rp-hplc method for the quantitative determination of fexofenidine hcl in coated tablets and human
TRANSCRIPT
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O R I G I N A L R E S E A R C H
RP-HPLC method for the quantitative determination
of 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 2C using two different chromatographs and five
different stationary phases. The isocratic mobile phase was phosphate buffer pH 7.4and methanol (methanolphosphate 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 515 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 andLOQ 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. HaiderDepartment of Chemistry, University of Karachi, Karachi 75270, Pakistan
e-mail: [email protected]
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
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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 inrats indicated that fexofenadine does not cross the bloodbrain 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 phaseextraction 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; Pathaket 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 3.784.15 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 offexofenadine 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 MachereyNagel (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. Theinjection 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 2C).
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 weighedand 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 -20C until analyzed. Human plasma samples were spiked with
fexofenadine with mobile phase to 15 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 suitabilitymethod 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 brandsof 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 fivestandard concentrations in a range 515 lg ml-1 for fexofenadine. This concen-
tration range corresponds to 50150% 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 50150% 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 standardsolution, corresponding to 50150% 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 proceduredescribed for the sample solutions and injected thrice (Table 3) and the charac-
teristic chromatograms are shown in Figs. 28.
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 sameestablished 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 analysts 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
MachereyNagel
NUCLEOSIL4.15 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 (15 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 Relativeerror (%) 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
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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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