Development and Validation of Spectrophotometric Determination of Cefpodoxime Proxetil in Pure Form and Pharmaceutical Formulation through Ion-Pair Complex Formation Using Bromocresol Purple


Abdul Aziz Ramadan1*, Hasna Mandil, Rasha Shamseh

Department of Chemistry, Faculty of Science, University of Aleppo, Syria

*Corresponding Author E-mail:  dramadan@scs-net.org

 

ABSTRACT:

A simple, direct and accurate spectrophotometric method has been developed for the determination of cefpodoxime proxetil (CEFP) in pure form and pharmaceutical formulations by complex formation with bromocresol purple (BCP). The method involves the formation of yellow ion-pair complexes between BCP reagent and CEFP in chloroform. The two formed complexes ([CEFP]: [BCP] and [CEFP]: [BCP]2) have maximum absorption at λmax 414 nm. The proposed method was validated for specificity, linearity, precision and accuracy, repeatability, sensitivity (LOD and LOQ), robustness and solution stability with an average recovery of 99.2-101.0%.The formed complexes ([CEFP]:[BCP] and [CEFP]:[BCP]2) were measured against the reagent blank prepared in the same manner. Variables were studied in order to optimize the reaction conditions. Molar absorptivity (ε) for two complexes were 10500 and 15700 L.mol-1.cm-1, respectively. Beer’s law was obeyed in the concentration range of 0.5576-5.576 and 5.576-55.760 μg/ml in the present of 2x10-4 and 1x10-3 mol/l of BCP, respectively, with good correlation coefficient (R2= 0.9988 and R2= 0.9995, respectively). The relative standard deviation did not exceed 4.4%. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.083 and 0.25 μg/ml, respectively. The developed method is applicable for the determination of CEFP in pure and different dosage forms with the average assay of marketed formulations 91.6 to 106.2%, and the results are in good agreement with those obtained by the RP-HPLC reference method.

 

KEYWORDS: Direct spectrophotometric method, Cefpodoxime proxetil, Bromocresol purple, Ion-pair complex.

 

 

 

INTRODUCTION:

Scheme 1: Chemical structure of cefpodoxime proxetil (CEFP).

 

Cefpodoxime Proxetil (CEFP) is a third generation cephalosporin antibiotic indicated for the treatment of patients infected with susceptible strains of microorganisms which include a wide range of gram-positive and gram-negative bacteria. It is commonly used to treat acute otitis media, pharyngitis, and sinusitis. The molecular formula of CEFP is C21H27N5O9S2 and the molecular weight is 557.6 g/mol. It is freely soluble in dehydrated alcohol, acetonitrile, methanol and very slightly soluble in water 1-3, see Scheme 1.

 

Scheme 2: Chemical structure of Bromocresol purple (C21H16Br2O5S).

Bromocresol purple C21H16Br2O5S (BCP), acts as a weak acid in solution. It can thus be in protonated or deprotonated form, appearing yellow or purple, respectively, mol. mass 540.22 g4, see scheme 2. Bromocresol purple has been used as a reagent to form ion pair complexes with drugs as gatifloxacin5.

 

A simple, sensitive, accurate and rapid UV-Vis spectrophotometric methods have been developed for the estimation of cefpodoxime proxetil in bulk drug and in pharmaceutical dosage form, which shows maximum absorbance at 415 and 425 nm for ion-pair complexes between cefpodoxime proxetil with BCP and bromocresol green, receptively, by extraction it in chloroform6.

 

Various spectrophotometric methods 6-24 have been reported for the determination of cefpodoxime proxetil in pure as well as in dosage forms. Most spectrophotometric methods employ extraction procedures. The complex extraction technique has some difficulties and inaccuracies due to incomplete extraction or the formation of emulsions between the hydrocarbon solvent and the basic compound-containing solution. In response to the problems resulting from the extraction of the complex, it is better to determine formed complex without extraction 25. Also, none of the direct methods reported in the literature are based on the formation of a complex between BCP and CEFP.

 

Several analytical methods for the determination of cefpodoxime proxetil have been reported including high-performance liquid chromatography (HPLC)26-30 and electrochemical methods31-33.

 

In this study, a extraction-free spectrophotometric method for determination of CEFP through ion-pair complex formation with BCP was developed.

 

MATERIALS AND METHODS:

Instruments and apparatus:

Spectrophotometric measurements were made in Spectro scan 80 DV UV-VIS spectrophotometry with 1 cm quartz cells. An ultrasonic processor model Powersonic 405 was used to sonicate the sample solutions. The diluter pipette model DIP-1 (Shimadzu), having 100 μl sample syringe and five continuously adjustable pipettes covering a volume range from 10 to 5000 μl (model Piptman P, GILSON). Centrifuge (Centurion Scientific Ltd., Model: K2080-Manufactured in the United Kingdom) was used for the preparation of the experimental solutions. SARTORIUS TE64 electronic balance was used for weighing the samples.

 

Reagents:

Cefpodoxime proxetil (96.138%) was supplied by Virchow group company (INDIA), its purity as cefpodoxime was (73.7%), (Mfg. 07/2015, Exp. 07/2018). Bromocresol purple (99%) of analytical grade and chloroform of extra pure were from MERCK. All solvents and reagents were analytical grade chemicals.

 

Stock standard solution of bromocresol purple (BCP) 1x10-2 mol/l:

Accurately weighed 136.42 mg of BCP was dissolved in chloroform into a volumetric flask (25 ml) and diluted up to mark with chloroform.

 

Stock standard solution of CEFP 1x10-3 mol/l:

This solution was prepared by dissolving 14.50 mg of CEFP in chloroform into a volumetric flask (25 ml) and diluted up to mark with chloroform.

 

Working standard solutions of CEFP:

The stock solution was further diluted daily just before the use to obtain working solutions of CEFP in the concentrations: 1.0, 2.0, 4.0, 6.0, 8.0, 10, 20, 40, 60, 80 and 100 μM (0.5576, 1.1152, 2.2304, 3.3456, 4.4608, 5.576, 11.152, 22.304, 33.456, 44.608 and 55.760 μg/ml of CEFP or 0.4275,  0.8549, 1.7098, 2.5647, 3.4197, 4.2746,  8.5492, 17.0983, 25.6475, 34.1966, and 42.7458 of CEF) by transferring different aliquots from stock standard solution: 10, 20, 40, 60, 80, 100, 200, 400, 600, 800 and 1000 μl into 10 ml volumetric flasks, then 0.20 and 1.00 ml from stock standard solution of BCP (1x10-2 mol/l) for concentrations 1.0–10.0 and 10.0-100.0 μM, respectively, were added, and diluted to 10 ml with chloroform.

 

Sample preparation:

Commercial formulations (as a tablet) were used for the analysis of CEFP. The pharmaceutical formulations subjected to the analytical procedure were:

(1) Oracef tablets, El-Saad pharma, Aleppo–SYRIA, each tablet contains 100 and 200 mg of cefpodoxime (CEF) (Mfg. 12/2013, Exp. 12/2017 and Mfg. 09/2014, Exp. 09/2018, respectively).

(2) Oraxime tablets, Asia pharmaceutical industries, Aleppo–SYRIA, each tablet contains 100 and 200 mg of CEF (Mfg. 12/2013, Exp. 12/2016 and Mfg. 11/2014, Exp. 11/2017, respectively).

(3) Oraluxe tablets, ALPHA. Aleppo pharmaceutical industries, Aleppo-SYRIA, each tablet contains 100 and 200 mg of CEF (Mfg. 01/2015, Exp. 01/2018 for two pharmaceuticals).

 

Stock solutions of pharmaceutical formulations:

20 tablets of each studied pharmaceutical formulation were weighed accurately, crushed to a fine powder and mixed well. An amount of the powder equivalent to the weight of one tablet was solved in chloroform using ultrasonic for 10 min, 20 ml of chloroform was added, filtered over a 25 ml flask and washed by the same solvent, then diluted to 25 ml with chloroform. This solution contains the follows: 4 and 8 mg/ml of CEF for all studied pharmaceutical formulations contain 100 and 200 mg/tab, respectively.

 

Working solutions of pharmaceuticals:

Five solutions were prepared daily by diluting 50 and 25 μl from a stock solution of pharmaceutical formulations for contents: 100 and 200 mg/tab, respectively. Then adding 1 ml from a stock standard solution of BCP and adjusting the volume up to 10 ml with chloroform (these solutions contain 20 μg/ml of CEF (26.09 μg/ml of CEFP); test solutions).

 

Procedure:

A solution (10 ml) containing an appropriate concentration of CEFP (or working solutions of pharmaceuticals) with appropriate amount of BCP in chloroform was ready for spectrophotometric measurement at λmax 414 nm.

 

RESULTS AND DISCUSSION:

The different experimental parameters affecting the spectrophotometric determination of CEFP through ion-pair complex ([CEFP]:[BCP]2) formation with BCP in chloroform were studied for determining the optimal conditions.

 

Spectrophotometric results:

UV-Vis spectra of CEFP, BCP and the formed complexes CEFP: BCP solutions (using pure chloroform or 2x10-4M and 1x10-3M of BCP in chloroform as blank) were obtained. CEFP solutions do not absorb in the range 360-600 nm. BCP solutions have small absorption at λmax 410 nm, molar absorptivity (ε)=470 L. mol-1. cm-1. [CEFP]: [BCP] and [CEFP]:[BCP]2 complexes solutions have maximum absorption at λmax 414 nm, (ε for two complexes were 10500 and 15700 L. mol-1. cm-1, respectively), see fig. 1.

 

The effect of time and temperature:

The effect of time and temperature on the complex ([CEFP]:[BCP]2) formation was studied within the ranges 5-120 min and 15-25oC. It was found that the formed complex wasn't affected by time or temperature at those ranges.

 

The effect of BCP concentration:

The effect of BCP concentration on complex ([CEFP]:[BCP]2) formation was investigated. It was observed that the absorbance of the formed complex increased coinciding with increasing the ratio of CBCP: CCEFP until the ratio (2:1), then slowly increased until the absorbance became a quasi-static at ratio more than 10.

 

Composition of CEFP: BCP complexes:

 

Fig. 1: UV-Vis spectra in chloroform of : 1-1.0x10-4 mol/l of CEFP; 2-1.0x10-4 mol/l of BCP; 3-1.0x10-4 mol/l ion-pair complex [CEFP]:[BCP] (1.0x10-4 mol/l of BCP with 4.0x10-4 mol/l of CEFP); 4 and 5-1.0x10-4 mol/l ion-pair complex [CEFP]:[BCP]2 (1.0x10-4 mol/l of CEFP with 1.0x10-3 mol/l of BCP); 1-4: Blank is chloroform; 5-Blank is 1.0x10-3 mol/l of BCP, ℓ =1 cm.

 

The composition of CEFP:BCP complexes were determined by the molar ratio method and Job's method of continuous variation.

 

Molar ratio method:

The stoichiometry of CEFP: BCP complexes were studied by molar ratio method according to following equation: Amax= f([BCP]/[CEFP]) at λmax 414 nm. It confirmed that the binding ratio of CEFP: BCP complexes are equal to (1:1 and 1:2); where the concentration of CEFP was constant (100 μM) and the concentrations of BCP changed from 0 to 400 μM (fig. 2). The formation constant of the ion pair complexes [CEFP]:[BCP] and [CEFP]:[BCP]2 are 2.23x105 and 2.71x106, respectively.

 

Fig. 2: Molar ratio method to calculate binding ratio of CEFP: BCP complexes at λmax=414 nm ([CEFP]= 100 μM, blank is chloroform, ℓ =1 cm).

 

Job’s method of continuous variation:

Continuous variation was utilized to check the composition of CEFP: BCP complexes at λmax 414 nm. The absorbance of the complexes were plotted against the mole fraction [BCP]/([CEFP]+[BCP]), where [CEFP]+[BCP]=200 μM. The plot reached maximum values at a mole fraction of 0.5 and 0.67, see fig. 3. This indicated complexes formation (CEFP: BCP) in the ratio of (1:1 and 1:2). The formation constant of the ion-pair complexes [CEFP]:[BCP] and [CEFP]:[BCP]2 are 2.25x105 and 2.76x106, respectively.

 

The optimum conditions for spectrophotometric determination of CEFP through ion-pair complex formation using BCP in chloroform are shown in table 1.

 

Fig. 3: Job's method of continuous variation to calculate binding ratio of CEFP: BCP complexes at λmax 414 nm ([CEFP]+[BCP]=200 μM, blank is chloroform, ℓ =1 cm).

 

Table 1: The optimum conditions for spectrophotometric determination of CEFP by complexes formation with BCP in chloroform.

Parameters

Operating modes

Temperature of solution

20±5oC

CBCP: CCEFP, M

≥10

Solvent

chloroform

Stability

2 h

λmax of CEFP: BCP complexes

414 nm

Light path (ℓ)

1.0 cm

Spectra range

300–600 nm

Mechanism of reaction:

Anionic dyes such as BCP form ion-pair complexes with the positively charged nitrogen-containing molecule. The colour of such dyes is due to the opening of lactoid ring and subsequent formation of the quinoid group (deprotonated). CEFP is protonated and forms yellow ion-pair complexes [CEFP]:[BCP] and [CEFP]:[BCP]2 with the dye. Each drug-dye complex with two oppositely charged ions (positive on the drug and negative on the dye) behaves as a single unit held together by an electrostatic binding. The suggested mechanism of CEFP: BCP ion-pair complexes formation are shown in Scheme 3.

 

Calibration curve:

The calibration curve of CEFP in pure form through complexation with BCP showed excellent linearity over the concentration range of 1.0-10.0 μM  and 1.0-100.0 μM (or 0.5576–5.576 μg/ml and 0.5576-55.760 μg/ml), see fig. 4  and  5. Regression equations at λmax 414 nm were as the follows:

y=0.0156x+0.0015; R2=0.9995 (or y=0.0279x+0.0009; R2=0.9995)   (I)

y=0.0158x+0.0039; R2=0.9988 (or y=0.0282x+0.0023; R2=0.9988) (II)

 

The spectra characteristics of the method such as the molar absorptivity (ε), Beer's law, regression equation at λmax 414 nm (y=a.x+b); where y=absorbance, a=slope, x=concentration of CEFP in μM or μg/ml,b=intercept, the correlation coefficient, limit of detection (LOD) and limit of quantification (LOQ) are summarized in table 2.

 

Analytical results:

Spectrophotometric determination of CEFP through complexation with BCP in chloroform within optimal conditions using calibration curve was applied. The results, summarized in table 3, showed that the determined concentration of CEFP was rectilinear over the range of 1.0 to 100.0 μM or 0.5576 to 55.760 μg/ml with relative standard deviation (RSD) not more than 4.4%. The results obtained from the developed method have been compared with the official RP-HPLC method 26 and good agreement was observed between them (table 3).

 

 

 

Scheme 3: Mechanism of [CEFP]:[BCP] and [CEFP]:[BCP]2 complexes formation.

 

Fig. 4: Spectra of [CEFP]:[BCP]2 complex in present 1.0×10-3 M of BCP; where CCEFP as the follows: 0.5576, 1.1152, 2.2304, 3.3456, 4.4608, 5.576, 11.152, 22.304, 33.456, 44.608 and 55.760 μg/ml for curves (1-11) {Blank is BCP solution in chloroform 2x10-4  and 1x10-3M for curves (1-6 and 1-11, respectively); ℓ = 1 cm}.

 

Fig. 5: Calibration curve for determination of CEFP according to optimal conditions at λmax 414 nm (in present of 1×10-3 M of BCP) where CCEFP: 0.5576 - 55.760 μg/ml (a) and (in present of 2×10-4 M of BCP) where CCEFP: 0.5576 – 5.576 μg/ml (b)  {Blank is BCP solution in chloroform 1x10-3 M (a) and 2x10-4M (b); ℓ = 1 cm}.

 

Table 2: The parameters established for spectrophotometric determination of CEFP by complex formation with BCP in chloroform

Parameters

Operating values

Molar absorptivity of [CEFP]:[BCP] complex (ε1 ), L. mol-1. cm-1

10500

Molar absorptivity of [CEFP]:[BCP]2 complex (ε2 ), L. mol-1. cm-1

15700

Regression equation for [CEFP]:[BCP]2 at λmax =414 nm (CCEFP= 1.0-10.0 μM):

 

Slope

0.0158

Intercept

0.0039

Correlation coefficient (R2)

0.9988

Regression equation for [CEFP]:[BCP]2 at λmax =414 nm (CCEFP= 1.0-100.0 μM):

 

Slope

0.0156

Intercept

0.0015

Correlation coefficient (R2)

0.9995

Regression equation for [CEFP]:[BCP]2 at λmax =414 nm (CCEFP= 0.5576-55.760 μg/ml):

 

Slope

0.0279

Intercept

0.0009

Correlation coefficient (R2)

0.9995

Beer’s Law Limit, for CCEFP by μM

1-100

Beer’s Law Limit, for CCEFP by μg/ml

0.5576-55.760

RSD%

4.4

LOD(3.3SD), for CCEFP by μg/ml

0.083

LOQ (10SD), for CCEFP by μg/ml

0.25

n=5, t=2.776.

 

Table 3: Spectrophotometric determination of CEFP through complex formation with BCP within optimal conditions using calibration curve in chloroform

Xi,

μg/ml (Taken)

* ±SD,

μg/ml (mean±SD)

mg/ml

mg/ml

RSD %

*, mg/ml

RP-HPLC 26

0.5576

0.577± 0.025

0.011

0.577± 0.031

4.4

0.559

1.1152

1.258± 0.050

0.023

1.258± 0.062

4.0

1.120

2.2304

2.369± 0.088

0.039

2.369± 0.109

3.7

2.210

3.3456

3.516± 0.120

0.053

3.516± 0.148

3.4

3.314

4.4608

4.412± 0.132

0.059

4.412± 0.164

3.0

4.600

5.576

5.774± 0.173

0.077

5.774± 0.215

3.0

5.592

11.152

11.258± 0.326 

0.146

11.258± 0.405 

2.9

11.182

22.304

21.473± 0.601

0.269

21.473± 0.746

2.8

22.310

33.456

33.301± 0.866

0.387

33.301± 1.075

2.6

33.415

44.608

45.129± 1.128

0.505

45.129± 1.400

2.5

44.620

55.760

55.882± 1.341

0.600

55.882± 1.665

2.4

55.695

* n=5, t= 2.776

 

 

 

METHOD VALIDATION:

The developed method for estimation of CEFP has been validated in accordance with the International Conference on Harmonization guidelines (ICH) 34. The proposed method has been validated for determination of CEF in tablet dosage form. Calibration curves were constructed and the regression equations were calculated. The calibration curves were plotted over the concentration range 0.5576-55.760 μg/ml for CEFP. Accurately measured working standard solutions of CEFP (0.5576, 1.1152, 2.2304, 3.3456, 4.4608, 5.576, 11.152, 22.304, 33.456, 44.608 and 55.760 μg/ml) were analysed under the operating conditions. 

 

Specificity:

Specificity test determines the effect of excipients on the assay result. To determine the specificity of the method, standard solution of CEFP, commercial product solution and blank solutions were analyzed. The results of the tests proved that the components other than the drug did not produce any interfere. The standard  spectra no interference from excipients present in the formulation indicate specific of the method.

 

Linearity:

Several aliquots of a standard stock solution of CEFP were taken in different 10 ml volumetric flask and diluted up to the mark with chloroform such that their final concentrations were 0.5576-55.760 μg/ml for CEFP. Absorbance was plotted against the corresponding concentrations to obtain the calibration graph, see fig. 5. Linearity equations obtained were y = 0.0279x+0.0009 for the range 0.5576-55.760 μg/ml (R2=0.9995) .

 

Precision and accuracy:

The precision and accuracy of proposed method were checked by recovery study by addition of standard drug solution to pre-analyzed sample solution at three different concentration levels (80%, 100% and 120%) within the range of linearity for CEFP. The basic concentration level of sample solution selected for spiking of the CEFP standard solution was 11.152 μg/ml. The proposed method was validated statistically and through recovery studies and was successfully applied for the determination of CEFP in pure and dosage forms with average percent recoveries ranged from 99.2% to 101.0%, see table 4.

 

Table 4: Results of recovery studies

Level

% Recovery

80% (n=5)

99.2

100% (n=5)

100.8

120% (n=5)

101.0

 

The results of recovery studies indicate that the proposed method is highly accurate. The results obtained for CEFP were comparable with the corresponding labeled amounts. No interference of the excipients with the absorbance of interest appeared; hence, the proposed method is applicable for the routine simultaneous estimation of CEFP in pharmaceutical dosage forms.

 

Repeatability:

The repeatability was evaluated by performing 10 repeat measurements for 11.152 μg/ml of CEFP using the studied spectrophotometric method under the optimum conditions. The found amount of CEFP (±SD) was 11.181±0.33 μg/ml and the percentage recovery was found to be 100.9±2.9 with RSD of 0.029. These values indicate that the proposed method has high repeatability for CEFP analysis.

 

Sensitivity (limit of detection [LOD] and limit of quantitation [LOQ]):

The sensitivity of the method was evaluated by determining the LOD and LOQ. The values of LOD and LOQ for CEFP are 0.083 and 0.25 μg/ml, respectively.

 

Robustness:

The robustness of the method adopted is demonstrated by the constancy of the absorbance with the deliberated minor change in the experimental parameters such as the change in the concentration of excipients, BCP (±5%), temperature (±5oC) and reaction time (30 min).

 

Solution stability:

The difference in the initial value of percentage assay and the values obtained at 5, 15,  30, 60, 90 and 120 min (in 15-25oC) of percentage assay should not be more than 2.4%. The assay obtained at different time intervals were compared with the initial assay values. Solution stability period for sample solution and standard solution was determined. Standard and sample solutions were stable till 120 min. Solution stability period for standard preparation and sample preparation were found to be within the acceptance criteria.

 

Applications:

The developed spectrophotometric method was applied to determine CEFP in some pharmaceutical preparations through complex formation by BCP in chloroform according to the optimal conditions. The amount (m) of CEFP in one tablet was calculated from the following relationship: m = h. m', where: m' is the amount of CEFP in tablet calculated according to the regression equation (II), h conversion factor is equal to 2.5 and 5.0 for pharmaceutical formulations contain 100 and 200 mg/tab, respectively. The results of quantitative analysis for CEFP in pharmaceutical preparations were summarized in Tables 5.

 

 

 

 

 

Table 5: Determination of CEFP, as cefpodoxime (CEF), in some Syrian pharmaceutical preparations using spectrophotometric method through complex formation with BCP in chloroform, λmax 414 nm

* (Assay%), by RP-HPLC 26

Assay%

RSD%

*mean±SD (as CEF),

mg/tab.

Label claim

of CEFP as CEF, mg/tab.

Tablet dosage form

105.8

106.2

2.4

106.2±2.55

100

Oracef

91.9

91.6

2.5

183.2±4.58

200

102.1

102.4

2.4

102.4±2.46

100

Oraxime

101.9

101.9

2.2

203.8±4.48

200

93.7

93.5

2.3

93.5±2.15

100

Oraluxe

102.4

102.5

2.2

205.0±4.51

200

* n=5,  Assay=(found mean/label claim)x100.

 

 

The proposed method was simple, direct, specific and successfully applied to the determination of CEFP in pharmaceuticals without any interference from excipients. Average assay of marketed formulations ranged between 91.6 to 106.2%. The results obtained by this method agree well with the contents stated on the labels and were validated by RP-HPLC method 26.

 

CONCLUSION:

The developed spectrophotometric method is simple, direct (extraction-free) and cost-effective for the determination of CEFP in pure and tablet dosage forms. This method is based on formation of two ion-pair complexes between CEFP and BCP in chloroform ([CEFP]:[BCP] and [CEFP]:[BCP]2). Beer’s law in the optimum experimental conditions using [CEFP]:[BCP]2 complexes is valid within a concentration range of 0.5576-55.760 μg/ml. The developed method is applied for the determination of CEFP in pure and its commercial tablets without any interference from excipients with the average assay of marketed formulations between 91.6 to 106.2%.This method was validated for specificity, linearity, precision and accuracy, repeatability, sensitivity (LOD and LOQ), robustness and solution stability with an average recovery of 99.2-101.0%. No interference of the excipients; hence, the proposed method is applicable for the routine estimation of CEFP in pharmaceutical dosage forms.

 

CONFLICT OF INTERESTS:

The authors have declared that no conflict of interests exists.

 

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Received on 03.01.2017             Modified on 30.01.2017

Accepted on 22.02.2017           © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(3): 843-851.

DOI: 10.5958/0974-360X.2017.00158.5