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Review Article CODEN: IJPRNK ISSN: 2277-8713 Verma Vikrant, IJPRBS, 2015; Volume 4(2): 225-241 IJPRBS

Available Online at www.ijprbs.com 225

A REVIEW ON DIFFERENT HPLC ANALYSIS METHOD OF VORICONAZOLE

VERMA VIKRANT, SINGH UMESH KUMAR

Department Of Pharmacy Kharvel Subharti College of Pharmacy Swami vivekanand Subharti University Meerut

Accepted Date: 09/04/2015; Published Date: 27/04/2015

Abstract: This review article was prepared with an aim to review different methods developed for Voriconazole drug by HPLC analytical method and strategies developed and optimized for efficient method development. There is a continuous research in this field and different researchers are exploiting different mobile phase combinations for their research work. Voriconazole is generally used as an antifungal drug under the brand name Vfend. The use of the Voriconazole as a drug essential in pharmaceutical formulations highlights the requirement for its determination and quantification with appropriate analytical methods

Keywords: HPLC, Voriconazole

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Corresponding Author: MR. VERMA VIKRANT

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Verma Vikrant, IJPRBS, 2015; Volume 4(2): 225-241



INTRODUCTION

Literature survey revealed that method development by HPLC has been taken in plasma

samples, solid, liquid and semisolid dosage formulations for estimation of antifungal drug

voriconazole. Till now few methods have been developed for estimation of antifungal drugs

voriconazole Thus the aim of this article is to be to discuss various high performance liquid

chromatographic methods developed by various researchers for determination of these

antifungal drugs with different mobile phase combinations.

M. Vamsi Krishna et al. developed an RP-HPLC method for evaluation of in vitro permeability of

voriconazole in the presence of enhancers through rat skin In this method an isocratic RP-

HPLC–UV method for the analysis of voriconazole in skin diffusate samples has been developed

and validated. In this method experimental design was employed to optimize the method. The

method was validated as per ICH guidelines. Linearity was observed over the concentration

range of 2–100 lg mL_1 (r2= 0.999). Limits of detection and quantification were 0.6 and 2 lg

mL_1, respectively. Intra-day and inter-day precision (% RSD) was within the ICH limits (62%).

The method was successfully used to analyze skin diffusate samples, and the effectiveness of

different permeation enhancers was compared with respect to flux and permeability

coefficient.

The main purpose of this research was to develop and validate an isocratic RP-HPLC method for

the quantitative analysis of VCZ in skin diffusate samples as well as to evaluate the enhancing

effects of three penetration enhancers, i.e., DMSO, 1% SLS, and eucalyptus oil on the

percutaneous absorption of VCZ through rat skin in vitro.1-6

B. Sridhar et al validated RP-HPLC method for the Estimation of Voriconazole in Bulk and tablet

dosage form .In this a simple, selective, linear, precise and accurate RP-HPLC method was

developed and validated for rapid assay of Voriconazole in bulk and tablet dosage form.

Isocratic elution was done at a flow rate of 1 mL/min on a Inertsil C8 column (250 x 4.6 mm; 5μ)

at ambient temperature. The mobile phase consisted of Buffer (0.01M sodium dihydrogen

orthophosphate, pH was adjusted to 5.0):Acetonitrile (50:50 v/v) the UV detection wavelength

was 254 nm and 20μl of sample was injected. The retention time for Voriconazole was found to

be 6.905 min. The % recovery was within the range between 99.73% and 99.85%. The

percentage RSD for precision and accuracy of the method was found to be less than 2%. The

method was validated as per the ICH guidelines. The method was successfully applied for

routine analysis of Voriconazole in bulk samples and its formulations.

In this method important parameters found are given in the Table 1 and Table 2 and the

chromatogram obtained is given in Fig. 1



Table 1: Statistical analysis of calibration curves in the HPLC determination of Voriconazole

(n=6) Parameters Values

S. No Parameters Voriconazole

1 λ max (nm) 1.11 2 Beer’s law limit (μg/ml) 25-75 3 Correlation coefficient 0.9996 4 Regression equation Y = 24.875X+1.65 5 Limit of detection (μg/ml) 0.65 6 Limit of quantification (μg/ml) 1.98

Table 2: System suitability and study of Voriconazole

S. No Parameters Voriconazole

1 Tailing factor 1.11 2 Asymmetric factor 1.20 3 Theoretical plates 5622 4 Capacity factor 1.50 5 HETP 0.0366

Fig.1 Typical chromatogram obtained from the analysis of voriconazole standard solution7-12

Saidulu Goli et al. developed and validated voriconazole for Injection by RP-HPLC Method In

this a new simple, precise, accurate and selective RP-HPLC method has been developed and

validated for voriconazole in parental dosage form. The method was carried out on an Intersil

ODS-C18 (150X4.6X5μ) column with a mobile phase consisting of mixed phosphate buffer, ACN

and Methanol (65:30:5) and flow rate of 2.0 mL min-1. Detection was carried out at 257 nm.



The retention time for VCZ was found to be 6.413 min. The VCZ % recovery was within the

range between 99.55-99.63%. The percentage RSD for precision and accuracy of the method

was found to be less than 2%. The method was validated as per ICH guidelines. The developed

method was validated for precision, accuracy, sensitivity and robustness. The developed

method can be used for routine analysis of titled drug in formulation.

In this method important parameters found are given in the table 3 and table 4 and the

chromatogram obtained is given in Fig.2 and Fig.313-18

Table 3 Accuracy data

Sr. No Conc.(ppm) Standard concentration

1 80% 7.94 2 90% 8.93 3 100% 9.92 4 110% 10.92 5 120% 11.91

Table 4 System suitability parameters

S.No Parameters Voriconazole

1 %R.S.D 0.12 2 %Tailing factor 1.04 3 %No of theoretical plates 8.022

Fig.2 Chromatographic conditions



Fig.3 Linearity calibration graph

F. Péhourcq et al. developed direct injection HPLC micro method for the determination of

voriconazole in plasma using an internal surface reversed-phase column. The method was

found to be easy to perform and requires 10 µL of a plasma sample. The chromatographic run

time was less than 9 min using a mobile phase of 17:83 v/v acetonitrile–potassium dihydrogen

phosphate buffer, 100 mm, pH 6.0 and UV detection at 255 nm. The flow rate was 1 mL/min. A

linear response was observed over the concentration range 0.5–10 µg/mL A good accuracy

(bias ≤7.5%) was achieved for all quality controls, with intra-day and inter-day variation

coefficients inferior to 6.7%. The lower limit of quantitation was 0.2 µg/mL, without

interference of endogenous components. In this method stability of voriconazole in plasma

stored at different temperatures was checked. Finally, the possibility of direct injection of

plasma samples into the column permits a reduction in reagent consumption and in analytical

steps, and hence in analytical error. The chromatogram obtained during the study is given in

figure 4.19-24

Figure 4. Chromatogram obtained from the study



Yuru Li et al. developed and validated a stability-indicating HPLC Method for Determination of

Voriconazole and its Related Substances.An isocratic reversed-phase high performance liquid

chromatographic (RP-HPLC) method has been developed and validated for the determination of

voriconazole and its related substances. The drug substance was subjected to stress conditions

of UV light, water hydrolysis, acid, base, oxidation, and deoxidization to observe the

degradation products. The successful separation of voriconazole from its synthetic impurities

and degradation products formed under stress conditions was achieved using an Agilent Zorbax

SB-C18 (250mm × 4.6 mm i.d., 5 μm) column maintained at 25°C with a mobile phase of a

mixture of ammonium phosphate dibasic buffer (pH adjusted to 6.0 using diluted

orthophosphoric acid; 50 mM)–acetonitrile (52:48, v/v). The mobile phase flow rate was 1.0

mL/min, and the detection wavelength was 250 nm. The stress sample solutions were assayed

against the qualified reference standard of voriconazole and the mass balance in each case was

close to 99.7%, confirming its stability-indication capacity. The developed HPLC method was

validated with respect to linearity, accuracy, precision, specificity, and robustness. The

developed HPLC method to determine the related substances and assay determination of

voriconazole can be used to evaluate the quality of regular production samples. It can be also

used to test the stability samples of voriconazole.25-28Important parameters found in the study

are given in table 5 and table 6.

Table 5. Recovery Results of Voriconazole Sample

Added(μg) (n = 3)* Recovered(μg % Recovery % RSD

25.3 25 98.8 0.9 50.6 50.8 100.4 0.6 7.5 74.8 99.5 0.7

* n = number of determinations

Table 6 Summary of Forced Degradation Results

Stress condition Time % Assay of active substance

% Mass balance(% assay + impurities)

Remarks

Acid hydrolysis(0.5N HCl)

48 h 87.9 99.7 Degraded to imp-A and imp-D

Base hydrolysis(0.5N NaOH)

48 h 0 99.8 Degraded to imp-A, imp-D, and other unknown degradants

Oxidation (3% H2O2)

48 h 91.9 99.6 Degraded to imp-D and other unknown degradants

Deoxidization (3.0% NaHSO3)

10 days 99.6 99.6 No degradation products formed

Water hydrolysis at 60°C

48 h 77.5 99.7 Degraded to imp-A and imp-D

UV (254 nm) 48 days 99.6 99.6 No degradation products formed

.



Gennethel J. Pennick et al. developed and validated a High-Performance Liquid

Chromatography Assay for Voriconazole.In this a analytical method for the determination of

voriconazole (UK-109,496; Pfizer) in plasma was developed and validated. The method utilizes

solid-phase extraction technology and high-performance liquid chromatography.The lower limit

of quantitation is 0.2 _g/ml, and the range of linearity tested was 0.2 to 10 _g/ml.

Important parameters found in the study are given in figure 5. 29-30

Figure 5 Representative chromatograms of VRC and the internal standard

Rafael Linden et al. developed Ultra-Performance Liquid Chromatographic Method for

Measurement of Voriconazole in Human Plasma and Oral Fluid. In this a simple, sensitive and

selective ultra-performance liquid chromatography method for the determination of

voriconazole in plasma and oral fluid was developed and validated. After a liquid-liquid

extraction with methyl-tert-butyl ether, the analyte and internal standard were separated on a

Hypersil Gold C18 column (2.1 × 100 mm, p.d. 1.9 μm), eluted with a mobile phase composed of

thietylammonium phosphate buffer and acetonitrile (70:30, v/v). Total run time was found to

be 4 min, total mobile phase consumption of 2.2 mL. Detection was performed with a

photodiode array detector with quantitation at 256 nm. Voriconazole concentrations in oral

fluid were on average 57.5% (± 5.3) of those measured in paired plasma samples.

Important parameters found in the study are given in figure 6.31-32



Figure 6

Michael Vogeser et al. quantified voriconazole in plasma by liquid chromatography-tandem

mass spectrometry.A convenient liquid chromatography-tandem mass spectrometry method

for the quantification of the triazole antifungal agent voriconazole in plasma samples is

described. Fenbuconazole is used as an internal standard. After protein precipitation,

automated solid-phase extraction is applied. Electrospray ionization in the positive mode is

used. The analytical run time is 4 min. The response was linear from 78 to 5000 mg/L. The total

coefficient of variation (ns16) was 12.6% for a low-concentration pool (143 mg/L), 4.7% for a

medium-concentration pool (419 mg/L), and 5.0% for a high-concentration pool (4304 mg/L).

The method is proposed for future investigations that should be performed to test the

hypothesis that therapeutic drug monitoring of voriconazole is clinically useful. Important

parameters found in the study are given in figure 7.



Figure 7 Representative chromatogram of voriconazole (350)126.6) and fenbuconazole

(337)125) used as the internal standard (concentration of voriconazole, 143 mg/L; the Y-axis

represents the relative intensity of the signal with respect to the base peak of the

chromatogram).33-37

Peter H Tang et al. quantified Antifungal Drug Voriconazole in Serum and Plasma by HPLC-

UV.In this a simple, sensitive and rapid high-performance liquid chromatographic (HPLC)

method for the determination of voriconazole in human serum or plasma was developed.

Voriconazole and internal standard clonazepam were extracted from plasma or serum with

methanol and analyzed on a Microsorb-MV C18 column with ultraviolet (UV) detection set at

wavelengths of 256 and 310 nm, respectively. The calibration curve was linear through the

range of 0.1-10 mg/L using a 0.1 mL sample volume. The within-run and between-run precisions

were all less than 6%. Accuracies ranged from 97 to 106%. Absolute recovery was 96.4 ± 1.3%

for voriconazole. The method has been applied to monitor voriconazole use in order to

ascertain clinical efficacy and minimize toxic effects.38-44

Reehana Shaik et al. developed an RP-HPLC method for quantitative estimation of voriconazole

for injection in pharmaceutical dosage forms In this a simple RP-HPLC method for the

determination of voriconazole in pharmaceutical dosage forms. Numerous HPLC conditions

were tested for determination of voriconazole. The best result was achieved by using inertsil

ods-2, c-18 (150×4.6mm) 5μm column and a mobile phase consisting of OPA: acetonitrile:

methanol(65:30:5 v/v/v), a flow rate of 2.0 ml/min with ultraviolet detection at 257nm. The

retention time of the drug was 6.438 min. The method produced liner responses in the

concentration range of 7 to 12 ppm of voriconazole. The method was found to be applicable for

determination of the drug in injection. Important parameters found in the study are given in

figure 8 and table7. 45-48



Figure 8 A model chromatogram of Voriconazole

Table 7: Method development conditions

S.No Mobile phase composition Type of column

Flow rate

Column temperature

Voriconazole retention time

Tailing factor

1 OPA buffer: acetonitraile: methanol(65:30:5)

kromosil 2.0ml ambient 6.472 1.54


Inertsil 1.6ml ambient 7.904 1.05






Inertsil 2.0ml 40oc 6.438 1.07

Mrinalini C. Damle et al. determined Voriconazole in Human Plasma by High Performance

Liquid Chromatography with Ultraviolet Detection.In this a simple, selective, and sensitive high

performance liquid chromatography method for the determination of voriconazole in human

plasma was developed. Fluconazole was used as an internal standard. The method utilizes

liquid-liquid extraction with n-hexane:ethyl acetate (3:1 v/v) as the sample preparation

technique. The samples were then analyzed on Neosphere C18 column with UV detection at

254 nm. The calibration curve was linear through the range of 0.2-12 μg/ml. The lower limit of

quantification was found to be 0.2 μg/ml. % R.S.D. was less than 3% for intra- and inter-day

precision. The mean recovery was found to be 93.09% for voriconazole. The method showed

acceptable values for accuracy, precision, recovery, sensitivity and stability. The method is well



suited for routine analysis of voriconazole in human plasma and can further be extended for

pharmacokinetic studies.49-58

Kabeer a. shaikh et al. validated Stability-Indicating Liquid Chromatographic Method for

determination of degradation Impurities and Diastereomers in Voriconazole Tablets.In this a

reversed-phase gradient liquid chromatographic method has been developed for the

quantitative determination of Voriconazole, along with its degradation and diastereomeric

impurities in tablet dosage form. Chromatographic separation has been achieved on an Inertsil

ODS 3V, 150 x 4.6 mm, 5 μm column. The mobile phase consisting of solvent A 0.05 molar (M)

potassium dihydrogen phosphate (pH 2.5 buffer) and solvent B (mixture of acetonitrile and

methanol in the ratio 90:10 (v/v)), was delivered at a flow rate of 1.2 mL min−1 with the

detection wavelength at 256 nm. Resolution of Voriconazole and all five potential impurities

was achieved at greater than 2.0 for all pairs of compounds. The drug was subjected to stress

conditions such as oxidative, acid and base hydrolysis, and thermal and photolytic degradation.

Voriconazole was found to degrade significantly under base hydrolysis stress conditions

compared to acid hydrolysis stress conditions. The degradation products were well-resolved

from the main peak and its impurities, thus proving the stability-indicating power of the

method. The stressed samples were assayed against a reference standard and the mass balance

was found to be close to 99.0%. The developed method was validated as per ICH guidelines

with respect to specificity, linearity, limit of detection, limit of quantification, accuracy,

precision, and robustness.58-60

CONCLUSION

It can be concluded from the entire review that HPLC is a versatile, reproducible

chromatographic technique for the estimation of drug products. It has wide applications in

different fields in term of quantitative and qualitative estimation of active molecules.

HPLC method development has taken place of voriconazole drug in different drug formulations

and there is huge potential for new methods to be developed .Research is a continuous process

and several regulatory agencies require the submission of analytical data and hence method

development gives an advantage for the analysis of drugs. Voriconazole is an antifungal drug. In

this article different HPLC methods of voriconazole are presented with different parameters

found after the research work ,the parameters analysed are accuracy, precision, LOD, LOQ,

system suitability, robustness parameters, if we compare these methods we came to the

conclusion that these is huge potential of developing a HPLC method for the drug voriconazole

in order to increase accuracy, system suitability and precision by overcoming the loopholes of

the present methods and lower limits of LOD and LOQ can be achieved by choosing suitable

mobile phase combinations and altering the flow rate and column parameters.



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