International Journal of Research in Pharmacy and Pharmaceutical Sciences

International Journal of Research in Pharmacy and Pharmaceutical Sciences


International Journal of Research in Pharmacy and Pharmaceutical Sciences
International Journal of Research in Pharmacy and Pharmaceutical Sciences
Vol. 6, Issue 2 (2021)

Itraconazole: A literature review on analytical and bio-analytical methods


Kirtimaya Mishra, Snigdharani Behera, Tikeswari Majhi, Biondini Majhi, Chintapalli Gowri Sankar

Itraconazole: A literature review on analytical and bio-analytical methods

Kirtimaya Mishra, Snigdharani Behera, Tikeswari Majhi, Biondini Majhi, Chintapalli Gowri Sankar*

Department of Pharmaceutical Analysis, Jeypore College of Pharmacy, Jeypore, Odisha, India

 

Abstract

This review is a collaborative overview of previously published approaches related to the analysis of Itraconazole either alone or in conjunction with other medications. Many spectroscopic approaches have been used, such as derivative techniques, chromogenic techniques. Newly developed and improved chromatographic methods are also available through the use of biological fluids and pharmaceutical formulations. Few LC-MS, GC, GC-MS and HPTLC approaches are also available in addition to these two techniques. World consistency by design or design by professional methodology is now used in this new analytical analysis to get better process validation methods. This succinct analysis work will direct an analyst to select the most suitable approach for designing and validating the best analytical method.

 

Keywords: chromogenic, LC-MS, GC-MS, Itraconazole

Introduction

A change in human health has occurred as pharmaceuticals advances every day. Impurities may develop in any stage, starting from manufacturing of bulk drug to packaging of finished product and further up to storage. Transportation and storage are the two phases in which impurities may occur frequently. In this condition, thus, impurities must be observed and quantified. Analytical instrumentation and techniques play an important part in identification and quantification [1].

Intermediate pharmaceutical research is an important method for the clinical phase control as it entails multiple stages such as examination of bulk medications, intermediate products, formulations of drugs, degradation products, structural stability of drugs and the toxic quality of drug materials. Itraconazole has a greater range of activity than fluconazole. In specific, it is potent against Aspergillus, which is not fluconazole. It is also approved for use in blastomycosis, sporotrichosis, histoplasmosis and onychomycosis [2].

Itraconazole is over 99% protein-bound and has virtually no penetration into cerebrospinal fluid. Therefore, it should not be used to treat meningitis or other central nervous system infections.

Candida virus is the most widespread source of opportunistic fungal infections worldwide that cause diseases ranging from superficial mucosal infections to spread systemic infections that are frequently life-threatening. Cutaneous Candidiasis or Skin Candidiasis is a fungal infection of the skin caused by candida fungi Epidemiological survey results from India shows that 67 to 90 per cent of cases of nosocomial candidemia were caused by Candida non-albicans of which C. tropicalis was the most dominant. In the last few decades, there have been numerous reports of Candida infections in India [3].

Itraconazole, invented in 1984, is a triazole fungistatic antifungal agent recommended for patients with fungal infections. The medication can be treated orally or intravenously. Itraconazole has a greater range of activity than fluconazole. In specific, it is potent against Aspergillus, which is not fluconazole. The mechanism of action of itraconazole is the same as the other azole antifungals [4].

Triazoles inhibit CYP P450 14 α- demethylase in fungi. This enzyme is involved in the Conversion of lanosterol to ergosterol biosynthesis may be affected. The basic nitrogen of the azole ring forms a tight bond. Ergosterol biosynthesis from squalene. Site of action of triazole antifungals (Fluconazole, Itraconazole, Voriconazole) [5].

They have a lower affinity for mammalian P450's. The effect is fungistatic, but may be fungicidal at higher concentrations. Detail about the Triazole derivatives given in table no.1

 

 

Table 1: Details of Triazole Derivatives

 

Drug

Structure

IUPAC Name

Molecular weight

Solubility

Fluconazole

2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl) propan-2-ol

306.27 g/mol

Fluconazole is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide, which should be exclude with an inert gas.

Itraconazole

 

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy] phenyl] piperazin-1-yl] phenyl]-1,2,4-triazol-3-one

705.64 g/mol

The solubility in 0.1N HCl is approximately 4-6 µg/mL and in water is 1-4 ng/mL.

Posaconazole

4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) oxolan-3-yl] methoxy] phenyl] piperazin-1-yl] phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

700.8 g/mol

Posaconazole is soluble in Organic solvents such as DMSO and dimethyl formamide. The solubility of Posaconazole in these solvents is approximately 0.5 mg/ml.

Voriconazole

4-[2-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl) butan-2-yl]-1,3-thiazol-4-yl] benzonitrile

349.3 g/mol

Voriconazole has a low aqueous solubility, its maximum solubility being in acidic conditions

Ravuconazole

4-{2-[(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butanyl]-1,3-thiazol-4-yl} benzonitrile

437.5 g/mol

Revuconazole is soluble in Organic solvents such as DMSO: 20mg/ml, clear.

Isavuconazole

4-[2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl) butan-2-yl]-1,3-thiazol-4-yl] benzonitrile

437.5g/mol

Isavuconazole is soluble in Organic solvents such as DMSO: 2mg/ml, clear.

 

 

Itraconzole

From all these Triazole derivatives in this present journal about Itraconazole is discussed briefly.

Itraconazole (ITZ) chemically, 2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy] phenyl] piperazin-1-yl] phenyl]-1,2,4-triazol-3-one[6]. (Fig.1)

 

 

 

 

Fig 1: Chemical structure and IUPAC name of Itraconazole.

 

 

Its bioavailability 55%, protein binding 99.8%, metabolism via hepatic, biological half-life 21 h and root of excretion through renal. Several analytical methods based on UV, RP-HPLC, LC-MS, GC and GCMS was reported for the pharmacokinetic determination of Itrconazole in plasma and urine of humans, rats and dogs [7].

This review paper focuses the analytical procedure available for the estimation of itraconazole i.e., electrochemical methods, UV/VIS- spectrophotometric methods, HPLC/LC-MS, GC-MS, The details about the previous studies are discussed in Table no. 2, 3, 4, 5 and 6.

 

 

Table 2: Summery of methods related to HPLC technique

 

S. No

Stationary phase

Mobile phase

PH

Wavelength

Flow rate

Reference

Itraconazole with Terbinafine

1

C18(250mmx50mm,5um)

Mixture of Acetonitrile& Triethalamine (90:10)

--

225nm

1.2ml/min

8

Itraconazole with Hydroxy Itaconazole

2

C18(250mmx4.6mm)

% triethylamine solution adjusted to pH 2.8 with orthophosphoric acid–acetonitrile (46:54)]–isopropanol (90:10, v/v)

2.8

264nm

1.0ml/min

9

Itraconazole

3

C18,5um column(250x4.6mm)

Tetrabutyl ammonium hydrogen sulphate buffer solution and acetonitrile (40:60v/v)

 

225nm

1.5ml/min

10

4

C18 column,150mmx4.6mm,5um

0.08M Tetra butyl ammonium hydrogen sulphate &Acetonitrile (65:35)

--

 

1.5ml/min

11

5

C18 column,1.8um(4.6x50mm)

0.08M Tetra butyl ammonium hydrogen sulphate buffer and Acetonitrile (80:20 v/v)

 

235nm

 

12

6

C18column 150x4.6mm,5um

Buffer: Acetonitrile (65:35)

 

225nm

1.5mi/min

13

7

C18 column (250mm,4.6mm,5um)

Acetonitrile and glacial acetic acid (50:50v/v)

5

264nm

1ml/min

14

8

C18-HS (250x4.6mm)

Acetonitrile and double distilled water (90:10)

--

263nm

1.0mi/min

15

9

C18 column (100x2.1mm,1.7um)

Triethalamine buffer&Tetrahydro furan (50:50)

2.5

260nm

0.4ml/min

16

 

Table 3: Summery of Analysis of Itraconazole by UV-Spectroscopy methods

 

S. No

Drug

Method

Description

Reference

1

Method Development and Validation of Itraconazole

Uv-Spectrophotometer

Detection wavelength: 267 nm in Methanol Linearity range: 0.2-1.0µg/ml Co-relation Co-efficient: 0.991% Recovery range: 99.5-100% RSD: ≤0.2%

17

2

Estimation of Itraconazole Bulk Drug and Pharmaceutical Formulation

Uv-Spectrophotometer

Detection wavelength: 262 nm in Methanol Linearity range: 4-14µg/ml Co-relation Co-efficient: 0.991% Recovery range: 99.11-101.18% RSD: ≤0.1%

18

 

Table 4: Summery of Analysis of Itraconazole by LCMS methods

 

S. No

Stationary phase

Mobile phase

Flow rate

Reference

Itraconazole with Hydroxy Itraconazole

1

Rod RP-18e column (50 mm × 4.6 mm)

10 mM ammonium formate buffer (pH 4.0): methanol (20:80, v/v)

0.6 ml/min.

19

2

HyPurity C18 (50 mm × 4.6 mm, 5 m) column

ammonia solution: acetonitrile (20:80, v/v)

0.50 mL/min

20

Itraconazole

3

Hypersil Gold (50x4.6) mm, 3µ column

methanol: buffer solution (90:10, v/v)

0.500 mL/minute

21

 

 

 

Table 5: Summery of Analysis of Itraconazole by GC methods

 

S.no

Stationary phase

Mobile phase

Flow rate

Reference

1

ZB-624, 30m length, 0.53 mm internal diameter, and 3.0 um

Nitrogen

3.0ml/min

22

 

Table 6: Summery of Analysis of Itraconazole by GCMC methods

 

S.no

Stationary phase

Mobile phase

Flow rate

Reference

1

ZB-5MS, 30 m × 0.25 mm × 0.25 µm

Helium

1.0 mL/min

23

2

ZB-5 ms 30 m × 0.25 mm × 0.25 µm column,

Helium

1.0 ml/min.

24

 

 

Quality by Design

For improving the analytical method presently Quality by Design technique is used widely. Quality by design (QBD) which is discussed in ICH Q8, Q9 and Q2 is well established for the development and manufacture of pharmaceuticals [25].

 

Benefits of Quality by Design Method

It helps in the development of a robust method. As per design setup sources of variability can be better controlled. Method Transfer success is greater when a method is transferred from research level to quality control department [26]. This methodology gives room for the invention of new methods by continual improvement over the life cycle [27].

 

Conclusion

This review did illustrate the various Spectrophotometric as well as the Chromatographic methods. Thus, the development and due validation for estimation of Itraconazole was done. According to this review it was concluded that for Itraconazole different Spectroscopic & Chromatographic methods are available for single component as well as for combination and also it was found that the mobile phase containing phosphate buffer, methanol and acetonitrile were common for higher of the chromatographic method to provide more resolution. It was observed that most common combination of Itraconazole was with Voriconazole (ex. SPORANOX). For chromatographic method flow rate is observed in the range of 0.4-1.5 ml/min to get good retention time. For higher of the Spectroscopic methods common solvent is Methanol. Hence this all methods found to be simple, precise, accurate, economic, and reproducible in nature. But from this review it was clear that available methods can be improved by using Design of Expert (DOE) technique, which will give more accurate and precise result.

 

Acknowledgment

The authors express their gratitude to the Management, Jeypore College of Pharmacy, Jeypore for providing their continuous support throughout the work. The authors are also grateful to Mr. Saswat Kumar Rath, Mr. Rama Krushna Gouda and Mr Sudhir Kumar Dash for their continuous encouragement and valuable inputs and cooperation while carrying out this study.

Conflict of interest

The authors declare that they have no conflict of interest.

 

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How to cite this article:
Kirtimaya Mishra, Snigdharani Behera, Tikeswari Majhi, Biondini Majhi, Chintapalli Gowri Sankar. Itraconazole: A literature review on analytical and bio-analytical methods. International Journal of Research in Pharmacy and Pharmaceutical Sciences, Volume 6, Issue 2, 2021, Pages 08-12
International Journal of Research in Pharmacy and Pharmaceutical Sciences