate-1.0 mL/min.

λ- 260 nm

Human Plasma

[116]

UV

·  Solvent -Ethanol.

λ- 240 nm

API and Tablets

[117]

HPLC

·  Column-Thermo Scientific C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile and Methanol (50:50 %V/V)

·  Flow rate-1.0 mL/min.

λ- 242 nm

API

[118]

HPLC

·  Column-Cosmosil C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Acetonitrile and Potassium dihydrogen Phosphate buffer(50:50 %V/V)

·  Flow rate-1.0 mL/min.

λ- 241 nm

API

[119]

UV

·  Using Potassium Hydroxide in Dimethyl Sulfoxide as reagent

·  Solvent -Methanol

λ- 425 nm

API and Tablets

[120]

UV

·  Using N-(1-Naphthyl) ethylene Diamine dihydrochloride reagent as reagent.

·  Solvent -Methanol

λ- 554 nm

API and Tablets

[121]

HPTLC

·  Stationary Phase –Pre-coated silica gel 60- F254 on aluminium sheet TLC plates.

·  MP – Toluene and Ethyl acetate. (60:40 % V/V)

λ- 238 nm

Densitometry

 

API and Tablets

[122]

LC-MS

·  Column-Cyanide C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-10 mM Ammonium Acetate buffer: Methanol (30:70 %V/V), adjusted to pH 5.0 with acetic acid

·  Flow rate-1.0 mL/min.

Tandem Mass Spectrometer

Human Plasma

[123]

HPLC

·  Column-Grace C-18 (250 mm × 4.6 mm, 5 µm)

·  MP-Metthanol and pH 3.0 0.05 M Phosphate buffer (80:20 %V/V)

·  Flow rate-1.0 mL/min.

λ- 254 nm

API and Tablets

[124]

 

CONCLUSION:

CCBs are widely used drugs for the treatment of hypertension and various coronary artery diseases. Various analytical methods tabulated for Amlodipine, Lacidipine, Isradipine, Felodipine, Nifedipine and Cilnidipine were obtained from literature survey of pharmacopoeias and research articles. The developed methods supported in understanding the Pharmacokinetics, Pharmacodynamics, therapeutic drug monitoring, drug interactions with the organism, developing pharmaceutical formulations, and determining the toxicity of these compounds. This review assists readers for application in routine analysis for quality assessment of pharmaceutical formulations and gives idea for further improvement of techniques. Based on survey, novel analytical techniques such as HPLC, HPTLC, LC-MS, GC, GC-MS and some simple spectrophotometric techniques are involved. Tabulated extensive method conditions gives support analyst in selection of analytical technique, solvent, mobile phase, column and detector for drugs. Selection can be done based on available chemicals and analytical instrument by referring the extensive method conditions tabulated for drugs.

 

List of Abbreviations:

HPLC - High Performance Liquid Chromatography;

GC - Gas Chromatography;

TLC - Thin Layer Chromatography;

LC - Liquid Chromatography;

LC-MS - Liquid Chromatography Mass Spectrometry;

UPLC - Upper Performance Liquid Chromatography;

CCBs - Calcium Channel Blockers;

UV - Ultra-Violet Spectrophotometry;

API - Active Pharmaceutical Ingredient;

MP - Mobile Phase;

%V/V - Percentage volume by volume. (Mobile Phase compositions);

Mm - Millimeter;

µm - Micrometer;

mM - Milli molar;

λ - Lamda max;

C-18 - Octadecylsilyl silica gel packed column;

HPTLC - High Performance Thin Layer Chromatography;

HF-LPME - Hollow fiber based liquid phase micro-extraction.

 

CONFLICT OF INTEREST:

We declare no conflicts of interest.

 

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Received on 14.12.2020          Modified on 05.02.2021

Accepted on 11.03.2021          ©AJRC All right reserved

Asian Journal of Research in Chemistry. 2021; 14(3):221-234.

DOI: 10.52711/0974-4150.2021.00039