Candesartan Cilexetil: A Review of Spectroscopic and Chromatographic Method

 

Sudhanshu I Chauhan1, 2*, Pankaj D. Savani1, Hasumati Raj1, Sagar Patel1

1Department of Quality Assurance, Shree Dhanvantary Pharmacy College, Kim, Surat, Gujarat, India.

2Research Scholar 2015, Gujarat Technological University, Gujarat, India.

*Corresponding Author E-mail: sudhanshuchauhan32@yahoo.com

 

ABSTRACT:

Candesartan Cilexetil is classified as an AT1 Angiotensin II receptor antagonist as a Antihypertensive agent. There are widely used in treatment of diseases like hypertension, heart failure, myocardial infarction and diabetic nephropathy. The clinical and pharmaceutical analysis of this drug requires effective analytical procedures for quality control and Pharmcodynamic and pharmacokinetic studies as well as stability study. There are many article examines published analytical methods reported so far in the literature for the determination of Candesartan Cilexetil in biological samples and pharmaceutical formulations. These article comprise reviews of analytical methods like Spectrophotometric methods, Chromatographic method including HPLC, HPTLC.

 

KEYWORDS: Candesartan Cilexetil, Spectrophotometry, HPLC, Anti-hypertensive Agent, AT1 Angiotensin II receptor antagonist.

 

 


INTRODUCTION:

Candesartan Cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II.[1]

 

Figure 1: Structure of Candesartan Cilexetil

 

Table 1: Structural identification of Candesartan Cilexetil[2]

S. No.

Class

Identification

1

Kingdom

Organic compound

2

Super class

Organoheterocyclic Compound

3

Class

Azoles

4

Subclass

Tetrazole derivative

5

Direct parent

Biphenyltetrazoles and Derivatives

6

Alternative parent

Biphenyls and Derivatives; Benzimidazoles; N-substituted imidazoles

7

Molecular framework

Aromatic heteropolycyclic compound

 

MECHANISM OF ACTION

Candesartan Cilexetil is an prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. In the Renin-Angiotensin system, Angiotensin I is converted by Angiotensin-converting enzyme (ACE) to form Angiotensin II.

 


Table 2: Drug Profile[1-3]

S. No.

PARAMETERS

DESCRIPTION

1

Category

Antihypertensive agent

2

Chemical formula

C33H34N6O6

3

IUPAC Name

(±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate,

cyclohexyl carbonate (ester).

4

Molecular Weight

610.66 gm/mol

5

Characteristic

White Crystalline Powder

6

Solubility

Highly Soluble in dimethyl sulfoxide or 1N Sodium carbonate solution Methanol, Ethanol, Acetonitrile

 

 

Figure 2: Mechanism of action Candesartan Cilexetil

 


Angiotensin II stimulates the adrenal cortex to synthesize and secrete Aldosterone, which decreases the excretion of sodium and increases the excretion of potassium. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle. Candesartan, by blocking the binding of Angiotensin II to the AT1 receptor, promotes Vasodilation and decreases the effects of Aldosterone. The negative feedback regulation of Angiotensin II on Renin secretion is also inhibited, but the resulting rise in plasma Renin concentrations and consequent rise in Angiotensin II plasma concentrations do not counteract the blood pressure–lowering effect that occurs.[4]

 

Combination of candesartan cilexetil:

1.      Candesartan Cilexetil+ Hydrochlorthiazide

2.      Candesartan Cilexetil + Nifedipine

3.      Candesartan Cilexetil + AmlodipinBesylate

4.      Candesartan Cilexetil + Cetrizine Hydrochloride

 

Marketed formulation of candesartan cilexetil:[5]

Candesartan Cilexetil formulation:

·        Blopress, Atacand, Amias, and Ratacand.

·        Candelong, Candesar

 

Candesartan Cilexetil combination formulation

Atacand HCT, Hytacand, Blopress Plus, Advantec and Ratacand Plus.

 

 

Pharmacokinetics:

Table 3: Pharmacokinetics Parameters of Candesartan Cilexetil[2]

PARAMETERS

DESCRIPTION

Absorption

Orally absorbed

Metabolism

Minor Hepatic metabolism by O- deethylation to an inactive metabolite

Excretion

Renal and Bile

 

Analytical method:

Compendial method:

Candesartan Cilexetil is official in Japanese Pharmacopoeia, European Pharmacopoeia and United State Pharmacopoeia.

 

Reported method:

1.      Spectroscopic method:

Spectrophotometric method is versatile and economical particularly for developing countries. Spectrophotometric method has several advantages such as being easy, less expensive and less time consuming compared with most of the other methods. A simple, precise and economical Spectrophotometric method for the estimation of Candesartan Cilexetil in pharmaceutical bulk and tablet dosage form was developed and validated. Various methods like Q-absorption ratio, Simultaneous equation and Derivative methods are used for determination of Candesartan Cilexetil alone or in combination with other drugs in marketed formulation and Synthetic mixture. Below in table describes the various Spectroscopic methods with the method description and condition which are reported on review literature.              

 

 


Table 4:Compendial method for Candesartan Cilexetil

Compen-dia

Me-thod

Column

Mobile phase

Detection wavelength

Flow rate (ml/min)

JP[6]

HPLC

A stainless steel

(15cm x 4mm, 4µm)

MP A: Acetonitrile: water: acetic acid (57:43:1)

MP B: Acetonitrile: water: acetic acid (90:10:1)

Between

 252  - 256  and 302 – 307

0.8

USP[3]

LC

(15cm x 3.9mm ;

4μm) packing L1

Diluent: Acetonitrile and water (3:2)

Solution A: Acetonitrile, glacial acetic acid, and water (57:1:43)

Solution B: Acetonitrile, glacial acetic acid, and water (90:1:10)

254 nm

0.8

 

Table 5: Summary of UV-Spectroscopic method for Candesartan Cilexetil.

Title

Method

Solvent

λmax (nm)

Ref.

Development and validation of a stability-indicating UV spectroscopic method for Candesartan Cilexetil in bulk and formulations.

Stability Indicating UV-Spectroscopy

Methanol:

water (9:1)

254

7

Stress degradation studies on Candesartan bulk drug and development of validated method by UV spectrophotometry in marketed tablet.

Stress degradation UV-Spectroscopy

Methanol

253

8

Spectrophotometric determination of Candesartan Cilexetil in presence of its alkaline induced degradation product

Simple stability-indicating second derivative spectrophotometric assay

Methanol

291.2

9

Quantitative estimation of Candesartan by UV spectrophotometry

Simple UV- Spectroscopy

Methanol

212

10

 

 

 


2.      Chromatographic methods:

The high-pressure liquid chromatography (HPLC) for residue determination and simultaneous estimation of single and combination drug and also used in impurity profiling. HPTLC method is widely used chromatographic methods in the analysis of Candesartan Cilexetil in plasma and pharmaceutical dosage form. RP-HPLC method also developed for determination of concentration of Candesartan Cilexetilin human serum and also for simultaneous determination in synthetic mixture, combination dosage form like hydrochlorothiazide, Nifedipine, AmlodipinBesylate, Cetrizine Hydrochloride.


 

Table 6: Summary of Chromatographic method for Candesartan Cilexetil.

Title

Method

Stationary phase

Mobile phase

Detection wavelength

(nm)

Flow-rate

(ml/min)

Ref.

Development and Validation of of RP-HPLC method for estimation of Candesartan from tablet dosage form

RP-HPLC

Inertsil ODS-3V C18,

( 250mm × 4.6 mm,

5 µm)

Buffer (0.5% tri ethyl amine) and methanol (50:50%v/v) and adjust pH to 4.5 by glacial acetic acid

210

1.0

11

Analytical method development and validation for Candesartan Cilexetil as bulk drug and in pharmaceutical dosage forms by HPLC

HPLC

OctaDecyl Silyl column (C18,

250mm x 4.6 mm, 5µm)

Phosphate buffer pH 2.5 and acetonitrile (20:80 v/v)

210

1.0

12

Method development and validation of Candesartan Cilexetil by RP-HPLC

RP-HPLC

Intersil column (C18, 256mm x 4.6mm id)

Acetonitrile: methanol (40:60 %v/v,  pH 6.0)

228

1.0

13

RP-HPLC method development and validation of Candesartan Cilexetil in bulk and their pharmaceutical dosage forms

RP-HPLC

ODS C18 (250mm x4.6 mm,5µ)

Acetonitrile:

KH2PO4 [0.05M] (65:35)

256

1.5

14

Development and validation of a dissolution test with reversed-phase high performance liquid chromatographic analysis for Candesartan Cilexetil in tablet dosage forms

RP-HPLC

Agilent,Zorbax C8 (150mm × 4.6 mm, 5 µm)

Phosphate buffer (pH 2.5): Acetonitrile (15:85 v/v)

215

1.0

15

RP-HPLC analysis for quantitation of Candesartan Cilexetil in solid dosage forms

RP-HPLC

Intersil ODS-3 C18 (250mm x 4.6mm, 5µm)

0.02M mono basic potassium phosphate buffer: Acetonitrile: Triethyl amine (40:60:0.2), pH=6.0 by ortho phosphoric acid

254

2.0

16

RP-HPLC determination of Candesartan in human plasma with fluorometric detection

RP-HPLC

Agilent Zorbax Eclipse SB-C18 (150mm x 4.6mm, 5µm)

 

Phosphate buffer 0.1% H3PO4 and 0.15% N(C2H5)3-acetonitrile (69:31)

254 and  380

1.0

17

 

 

Method development and validation for the estimation of Candesartan Cilexetil in bulk and tablet dosage forms by RP-HPLC

RP-HPLC

Hypersill BDS-C8 (150mm x 4.6mm, 5µm)

Degus mixture of buffer: acetonitrile(40:60 v/v)

210

1.5

18

A stability indicating UPLC methods for Candesartan in Bulk Drug Samples

UPLC

Zorbax extended C18 (50mm x 4.6mm, 1.8µm)

MP A: 0.1% triethyl amine in water pH 2.2 and TFA

MP B: 0.1% TFA in acetonitrile and water (95:5)

210

0.4

19

 

Table 7:Summary of Spectroscopic method for Candesartan Cilexetil and its combination

Title

Method

Wave-

length for

Candesartan Cilexetil

Wave-

length for other drug

Solvent

Ref

Q-Analysis spectrophotometric methods for estimation of Candesartan Cilexetil and Hydrochlorothiazide in tablet dosage form

Simple UV-Spectroscopy

258.14

271

Methanol

20

Simultaneous estimation of Candesartan Cilexetil and Hydrochlorthiazide in tablet dosage form by UV spectrophotometric method

Simple UV-Spectroscopy

251

273

0.1N NaOH

21

Q-Absorbance ratio spectrophotometric method for the simultaneous estimation of Amlodipine Besylate and Candesartan Cilexetil in Synthetic mixture

Simple UV-Spectroscopy

242

255

Methanol

22

Development and validation of spectrophotometric method for simultaneous estimation of Amlodipine besylate and Candesartan Cilexetil in synthetic mixture by simultaneous equation method

Simple UV- Spectroscopy

255

238

Methanol

23

UV spectrophotometric method for the simultaneous estimation of Candesartan Cilexetil and Levocetrizine hydrochloride

Simple UV- Spectroscopy

255

230

Methanol

24

Development and validation of UV- spectrophotometric method for simultaneous estimation of Nifedipine and Candesartan Cilexetil in synthetic mixture

Simple UV- Spectroscopy

255

235

Methanol

25

 

Table 8: Summary of Chromatographic method for Candesartan Cilexetil and its combination

Title

Method

Stationary phase

Mobile phase

Detection wavelength

(nm)

Flow rate

(ml/min)

Ref.

Development and validation of a RP-HPLC method for estimation of hydrochlorthiazide and Candesartan Cilexetil in pharmaceutical dosage form

RP-HPLC

Zorbax C8 (150mm x 4.6mm, 3.5µm)

Phosphate buffer: methanol (30:70), pH 3.0

230

1.0

26

Simultaneous determination of Candesartan and hydrochlorthiazide in Combined pharmaceutical dosage form by new RP-HPLC method

RP-HPLC

Chromosil C18 (250 mmx 4.6mm)

MeOH : THF : 0.1%O.P.A (85:05:10 v/v/v)

272

1.0

27

Simultaneous analysis of Candesartan Cilexetil and hydrochlorthiazide in human plasma and dosage forms using HPLC with a Photodiode array detector

HPLC

Supelcocil C18 (15cm x 4.6mm, 5µm)

10mM potassium dihydrogen phosphate : methanol : acetonitrile (2:80:18, v/v/v) pH 2.5

260

1.0

28

New stability indicating method for Quantification of Impurities in Candesartan Cilexetil and hydrochlorthiazide tablets by Validated HPLC

HPLC

Zorbax SB phenyl (250mm x 4.6mm, 3.5µ)

MP A: Buffer: 1000ml deionised water + 1.0 ml methane sulfonic acid

MP B: Acetonitrile

210

1.0

29

Single RP-HPLC method for the quantification of Candesartan and hydrochlorthiazide in Formulations

RP-HPLC

C18, (250 x 4.6mm, 5µ)

 

Methanol : acetonitrile : 0.1% Ortho phospharic acid (35:50:15v/v)

272

1.0

30

Stability indicating RP-HPLC method for the simultaneous determination of Candesartan Cilexetil and hydrochlorthiazide in bulk and dosage forms

 

RP-HPLC

Hypersil BDS C18 (150mm x 4.6mm, 5µ)

Phosphate buffer : acetonitrile (55:45), pH 4.6 by Ortho phosphoric acid

244

1.0

31

RP-HPLC method for simultaneous determination of atorvastatin calcium, OlmesartanMedoxomil, Candesartan, Hydrochlorthiazide and Chlorthalidone – application to commercially available drug products

RP-HPLC

Cosmosil PAQ (150mm x 4.6mm, 5µm)

0.05 M sodium dihydrogen phosphate : Acetonitrile

220

1.0

32

Development and validation of RP-HPLC method for the simultaneous estimation of Candesartan Cilexetil and Levocetrizine hydrochloride

RP-HPLC

Phenominex C8 (250mm x 4.6mm, 5µ)

Acetonitrile : buffer (Heptane sulphonic acid) 80:20, pH 4.4

230

1.0

33

RP-HPLC method for simultaneous estimation of Candesartan and Amlodipine in bulk and pharmaceutical dosage form

RP-HPLC

C18, (150mm x 4.6mm , 5µm)

Phosphate buffer pH 6.8 adjust by potassium hydroxide : acetonitrile (35:65 v/v)

238

1.0

34

Determination of two components in Candesartan Cilexetil and Amlodipine besylate combination tablets

RP-HPLC

DIONEX acclaim 120 C18 (250mm x 4.6mm, 5µm)

Acetonitrile : 0.05 mol/L KH2PO4 (55:45)

254

1.0

35

 

 

 

Table 9: Summary of other Chromatographic method for Candesartan with other.

Title

Method

Stationary phase

Mobile phase

Flow-rate (ml/min)

Ref.

Validated HPTLC technique for simultaneous estimation of Candesartan and hydrochlorthiazide in pharmaceutical dosage form

HPTLC

60F254 TLC pre-coated plates

Toluene: ethyl acetate: formic acid(85%) (6:4:1 v/v)

-

36

Improved simultaneous quantitation of Candesartan and hydrochlorthiazide in human plasma by UPLC-MS/MS and its application in bioequivalence studies

UPLC-MS/MS

C18 Phenomenex, Gemini NX (100 mm x 4.6 mm, 5µm)

Organic mixture: buffer solution (80:20 v/v)

0.8

37

Simultaneous determination of pioglitazone and candesartan in human plasma by LC-MS/MS and its application to a human pharmacokinetic study

LC-MS/MS

C18

Acetonitrile and 0.1% formic acid 80:20 v/v

0.8

38

 

 

 


The other analytical method like RP-HPLC, HPTLC, LC/MS/MS, UV, Voltametry, Electrochemical method is also used for determination of Candesartan Cilexetil in blood, serum, pharmaceutical dosage form, synthetic mixture and also stability study but most preferably high performance and other chromatography method is used for identification, separation, assay, impurity profiling, etc study.

 

CONCLUSION:

The presented review highlights on various analytical methods reported on Candesartan Cilexetil and its combination with other drug. HPLC-HPTLC-UV methods were found to be most widely used. Various chromatographic conditions are presented in under Table. The faster time, high sensitivity, specificity and better separation efficiency enable HPLC to be used frequently for the determination of Candesartan Cilexetil in the comparison with the other methods. Other methods are also useful. In this way various analytical methods for the estimation of Candesartan Cilexetil in bulk or in various matrixes like plasma, alone or in combination with other drugs is discussed. The presented information is useful for the researchers especially those involved in the formulation development and quality control of Candesartan Cilexetil in combination with other drug.

 

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Received on 07.01.2016       Accepted on 28.01.2016     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 6(1): January- March, 2016; Page 53-58

DOI: 10.5958/2231-5675.2016.00009.0