ORI GINAL RESEARCH

RP-HPLC method for the quantitative determinationof fexofenadine hydrochloride in coated tabletsand human serum

M. Saeed Arayne • Najma Sultana • Hina Shehnaz •

Amir Haider

Received: 26 May 2009 / Accepted: 4 December 2009

� Springer Science+Business Media, LLC 2009

Abstract Fexofenadine is a non-sedative and selective peripheral H1 receptor

antagonist prescribed for allergic rhinitis and chronic urticaria. This article deals

with a simple, feasible, and sensitive isocratic reverse-phase high-performance

liquid chromatographic method for the determination of fexofenadine hydrochloride

in bulk drug, pharmaceutical dosage forms and in human serum. The chromatog-

raphy was carried out at 20 ± 2�C using two different chromatographs and five

different stationary phases. The isocratic mobile phase was phosphate buffer pH 7.4

and methanol (methanol–phosphate buffer, 35:65, v/v), detection was made at

218 nm and the mobile phase flowed at 1 ml min-1. Validation parameters included

linearity, accuracy, precision, specificity, limit of detection (LOD), limit of quan-

tification (LOQ), and robustness over a linearity range 5–15 lg ml-1 according to

the ICH guidelines (r [ 0.9999), the inter- and intra-day precisions were relative

standard deviation (RSD) \ 0.8%. The system suitability was scrutinized by

capacity factor, tailing factor, and number of theoretical plates (capacity fac-

tor [ 2.0, tailing factor B 2.0, and theoretical plates [ 2000). The retention time

for five different stationary phases ranged from 3.78 to 4.15 min. The LOD and

LOQ for the procedure were executed on samples containing very low concentra-

tions of analytes on two different commercial brands of detectors.

Keywords Fexofenadine � Urticaria � High-performance liquid chromatography �Isocratic � Robustness � Five different stationary phases

M. S. Arayne � H. Shehnaz (&) � A. Haider

Department of Chemistry, University of Karachi, Karachi 75270, Pakistan

e-mail: hinashehnaz@gmail.com

N. Sultana

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi,

Karachi 75270, Pakistan

Med Chem Res

DOI 10.1007/s00044-009-9285-6

MEDICINALCHEMISTRYRESEARCH

Introduction

Fexofenadine, a,a-dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenyl-methyl)-1-pipe-

ridinyl]butyl]-benzene acetic acid (Fig. 1), is used to relieve the allergy symptoms

of seasonal allergic rhinitis (‘‘hay fever’’), including runny nose; sneezing; and red,

itchy, or watery eyes; or itching of the nose, throat, or roof of the mouth in adults

(Markham and Wagstaff, 1998; Simpson and Jarvis, 2000). It is carboxylic acid

metabolite of terfenadine, a non-sedating selective histamine H1 receptor antagonist

(Caballero et al., 1999). Unlike its precursor, fexofenadine lacks the cardiotoxic

potential, effective in the management of allergic rhinitis, and chronic idiopathic

urticaria for which it is a suitable option for first-line therapy (Inomata et al., 2009).

Fexofenadine is a substrate of P-glycoprotein, used to explore activity in vivo

because it is not metabolized in human body. Besides, no sedative or other central

nervous system effects were observed and radiolabeled tissue distribution studies in

rats indicated that fexofenadine does not cross the blood–brain barrier (British

Pharmacoepia, 2000; Barnes et al., 1993).

On pharmaceutical dosage forms, very few methods from quality control are

presented to determine fexofenadine in dosage form, in urine, serum, and

pharmaceutical formulations (Drescher et al., 2002; Mattila and Paakkari, 1999).

Three methods were presented for determination of fexofenadine in pure form and

its R(1) and S(-) enantiomers were analyzed in plasma and urine by validated

performance liquid chromatographic (HPLC) methods in commercial dosage forms

(Gazy et al., 2002). Another bioanalytical method was reported using solid phase

extraction and liquid chromatography with electrospray (Naidong et al., 2002).

Mass spectrometry (LC/MS/MS), RPLC, ionspray tandem mass spectrometry

detection (Gergov et al., 2001; Fu et al., 2004), and fluorescence detection (Uno

et al., 2004) are used in the pharmaceutical dosage form using ultraviolet

spectrophotometry (Pratt et al., 1999; Radhakrishna and Om Reddy, 2002; Milne

et al., 2000; Hamman et al., 2001; Russell et al., 1998; Pathak et al., 2008; Karakus

et al., 2008).

HPLC is the most widely used technique in pharmaceutical companies, clinical

laboratories, and research and development laboratories. Fexofenadine is the most

frequently prescribed H1 receptor antagonist manufactured by many pharmaceutical

companies world wide. The methods reported in the literature for the determination

of fexofenadine are time-consuming, difficult, and expensive making them

unpractical for everyday clinical trials. Also, there is no specific method for the

Fig. 1 Fexofenadine

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determination of only fexofenadine in pharmaceutical dosage forms as well as in

human serum. Therefore, there was a need for developing an HPLC method for the

determination of fexofenadine in reference drug material, pharmaceutical formula-

tions, and in human serum, which should have adequate sensitivity and short elution

time making it suitable as a regular method for pharmaceutical and clinical labs.

Various HPLC methods have been reported for the quantitation of H1-receptor

antagonists like cetirizine, buclizine, and levocetirizine in dosage formulations and

human serum (Sultana et al., 2009; Arayne et al., 2005; Arayne et al., 2008;

Gowekar et al., 2007). The aim of this study was to present the method which

should be rapid, selective, linear, precise and sensitive, and should be less time-

consuming (analysis time 3.78–4.15 min). The method presented in this article was

validated according to the ICH guidelines (ICH guidelines Topic Q2 (R1)

Validation of Analytical Procedures), and the low limit of quantification (LOQ)

and limit of detection (LOD) values make it a better choice for the estimation of

fexofenadine in human serum. This validated method was also applied on different

brands of fexofenadine available in Pakistan (60 mg tablets) which supports the

analysis of fexofenadine in bulk, in dosage formulations, and in human serum for

therapeutic purpose using HPLC.

Experimental

Reagents and chemicals

Fexofenadine hydrochloride reference substance (99.6%) was obtained from Aventis

Pharma (Pvt.) Limited, Pakistan. Monobasic potassium phosphate, potassium

hydroxide, HPLC, and analytical grade solvent (methanol) were purchased from

Merck (Germany), water for HPLC was prepared by double distillation and filtration

through Millipore 0.45 lm membrane filter (Millipore, Milford, MA, USA), and

degassed with Branson 3200 ultrasonic bath. Three commercial preparations, Fexet�

tablet (Getz Pharma Pakistan (Pvt.) Ltd., Fexofast� tablet (Platinum Pharmaceuticals

(Pvt.) Ltd., and Telfast� tablet (Sanofi Aventis Pharma (Pvt.) Ltd., Pakistan, all

containing 60 mg fexofenadine/tablet were assayed.

Chromatographic system and conditions

Two chromatographs were used (a) Shimadzu liquid chromatograph equipped

with a model LC-10AVP isocratic pump, and model SPD-10AVP UV detector.

Detection was made at 218 nm. CLASS-GC chromatography software. (b) The HPLC

Chromatograph Series 200 was produced by Perkin Elmer, USA, and equipped

with autosampler, pump, UV/VIS detector, Totalchrom Navigator Version 6.3.1.0504

software, interface 600 series LINK were used. Five different brands of station-

ary phase were used: (i) 250 9 4.6 i.d. mm KROMASIL� 100-5 C-18 column

(5 lm particle size) HICHROM (UK), (ii) 250 mm 9 4.6 mm i.d. 9 5 lm parti-

cle size GEMINI� C18 Phenomenex (USA), (iii) 250 mm 9 4.6 mm i.d. 9

5 lm particle size NUCLEOSIL� 100-5 C18 Macherey–Nagel (Germany),

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(iv) 250 mm 9 4.6 mm i.d. 9 5 lm Discovery� C18 SUPELCO (USA), (v)

250 mm 9 4.6 mm i.d. 9 5 lm HypersilTM ODS column Thermo Electron Corpo-

ration (UK). On both systems, mobile phase run isocratically, the mobile phase was

prepared by mixing methanol and 6.8 g monobasic potassium phosphate in 1000-ml

water and pH 7.4 (adjusted with potassium hydroxide), 35:65 (v/v), respectively. The

injection volume was 20 ll and the run time was 10 min. The mobile phase was

filtered using a 0.45-lm membrane filter (Millipore) and degassed with Branson 3200

ultrasonic bath. The mobile phase flow rate was 1.0 ml min-1. Injections were carried

out using a 20-ll loop at room temperature (20 ± 2�C).

Preparation of stock standard solution

A 10 mg amount of fexofenadine reference substance was accurately weighed,

dissolved in mobile phase, and diluted to volume in a 100-ml volumetric flask.

Standard solution was obtained by diluting the above solution with mobile phase to

a concentration of 10 lg ml-1.

Preparation of sample solutions

All the three commercially available brands of fexofenadine were analyzed

separately by preparing a composite of 20 tablets by grinding them to a fine,

uniform size powder, using mortar and pestle. After calculating the average tablet

weight, amount corresponding to 10 mg of fexofenadine was accurately weighed

and quantitatively transferred into a 100-ml volumetric flask. Approximately, 60 ml

mobile phase was added and the solution was shaken mechanically for 15 min, then

flask was made up to volume with mobile phase, and mixed. After filtration through

Millipore 0.45 lm membrane, the solution was diluted with mobile phase to a

concentration of 10 lg ml-1.

Extraction and storage of blood samples

Fresh blood samples from healthy volunteers were collected daily, centrifuged, and

separated, and then 10 ml of acetonitrile was added in 1.0 ml of plasma and

vortexes for 1 min, centrifuged for 10 min at 10,000 rpm. After that, supernatant

was filtered by 0.45-lm pore size membrane filter. An aliquot serum sample was

prepared with fexofenadine hydrochloride to achieve final concentration; the serum

was kept at -20�C until analyzed. Human plasma samples were spiked with

fexofenadine with mobile phase to 1–5 lg ml-1 final solution concentrations.

Result and discussion

Method validation

The method was validated according to the ICH guidelines (ICH guidelines

Topic Q2 (R1) Validation of Analytical Procedures). The following validation

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characteristics were addressed: linearity, accuracy, precision, and specificity, LOD,

LOQ, robustness, and their chromatograms are illustrated in Figs. 2, 3, 4, 5, 6, 7, 8,

9, and 10.

Fig. 2 Chromatogram of 10 lg ml-1 of fexofenadine reference standard

Fig. 3 Chromatogram of Fexet� tablet placebo

Fig. 4 Chromatogram of Fexet� tablet contains 10 lg ml-1 of fexofenadine

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Fig. 5 Chromatogram of Fexofast� tablet placebo

Fig. 6 Chromatogram of Fexofast� tablet contains 10 lg ml-1 of fexofenadine

Fig. 7 Chromatogram of Telfast� tablet placebo

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Fig. 8 Chromatogram of Telfast� tablet contains 10 lg ml-1 of fexofenadine

Fig. 9 Chromatogram of blank plasma sample from healthy volunteer

Fig. 10 Chromatogram of plasma sample spiked with 2.0 lg ml-1 of the fexofenadine

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System suitability

Having optimized the efficiency of a chromatographic separation, the quality of

chromatography was monitored by applying the following system suitability tests:

capacity factor, tailing factor, and of theoretical plates. The system suitability

method acceptance criteria set in each validation run were capacity factor [ 2.0,

tailing factor B 2.0, and theoretical plates [ 2000 (CDER: Center for Drug

Evaluation and Research, 1994). In all cases, the RSD for the analyte peak area

for two consecutive injections was \2.0%.

LOD and LOQ

The LOD and LOQ studies for the developed procedure were performed on samples

containing very low concentrations of analytes on two different commercial brands

of detectors according to the ICH guidelines as shown in Table 1. According to the

visual evaluation method, LOD was uttered by establishing the minimum level at

which the analyte can be reliably detected. LOQ was considered as the lowest

concentration of analytes in standards that can be reproducibly measured with

acceptable accuracy and precision.

Linearity

Standard curves were constructed daily, for three consecutive days, using five

standard concentrations in a range 5–15 lg ml-1 for fexofenadine. This concen-

tration range corresponds to 50–150% w/w levels of the nominal analytical

concentration (Table 2). The linearity of peak area responses versus concentrations

was demonstrated by linear least square regression analysis. The regression equation

and correlation coefficient (r) were y = 24340x ? 120 (y peak area, x concentra-

tion) and 0.9999, respectively.

Accuracy

The accuracy of the method was evaluated by determination of the recovery of

fexofenadine on 3 days at three levels of concentrations. Commercial preparation C

Telfast� tablet (60 mg) was spiked with fexofenadine standard solution, corre-

sponding to 50–150% of the nominal analytical concentration (10 lg ml-1). The

results showed good recoveries ranging from 98.77 to 101.45%. The mean recovery

data obtained for each level as well as for all levels combined (Table 2) were within

Table 1 LOD and LOQ on different brands of detectors

Shimadzu SPD-10AVP

UV detector (ng ml-1)

Perkin Elmer UV/VIS

detector Series 200 (ng ml-1)

LOD 20 10

LOQ 35 20

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2.0% of the label claim for the active substance with an RSD \ 2.0%, which

satisfied the acceptance criteria set for the study.

Precision

Precision of the method was determined by measuring the repeatability (intra-day

precision) and intermediate precision (inter-day precision), both expressed as

%RSD. The repeatability was evaluated by assay of six samples from each

pharmaceutical commercial preparation (Table 3), at the same concentration

(10 lg ml-1), on the same day. The intermediate precision was calculated from

the results obtained on three different days.

Specificity

Fexet� tablet contains 60 mg of the drug and the following excipients: pregela-

tinized starch, lactose, croscarmellose sodium, and microcrystalline cellulose.

Fexofast� tablet contains 60 mg of the drug and the following excipients: lactose,

croscarmellose sodium, and microcrystalline cellulose. Telfast� tablet contains

Table 2 Accuracy and linearity of method determined by recovery of fexofenadine from tablets

solutions spiked with standard solution

5 lg ml-1

50%

7.5 lg ml-1

75%

10 lg ml-1

100%

12.5 lg ml-1

125%

15 lg ml-1

150%

Day 1 99.98 98.77 100.21 101.45 99.88

Day 2 99.96 98.88 100.08 100.33 100.60

Day 3 100.24 98.78 100.78 100.44 99.96

Mean (n = 3) 100.06 99.14 100.36 100.74 100.15

%RSD 0.15 0.54 0.37 0.67 0.39

Total mean

(n = 15)

100.022

%RSD 0.743

Telfast� tablet 60 mg (Sanofi Aventis Pharma (Pvt) Ltd.) were spiked with fexofenadine standard

solution, corresponding to 50–150% of the nominal analytical concentration (10 lg ml-1)

Table 3 Intra-day (n = 6) and inter-day (n = 18) precision results from each commercial preparation

tablets assay on three consecutive days

Day Fexet� tablet (60 mg) Fexofast� tablet (60 mg) Telfast� tablet (60 mg)

Intra-day Inter-day Intra-day Inter-day Intra-day Inter-day

Mean %RSD Mean %RSD Mean %RSD Mean %RSD Mean %RSD Mean %RSD

1 99.94 0.49 99.96 0.45 99.91 0.65 99.71 0.66 99.89 0.52 99.81 0.77

2 99.97 0.44 99.93 0.56 99.82 0.55

3 99.87 0.24 99.89 0.22 99.80 0.67

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60 mg of the drug and the following excipients: lactose, croscarmellose sodium, and

microcrystalline cellulose. Specificity was evaluated by preparing placebo samples

of each placebo of the commercial formulation of tablets containing the same

excipients and specificity was performed by preparing placebo tablets of the

commercial products. The solutions were prepared using the same procedure

described for the sample solutions and injected thrice (Table 3) and the charac-

teristic chromatograms are shown in Figs. 2–8.

Robustness

International variations in liquid chromatographic conditions were used to evaluate

the robustness of the assay method. In this study, the chromatographic parameters

monitored were retention time, area, capacity factor, tailing factor, and theoretical

plates. The robustness acceptance criteria set in the validation was the same

established on system suitability test described earlier.

Different brand of chromatographic columns

Three injections of Telfast� tablet (Sanofi Aventis Pharma (Pvt.) Ltd., containing

60 mg fexofenadine/tablet) solutions having a concentration of 10 lg ml-1 were

injected on each brand of column to evaluate robustness (Table 4).

Different instruments

Three injections of each commercial preparation were injected on two different

brands of liquid chromatograph by two different analysts data established in

Table 5.

Different personnel

Variation in results due to different analyst’s data is established by taking the %RSD

of recovered % as shown in Table 5, which is found 0.28 and 0.45 for analysts A

and B, respectively.

Table 4 Chromatographic parameters of robustness evaluation

Different columns brands

(n = 3)

Retention

time

Peak

area

Capacity

factor

Resolutiona Tailing

factor

Theoretical

plates

HICHROM KROMASIL� 3.78 242798 3.15 3.12 1.21 2366

Phenomenex GEMINI� 3.80 243375 1.68 3.48 1.08 3365

Macherey–Nagel

NUCLEOSIL�4.15 241624 2.39 3.54 1.02 3687

SUPELCO Discovery� 4.12 239963 2.17 3.02 1.34 2489

Thermo Electron Corporation

HypersilTM3.98 241840 2.36 3.21 1.22 2562

a In relation to the nearest peak

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Recovery and regression characteristics of fexofenadine, in human serum

Different concentrations of human plasma samples (1–5 lg ml-1) were linear,

accurate, precise, and selective by running three replicates of each concentration

measured for 5 days; typical chromatogram for the concentration of 2 lg ml-1 is

shown in Fig. 10. The mean recoveries, coefficient of variation, LOD, and

quantification values are summarized in Table 6.

Conclusions

The LOD and LOQ were carried out on two different commercial brands of detectors

according to the ICH guidelines. The intra- and inter-day precision studies showed

good reproducibility with coefficients of variation \0.77%. The ruggedness of the

method was determined by carrying out the experiment on different instruments like

Shimadzu HPLC (LC-10), Perkin Elmer Series 200 HPLC by different operators

using different columns. Robustness of the method was determined by making slight

changes in the chromatographic conditions. No marked changes in the chromato-

grams were observed.

Thus, the proposed RP-HPLC method for the estimation of fexofenadine in

dosage forms is accurate, precise, linear, rugged, robust, simple, and rapid. Hence,

Table 5 Different instrument and different personnel variation

Commercial

preparation

(n = 3)

Shimadzu liquid chromatograph Perkin Elmer Series 200 liquid

chromatograph

%

Difference

in

instrumentsAnalyst ‘‘A’’ Analyst ‘‘B’’

Found ± (mg) %RSD %Recovery Found ± (mg) %RSD %Recovery

Fexet� 59.79 ± 1.1245 1.12 99.65 60.10 ± 1.0132 1.01 100.16 0.51

Fexofast� 59.89 ± 1.0325 1.03 99.81 59.60 ± 1.2261 1.22 99.33 0.48

Telfast� 60.12 ± 1.0576 1.05 100.20 60.05 ± 1.0463 1.04 100.08 0.12

Table 6 Recovery of fexofenadine from human serum (n = 3)

S. no Concentration

(lg ml-1)

Mean

(lg ml-1)

(%) Recovery Relative

error (%)

CV (%)

1 1 0.995 99.5 0.5 0.9

2 2 2.0 100 -0.15 1.21

3 3 3.009 100.3 -0.3 0.8

4 4 3.998 99.95 0.05 0.68

5 5 5.085 101.7 -1.7 0.16

Correlation coefficient (r2) 0.9997

LOD 0.03

LOQ 0.1

Med Chem Res

the RP-HPLC method is suitable for the quality control and routine testing of the

raw materials, different dosage forms, different formulations, and in human serum.

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