Analytical Methods Review on Anti-Hypertensive Drug: CANDESARTAN (CAND)

Nikita Sonawane , Ritik Ahire, Mayur Chavan, Vinod Chaure, Ravindra Patil,

doi:10.5281/zenodo.14927417

Review Paper | Open Access
Volume 03 | Issue 02 | Article Id IJPS/250302232

Analytical Methods Review on Anti-Hypertensive Drug: CANDESARTAN (CAND)
Nikita Sonawane * Ritik Ahire Mayur Chavan Vinod Chaure Ravindra Patil
Jijamata Education Society's College of Pharmacy, Nandurbar (425412), Maharashtra (India)

Abstract

Hypertension is a serious condition that significantly increases the chances of developing heart failure, stroke, and kidney problems. For managing stage 2 hypertension, experts from the Joint National Committee recommend using a combination of two drugs. This approach helps in effectively controlling blood pressure, reducing the number of pills patients need to take, and improving their overall adherence to treatment, which ultimately lowers the risk of complications. One effective option is candesartan cilexetil, an angiotensin II receptor blocker (ARB) that works as a prodrug with 40% bioavailability. Candesartan stands out due to its strong receptor binding, long-lasting effects, and minimal side effects, making it a preferred choice over ACE inhibitors, which can have drawbacks like raising renin and angiotensin I levels. To ensure accurate dosing and quality, advanced techniques like HPLC and UPLC are used to analyze candesartan in both bulk and combination drug forms. These methods are highly precise, reliable, and efficient, relying on polar solvents, different flow modes, and wavelengths between 210–254 nm to deliver accurate results, making candesartan a well-supported choice in hypertension treatment.

Keywords

Candesartan, ARB, Hypertension, HPLC, UPLC

Introduction

Hypertension increases heart failure, stroke, hypertension, and renal disease. The Joint National Committee recommends a two-drug combination for stage 2 hypertension. Pharmacological combinations lower blood pressure effectively, minimize pills, increase compliance, and reduce morbidity and death. Angiotensin II receptor blocker medication is well tolerated and useful in treating hypertension, heart failure, and diabetes.¹ ARB candesartan, also known as candesartan cilexetil, is an oral medication with a 40% oral bioavailability due to partial absorption.² Candesartan, with its high receptor affinity, is an effective antagonist against angiotensin II, effectively blocking its detrimental effects on the cardiovascular system, even at elevated concentrations, and reducing medication-related issues in patients.^3,4 Kidneys are primarily responsible for the clearance of candesartan, with biliary or intestinal pathways playing a minor role.⁵ Because of its tight and sustained binding to the receptor in the target tissues, candesartan cilexetil has an effective half-life that is longer than its plasma half-life of 4–9 hours.⁶

Chemistry of CAND

Effect of candesartan on high BP

Candesartan oral monotherapy significantly reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to placebo, with a placebo-corrected reduction of 4.0 mmHg at 4 mg, 6.0 mmHg at 8 mg, and 7.8 mmHg at 16 mg.^7,8 8 mg of candesartan decreased the DBP by 8.9 mmHg, while 50 mg of losartan significantly lowered the DBP by 3.7 mmHg (p = 0.013) in a head-to-head 8-week comparison in hypertension patients.⁹

Mode of action

Angiotensin II receptor blockers (ARBs) are a recent class of antihypertensive medications that address drawbacks of ACE inhibitors, such as potential accumulation of nonspecific substrates, competitive inhibition resulting in increased renin and angiotensin I levels, and the inability to produce angiotensin II through both major and non-ACE pathways.¹⁰

Pharmacokinetic Profile

The Candesartan cilexetil prodrug has an estimated 15% bioavailability and 0.13 L/kg distribution. It is highly bound to plasma proteins and does not penetrate red blood cells. After oral administration, 33% of radioactivity is recovered in urine and 67% in feces. Its plasma clearance is 0.37 mL/min/kg and renal clearance is 0.19 mL/min/kg.¹⁰

Pharmacodynamic Profile

Candesartan inhibits the pressor effects of angiotensin II infusion dose-dependently. 8 mg of Candesartan cilexetil daily for a week showed a 90% peak inhibition, with 50% remaining for 24 hours. It increased angiotensin I and II levels and plasma renin activity in hypertension patients and healthy participants.¹⁰

Fig. 3 Chemical Structure of Candesartan

HPLC methods for CAND in alone and combinations

HPLC is a crucial analytical tool for drug product assessment, separating, detecting, and quantifying drugs and drug-related degradants. Validation establishes method performance characteristics and limitations, identifying influences on these characteristics. This article discusses strategies for HPLC method development and validation.¹¹ Total twenty-two methods reported for estimation of CAND in single and combination dosage form by using HPLC methods.

Table no 1. That provides the summary of reported HPLC methods including sample matrix, column, linearity and Detection wavelength.^12-32

Table no 1 Pharmaceutical Analysis of CAND via HPLC methods alone and combinations.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL or ppm	Ref.
1.	CAND	Bulk Material & Pharmaceutical dosage form	cosmosil C18 Column (250 cm x 4.6 mm, 5 μm)	M.P - ACN: KH2PO4 Buffer (pH 2.8) (80:20, % v/v) Flow rate- 1.2mL/min Mode of analysis –Isocratic Detection-230 nm	100-180 ppm	12
2.	CAND	Bulk Material & Pharmaceutical dosage form	Hypersil ODS C-18 Column (250 x 4.6 mm, 5 μm))	M.P- ACN :0.05 M KH2PO4 buffer [0.05M] (65:35%v/v) Flow rate – 1.5 mL/ min. Mode of analysis- Gradient Detection – 256 nm	0.5- 400 mg/ml.	13
3.	CAND	Bulk Material & Human Plasma	C-18 Column 25cm x 4.6 mm (Supelcosil)	M.P-ACN: water in 1:1 ratio pH -2.5±0.1. Flow rate – 1.1mL/min Mode of analysis – Isocratic Detection-392 nm	200ng/ml -3.125ng/ml	14
4.	CAND	Bulk Material & Human Plasma	Shim-pack Column (15x4.6mm ,4.6 µm.)	M.P-ACN: formic acid (80:20 %v/v) Flow rate – 1 mL/min Mode of analysis – Isocratic Detection – 254 nm	-	15
5.	CAND	Bulk Material & Pharmaceutical dosage form	Inertsil ODS-3 C18 Column (250 × 4.6 mm), 5μm	M.P-0.02M Mono Basic Potassium Phosphate Buffer: ACN: Triethyl Amine (40:60:0.2) pH -6.0 Flow rate – 2 mL/min Mode of analysis- Isocratic Detection – 254nm	4-24 μg/ml	16
6.	CAND	Bulk Material & Tablet formulation	Zorbax C8 Column (150 mm × 4.6 mm, 5 μm)	M.P-phosphate buffer (pH 2.5): ACN(15:85, % v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 215 nm	2.0–20.0 mcg/ml	17
7.	CAND	Bulk Material & Tablet formulation	column Zorbax SB- CN, (150x 4.6 mm, 5µm))	M.P-CN column with a 50:50 (%v/v) mixture of phosphate buffer: ACN Flow rate – 1.0 mL/ min. Mode of analysis – Isocratic Detection – 210 nm	2-24 μg /ml	18
8.	CAND	Bulk Material & Pharmaceutical dosage form	C-18 Column, (2.1 X 100) mm, 1.7µ	M.P-(0.1% TFA in water): ACN (5:95v/v), Flow rate – 0.40mL/min Mode of analysis – Isocratic Detection-255 nm	50-150μg/ml	19
9.	CAND	Bulk Material & Tablet formulation	Shim-pack VP-ODS Column (4.6 mm X 150 mm,5mm)	M.P-ACN: methanol (60:40% v/v) at pH 6.0 Flow rate – 1 mL/min Mode of analysis – Isocratic Detection – 255 nm	0.2–100 mg/ml	20
10.	CAND & AMLO	Bulk Material & Pharmaceutical dosage form	ColumnC18 (150 x 4.6mm, 5µ)	M.P-water:methanol (10:90%v/v) Flow rate – 1mL/min. Mode of analysis – Isocratic Detection -355nm	4-24 µg/ml	21
11.	CAND & LEVO	Bulk Material & Tablet dosage form	Inertsil-ODS C18 Column (250 x 4.6 mm, 5 µ),	M.P- Methanol: ACN (90:10%v/v) Flow rate – 0.8mL/ min Mode of analysis – Isocratic Detection – 230 nm	20 ppm-80 ppm	22
12.	CAND & HCTZ	Bulk Material & Pharmaceutical dosage form	Inertsil ODS C-18 Column (250 x 4.6mm ,5µm)	M.P-ACN: 0.1% OPA (35:50:15%v/v) Flow rate – 1.0 mL/min Mode of analysis – Isocratic Detection – 272 nm.	30-90 ppm	23
13.	CAND & LEVO	Bulk Material & Pharmaceutical dosage form	phenominex C8 Column (250 mm x 4.6 mm, 5 µ)	M.P-ACN: Buffer (Heptane sulphonic acid) in ratio 80:20%v/v (pH 4.4) Flow rate – 1mL/min Mode of analysis – Isocratic Detection – 230 nm	1-30 µg/ml	24
14.	CAND & AMLO	Bulk Material & Tablet formulation	Water Xterra R18,C18 Column (150×4.6 mm, 3.5u)	M.P-A : ACN: Water: OPA (950:50:01) B: ACN: Water: OPA (50:950:01) Flow rate – 1.5mL/min Mode of analysis – Isocratic Detection – CAND-254 nm AMLO-237nm	CAND-[64 ug /ml] AMLO-[28 ug/ml]	25
15.	CAND & ROS	Bulk Material & Rat Plasma	Waters C18 Column (250 × 4.6 mm, 5 µm)	M.P-ACN: 5 mM Sodium acetate buffer (70:30, %v/v; pH -3.5 with acetic acid Flow rate – 1.0 mL/min Mode of analysis – Isocratic Detection – 254 nm	CAND- (10–300 ng/ml) ROS -(5–150 ng/ml)	26
16.	CAND & PIT	Bulk Material & Rat Plasma	Waters Reliant C18 Column (4.6 × 250 mm, 5 µm)	M.P-ACN-5 mM Sodium acetate buffer (80:20, %v/v; PH- 3.5 with acetic acid) Flow rate – 0.8 mL/min Mode of analysis –Gradient Detection – 234 nm	CAND- 3–400 ng/ml PIT- 2–400 ng/ml	27
17.	CAND & PIOG	Bulk Material & Tablet formulation	kromasil C18 Column (150 × 4.6 mm, 5 µm)	M.P-60% 20 Mm Potassium dihydrogen orthophosphate :40% ACN (%v/v) Flow rate – 0.9 mL/min Mode of analysis – Isocratic Detection – 220 nm	CAND -4–24 µg/ ml PIT-7.5–45 µg/ ml	28
18.	CAND & RAM	Bulk Material & Pharmaceutical dosage form	Phenomenex C18 Column (250 mm×4.6 mm, 5 µm )	M.P-ACN:water (0.5% TEA, pH-4.5 with 10% orthophosphoric acid) (85:15%v/v) Flow rate – 1 mL/min Mode of analysis – Isocratic Detection – 220 nm	CAND- 1.60–2.88 µg/ml RAM - 0.5–0.9 µg/ml	29
19.	CAND & VALS &IRB	Bulk Material & Pharmaceutical dosage form	Synergi Hydro RP analytical Column (250 × 4.6 mm) 4 m)	M.P-OPA: ACN: sodium hydroxide Flow rate– (±0.2 mL min−1) Mode of analysis –Gradient Detection – 205 nm	-	30
20.	CAND & CARVE & HCLT	Bulk Material & Tablet dosage form	Hypersil gold C18 Column (15 μm, 100 x 4.6 mm)	M.Pmethanol:ACN: 0.1 % OPA pH 1.8 (35:50:15,% v/v/v) Flow rate – 0.8 mL/min Mode of analysis-Isocratic Detection – 215 nm	1-90 μg/ml	31
21.	CAND & PIT & ROS & CLO	Bulk Material & Tablet dosage form	C18 analytical Column (250 x 4.6 mm x 5μm)	M.P-ACN: SDP (pH 2.OPA) in the ratio of (70:30% v/v Flow rate-1 mL/min Mode of analysis – Isocratic Detection – 220 nm	CAND- 8-20 µg/ml PIT - 2-10 µg/ml ROS- 4-20 µg/ml CLO- 10-50 µg/ml	32
22.	CAND & CHL & EPR & HCTZ & IRB & LOS & VAL	Bulk Material & Tablet dosage form	octadecylsilyl Column (250 x 4.6 mm i.d.; 5 µm))	M.P-methanol/sodium phosphate monobasic buffer (0.01M, pH 6.5) Flow rate – 1mL/min Mode of analysis – Gradient Detection – 254 nm	-	33

UPLC methods for CAND in alone and combinations

Ultra-Performance Liquid Chromatography (UPLC) is a technique that enhances chromatographic resolution, speed, and sensitivity analysis using fine particles. It saves time and reduces solvent consumption, and is widely used in laboratories worldwide. Advancements in packaging materials stimulate separation, governed by the Van Demter equation.³⁴ Total three methods have been reported for estimation of CAND in pharmaceutical dosage form and biological matrix using human plasma and rat plasma. Separation was done by using isocratic mode for CAND. Maximum RP-HPLC was used as a stationary phase and polar solvents like Perchloric acid, water and buffer solutions having acidic pH are commonly used for separation of CAND in various proportion. Wavelength for detection was used in between 210 -254 nm for estimation of CAND. Literature survey summarized in Table no 2 that will provide the information about drugs, Matrix, Column, Chromatographic Conditions (Mobile Phase, flow rate, mode of analysis and wavelength detection) and Linearity.^35-37

Table no 2 Pharmaceutical Analysis of CAND via UPLC methods in alone and combination

Sr. No	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL	Ref.
1.	CAND	Bulk Material & Tablet dosage form	RP18 Column, (100 mm × 2.1 mm, 1.7 µm)	M.P – A: 0.01 M phosphate buffer pH -3.0with OPA B: 95% ACN5% Milli Q Water Flow rate - 0.35 mL/ min Mode of analysis – Gradient Detection – 254 nm & 210 nm	2.0 µg/ml	35
2	CAND & HCLT	Bulk Material & Tablet dosage form	Acquity UPLC HSS T3, Column C18, (100 mm x 2.1 mm with 1.8 mm)	M.P–A. 0.1% Perchloric acid: water B. 0.1% Perchloric acid: ACN Flow rate – 0.5 mL.min-1 Mode of analysis – Gradient Detection – 220 nm.	> 0.995	36
3.	CAND & HCLT	Bulk Material & Human Plasma	Column C18 Phenomenex, Gemini NX (100x4.6mm,5μm)	M.P- organic mixture: buffer solution (80:20 % v/v) Flow rate - 0.800 mL/min. Mode of analysis – Isocratic Detection – -	CAND -1.00 to 499.15 μg/ml HCLT- 1.00 to 601.61 μg/ml	37

LC methods for CAND in alone and combinations

Liquid chromatography (LC) is a versatile separation tool in analytical laboratories, used in academia and industry for complex non-volatile samples. Traditional LC is insufficient for these samples, making two-dimensional (2D) LC an attractive option.³⁸ Total Five methods reported for estimation of CAND in single and combination dosage form by using LC methods. Table no 3. That provides the summary of reported LC methods including sample matrix, column, linearity and Detection wavelength.^39-43

Table no 3 Pharmaceutical Analysis of CAND via LC methods alone and combinations.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/ML & µg /band	Ref.
1	CAND	Bulk Material &Tablet Dosage form	C18 Column (250 mm · 4.6 mm, 5 lm)	M.P: phosphate buffer: ACN (50:50% v/vpH 3.0) Flow rate- 1.0 mL min)^-1Mode of analysis – isocratic Detection –210 nm	(12.5–75 μg/ml)^-1	39
.2	CAND & HCLT	Bulk Material & Pharmaceutical dosage form	Hypersil Phenyl-2 column C18 ( 250 mm × 4.6 mm, 5-µm)	M.P0.02 M PDP:methanol:triethylaminea (25:75:0.2%v/v/vpH 6.0 ± 0.1, 10% OPA) Flow rate – 1 mL min−1 . Mode of analysis – Isocratic Detection – 271 nm	CAND – 5–45 µg mL−1 HCLT- 12–56 µg mL−1	40
3	CAND & HCLT	Bulk Material & Human Plasma	ACE C18 Column (50 × 4.6 mm; 5 µm)	M.P-10 mM ammonium acetate:ACN (20:80, %v/v) Flow rate -0.5 mL/min Mode of analysis- Isocratic Detection – -	-	41
4	CAND & HCLT	Bulk Material & Tablet formulation	RP-18 Column (125 mm × 4 mm, 5 μm)	M.P- Flow rate – 0.6 mL min−1 Mode of analysis – Isocratic Detection - -	CAND -32–160 μg/ml HCLT- 25–125 μg/ml	42
5.	CAND	Bulk Material & Human Plasma	analytical Spherisorb S3P Column (100×4.6 mm, 3 μm )	M.P- 100 ml citrate buffer (pH 3.1, I50.5 containing 50 mM TBA), 185 ml ACN:180 ml methanol diluting to 1000 ml with water. Flow rate -0.9 ml/min Mode of analysis – Isocratic Detection - -	-	43

HPTLC methods for CAND in alone and combinations

HPTLC is a versatile analytical separation method known for uniformity, purity, precision, and accuracy, capable of handling diverse samples and demonstrating great potential for future research and development.⁴⁴ Total One methods reported for estimation of CAND in single and combination dosage form by using HPTLC methods. Table no 4. That provides the summary of reported LC methods including sample matrix, Solvent, column, linearity and Detection wavelength.⁴⁵

Table no 4 Pharmaceutical Analysis of CAND via HPTLC methods alone and combinations

Sr.

No.

Drugs

Method

Stationary Phase

Solvents & Detection Lod, Lqd Values

Linearity

Ref.

CAND

HCLT

HPTLC

silica gel 60 GF254 plate

M.P – ethyl acetate: chloroform:acetone:methanol (3:3:3:0.5 %v/v)

Detection – 280 nm

CAND – 325 μg ml–1

HCLT- 253.0 μg mL–1

UV Spectrophotometric methods for CAND in alone and combinations

Combination drug products are crucial in therapeutics, but analyzing samples with multiple components presents challenges. Multi-component analysis has become popular in fields like clinical chemistry, drug analysis, and pollution control. UV spectrophotometric methods are used for simultaneous drug determination, minimizing the task of separating interferents and reducing analysis time and cost. These methods are based on recording and mathematically processing absorption spectra, offering advantages such as avoiding prior separation techniques, easy acquisition of spectral data, fast, accurate, and simple processes, wide applicability to both organic and inorganic systems, and typical detection limits of 10-4 to 10-5 M.⁴⁶ Total seven methods reported for estimation of CAND in single and combination dosage form by using UV Spectro methods. Table no 4. That provides the summary of reported LC methods including sample matrix, Solvent, column, linearity and Detection wavelength.^47-53

Table no 5 Pharmaceutical Analysis of CAND via UVSpectrophotometric methods alone and combinations

Sr. No.	Drugs	Solvent & Method	λmax (nm)	R²	LINEARITY	Ref.
1	CAND	Solvent – Methanol Method- spectrofluorimetric	270 nm	0.9997 and 0.9943	0.1 - 4.0 µg/ml & 0.03 to 2.0 µg/ml	47
2	CAND	Solvent – Ethanol Method – Spectrofluorimetric	260 nm & 381 nm	0.9999	3.00 – 288.60 ng/ ml	48
3	CAND	Solvent – Methanol Method – First Order& Second Order	268.8 nm	0.989.	10 – 20µg/ml.	49
4	CAND	Solvent – Methanol Method – Uv Spectrophotometric	253nm	0.9993	2-25 µg/ml	50
5	CAND	Solvent – Methanol Method – Uv Spectrophotometric	270.1 nm	0.9990	6–32 µg/ml	51
6	CAND & HCLT	Solvent – Methanol Method – Uv Spectrophotometric	CAND-250nm HCLT-280	CAND- 0.9998 HCLT- 0.9995	-	52
7	CAND & AMLO	Solvent – Methanol Method – Uv Spectrophotometric	300 - 360 nm	CAND- 0.9995 AMLO- 0.9989	CAND- 8–24 µg/ml AMLO- 5–15 µg/ml	53

DISCUSSION

There are Thirty eight analytical techniques for estimating the amounts of pharmaceuticals like CAND in conjunction with other drugs like AMLO, LEVO, ROS, PIT, PIOG, HCLT, & CARVE etc.. employing HPLC, UPLC, LC, HPTLC and UV Spectrophotometry. In this review, it has been mentioned how many papers have been published for which method from 1999 to 2023.

Fig no. 01: NO. OF PAPER

Fig no. 02: No of Research Paper during 1999-2023

ACKNOWLEDGEMENT

The principal of the JIJAMATA COLLAGE OF PHARMACY NANDURBAR, Dist. Nandurbar (MS) 425412, is gratefully acknowledged by the authors for providing the essential library resources.

Abbreviations Used

ACN – Acetonitrile
CAND – Candesartan
HPLC- High performance liquid chromatography
AMLO – Amlodipine
LC- Liquid chromatography
LEVO – Levostatin
PIOG - Piogliptazone
CARVE - Carvedilol.

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