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 Table of Contents  
RESEARCH ARTICLE
Year : 2013  |  Volume : 5  |  Issue : 3  |  Page : 184-190  

Stability-indicating assay of repaglinide in bulk and optimized nanoemulsion by validated high performance thin layer chromatography technique


1 Department of Pharmaceutics, Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, India
2 Department of Pharmacy, King Khalid University, Abha, Saudi Arabia
3 Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India

Date of Submission17-Aug-2012
Date of Decision20-Oct-2012
Date of Acceptance11-Dec-2012
Date of Web Publication23-Aug-2013

Correspondence Address:
Mohd Aqil
Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.116800

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   Abstract 

A sensitive, selective, precise and stability-indicating high-performance thin-layer chromatographic (HPTLC) method for analysis of repaglinide both as a bulk drug and in nanoemulsion formulation was developed and validated. The method employed TLC aluminum plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform/methanol/ammonia/glacial acetic acid (7.5:1.5:0.9:0.1, v/v/v/v). This system was found to give compact spots for repaglinide (R f value of 0.38 ± 0.02). Repaglinide was subjected to acid and alkali hydrolysis, oxidation, photodegradation and dry heat treatment. Also, the degraded products were well separated from the pure drug. Densitometric analysis of repaglinide was carried out in the absorbance mode at 240 nm. The linear regression data for the calibration plots showed good linear relationship with r 2 = 0.998 ± 0.032 in the concentration range of 50-800 ng. The method was validated for precision, accuracy as recovery, robustness and specificity. The limits of detection and quantitation were 0.023 and 0.069 ng per spot, respectively. The drug undergoes degradation under acidic and basic conditions, oxidation and dry heat treatment. All the peaks of the degraded product were resolved from the standard drug with significantly different R f values. Statistical analysis proves that the method is reproducible and selective for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one. Moreover, the proposed HPTLC method was utilized to investigate the degradation kinetics in 1M NaOH.

Keywords: Degradation, high-performance thin-layer chromatography, repaglinide, stability-indicating


How to cite this article:
Akhtar J, Fareed S, Aqil M. Stability-indicating assay of repaglinide in bulk and optimized nanoemulsion by validated high performance thin layer chromatography technique. J Pharm Bioall Sci 2013;5:184-90

How to cite this URL:
Akhtar J, Fareed S, Aqil M. Stability-indicating assay of repaglinide in bulk and optimized nanoemulsion by validated high performance thin layer chromatography technique. J Pharm Bioall Sci [serial online] 2013 [cited 2019 Oct 14];5:184-90. Available from: http://www.jpbsonline.org/text.asp?2013/5/3/184/116800

Repaglinide (RPG), chemically, (S)-2-ethoxy-4- [2-[[3-methyl-1-[2-(1-piperidinyl) phenyl] butyl] amino]-2-oxoethyl] benzoic acid [Figure 1], is a new nonsulphonyl urea oral hypoglycemic drug. [1] It is used in the treatment of Type-2 diabetes mellitus. [2] It is official in the United State Pharmacopoeia (USP) which describes liquid chromatographic method for its quantification. [3] Literature survey reveals that one HPLC method has been developed for determination of repaglinide in human plasma, [4]. Two HPLC methods, [5],[6] one rapid performance thin layer chromatography (RPTLC) [7] and one spectrophotometric method [8] in pharmaceutical dosage forms are also reported. To our knowledge, no article related to the stability-indicating HPTLC determination of repaglinide in pharmaceutical dosage forms has been reported in the literature. An ideal stability-indicating method is one that quantifies the standard drug alone and also resolves its degradation products. Ferenczi-Fodor and colleagues [9],[10] explained basic acceptance criteria for evaluation of validation experiments based on practical experience for planar chromatographical procedures, which may be used at different levels either in qualitative identity testing, assays, semi-quantitative limit tests or quantitative determination of impurities. The parameters for robustness testing of the given procedures and quality assurance of quantitative planar chromatographical testing have been described as per International Conference on Harmonization (ICH) guidelines. The aim of the present work is to develop an accurate, specific, repeatable and stability-indicating HPTLC method for the determination of repaglinide in the presence of its degradation products and related impurities for assessment of purity of bulk drug and stability of its bulk dosage forms. The proposed method was validated as per ICH guidelines. [11],[12] Acid-induced degradation kinetics were investigated by quantitation of drug by validated stability-indicating HPTLC method.
Figure 1: Typical chromatogram of standard RPG (400 ng spot-1); peak 1: Rf: 0.38 ± 0.02, mobile phase Chloroform/methanol/ammonia/glacial acetic acid (7.5:1.5:0.9:0.1, v/v/v/v) at 240 nm

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   Experimental Top


Materials

Pharmaceutical grade of repaglinide was kindly supplied as a gift sample by Ranbaxy Laboratory, India, used without further purification and certified to contain 99.98% w/w. All chemicals and reagents used were of analytical grade and were purchased from Merck Chemicals, India.

Instrumentation

Chromatography was performed in the same manner as reported earlier. [13] In brief, samples were spotted in the form of bands of width 6 mm with a Camag microlitre syringe on precoated silica gel aluminum Plate 60 F-254 (20 × 10 cm with 250 μm thickness; E. Merck, Darmstadt, Germany, supplied by Anchrom Technologists, Mumbai, India) using a Camag Linomat IV (Muttenz, Switzerland). The plates were prewashed by methanol and activated at 60°C for 5 min prior to chromatography. The slit dimension was kept at 5 × 0.45 mm and 10 mm/s scanning speed was employed. The monochromatic bandwidth was set at 20 nm, each track was scanned thrice and baseline correction was used. The mobile phase consisted of chloroform/methanol/ammonia/glacial acetic acid (7.5:1.5:0.9:0.1, v/v/v/v) and 15 mL of mobile phase was used as per chromatography. Linear ascending development was carried out in 20 × 10 cm twin trough glass chamber (Camag, Muttenz, Switzerland) saturated with the mobile phase. The optimized chamber saturation time for mobile phase was 30 min at room temperature (25 ± 2°C) at relative humidity of 60 ± 5%. The length of chromatogram run was 8 cm. Subsequent to the development, TLC plates were dried in a current of air with the help of an air dryer. Densitometric scanning was performed on Camag TLC scanner III in absorbance mode at 240 nm and was operated by CATS software (V 3.15, Camag). The source of radiation utilized was deuterium and tungsten lamp.

Calibration curve of repaglinide

A stock solution of repaglinide (1000 μg mL -1 ) was prepared in methanol. Standard solutions were prepared by dilution of the stock solution with methanol to give solutions containing repaglinide in a concentration range of 50-800 ng spot−1 . Each concentration was spotted thrice on the TLC plate. The data of peak areas and corresponding concentrations were treated by linear least-square regression analysis.

Method validation

Precision

Precision of the method was determined with the product. An amount of the product powder equivalent to 100% of the label claim of repaglinide was accurately weighed and assayed. System intra-day repeatability was determined by six replicate application and six times measurement of a sample solution at the analytical concentration of 300 ng spot−1 . The repeatability of sample application and measurement of peak area for active compound were expressed in terms of percentage relative standard deviation (% RSD) and standard error (S.E.), and were found to be less than 2%. Intermediate precision was assessed by the assay of two sets of six samples on different days (inter-day precision). The intra- and inter-day variation for determination of repaglinide was carried out at three different concentration levels: 100, 300 and 500 ng spot−1 , respectively.

Accuracy (as recovery)

The analyzed samples were spiked with extra 50%, 100% and 150% of the standard repaglinide, and the mixtures were reanalyzed by the proposed method. The experiment was conducted in triplicate. This was done to check for the recovery of the drug at different levels.

Robustness

By introducing small changes in the mobile phase composition, the effects on the results were examined. Mobile phases having different compositions like chloroform/methanol/ammonia/ glacial acetic acid (7.7:1.3:0.9), (7.3:1.7:0.9), (7.5:1.7:0.5), (7.5:1.3:1.1), (7.7:1.5:0.7) and (7.3:1.5:1.1) were tried (keeping volume of glacial acetic acid constant) and chromatograms were run. The amount of mobile phase, temperature and relative humidity was varied in the range of ± 5%. The plates were prewashed by methanol and activated at 60 ± 5°C for 2, 5 and 7 min prior to chromatography. Time from spotting to chromatography and from chromatography to scanning varied from 0, 20, 40 and 60 min. Robustness of the method was done at three different concentration levels: 100, 300 and 500 ng spot−1 .

Specificity

The specificity of the method was ascertained by analyzing standard drug and sample. The spot for repaglinide in the sample was confirmed by comparing the R f and spectra of the spot with that of standard. The peak purity of repaglinide was assessed by comparing the spectra at three different levels; i.e., peak start (S), peak apex (M) and peak end (E) positions of the spot.

Sensitivity

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value. The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Limit of detection (LOD) and Limit of quantification (LOQ)

LOD and LOQ were determined by standard deviation method. For the determination of LOD and LOQ, blank sample was injected in triplicate and peak area of this blank was recorded. The LOD and LOQ were calculated using the slope (S) of the calibration curve and standard deviation (α) of the blank sample by the following formulae: LOD = 3α/S and LOQ = 10α/S; where α is the standard deviation of the blank response and S is the slope of the calibration curve.

Nanoemulsion analysis for repaglinide

To determine the content of repaglinide in nanoemulsion formulation. An accurately weighed quantity of formulation equivalent to 20 mg RPG was extracted with 100 mL methanol by sonication for 30 min and volume was made up to 100 mL. The resulting solution was centrifuged at 3000 rpm for 5 min and supernatant was analyzed for drug content. Two μL (400 ng spot−1 ) of the filtered solution was applied to a TLC plate followed by development and scanning as described earlier. The analysis was repeated in triplicate. The possibility of excipient interference in the analysis was studied.

Forced degradation of repaglinide

Acid and base-induced degradation

FIfty mg of repaglinide was dissolved in 25 mL of methanolic solution of 1M HCl and 1M NaOH. These mixtures were refluxed for 6 h at 90°C in the dark in order to exclude the possible degradative effect of light. The resultant solutions were diluted 10 times, and applied on the TLC plate in triplicate (2 μL, i.e., 400 ng spot−1 ). The chromatograms were run as described above.

Photo-UV degradation

Fifty mg of repaglinide was dissolved in 25 mL of methanol and exposed to direct sunlight for 3 days and UV irradiation for 10 days in UV stability chamber. The resultant solutions were diluted appropriately and applied on TLC plate (400 ng spot−1 ) and then chromatograms were run as described above. In all degradation studies, the average peak area of repaglinide after application (400 ng spot−1 ) of three replicates was obtained.

Dry and wet heat degradation

The standard drug was placed in an oven at 80°C for 2 h to study dry heat degradation and the stock solution was refluxed for 2.0 h on boiling water bath for wet heat degradation.

Peroxide-induced degradation

To 25 mL of methanolic solutions of repaglinide, 25 mL of hydrogen peroxide (30.0%, v/v) was added. The solutions were heated at temperature 65°C in boiling water bath for 6 h to remove completely the excess of hydrogen peroxide. The resultant solutions were diluted appropriately and applied (2 μL, i.e., 400 ng spot−1 ) on TLC plate in triplicate. The chromatograms were run as described above.

Detection of related impurities

The related impurities were determined by spotting higher concentrations of the drug so as to detect and quantify them. Repaglinide (2000 mg) was dissolved in 100 mL of methanol, and this solution was termed as sample solution (20 mg/mL). Two mL of the sample solution was diluted to 100 mL with methanol and this solution was termed as standard solution (0.4 mg/mL). One microliter of both the standard (400 ng spot−1 ) and the sample solution (20,000 ng spot−1 ) were applied on TLC plate and the chromatograms were run as described above.

Study of base-induced degradation kinetic

Accurately weighed 100 mg of the drug was dissolved in 100 mL methanol. Twenty mL of this standard solution was transferred into 100 mL double neck round bottom flask. To it 20 mL of 1M NaOH was added and refluxed at different temperatures (50, 70 and 90°C). At specified time intervals the contents of the flask were quantitatively transferred to 10 mL volumetric flasks and estimated by HPTLC method. The experiment was carried out in triplicate. The concentration of the remaining drug was calculated for each temperature and time interval. Data was further processed and degradation kinetic constants were calculated.


   Results and Discussion Top


Mobile phase optimization

The TLC procedure was optimized with a view to developing a stability-indicating assay method. Both the pure drug and the degraded drug solution were spotted on the TLC plates and run in different solvent systems. Initially, chloroform/methanol/ammonia was tried. The mobile phase chloroform/methanol/ammonia (7.5:1.5:0.9, v/v/v) gave good resolution with Rf value of 0.38 for repaglinide but typical peak nature was missing. Also, the spot for repaglinide was slightly diffused. Addition of 1.5 mL of glacial acetic acid to the above mobile phase improved the spot characteristics. Finally, the mobile phase consisting of chloroform/methanol/ammonia/glacial acetic acid (7.5:1.5:0.9:0.1, v/v/v/v) gave a sharp and symmetrical peak with R f value 0.38 ± 0.02 [Figure 1]. Well-defined spots were obtained when the chamber was saturated with the mobile phase for 30 min at room temperature.

Validation

Linearity

The linear regression data for the calibration curves (n0 = 3) showed a good linear relationship over a concentration range of 50-800 ng spot−1 with respect to the peak area. The regression equation was found to be Y = 12.138 + 74.235 with correlation coefficient (r ± S.D.) of 0.998 ± 0.032. No significant difference was observed in the slopes of standard curves (ANOVA, P > 0.05).

Precision

Precision was considered at two levels of ICH suggestions i.e., repeatability and intermediate precision. Repeatability of sample application was determined as intra-day variation whereas intermediate precision was determined by carrying out inter-day variation at three different concentration levels, 100, 300 and 500 ng spot−1 in triplicates; % relative standard deviation (RSD) was found in the range between 0.1648-0.2859% and 0.1285-0.3539%, respectively [Table 1]. The low value of % RSD (<1%) reveals an excellent precision of the method.
Table 1: Precision (n=3)


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Accuracy (as recovery)

The proposed method when used for extraction and subsequent estimation of repaglinide from bulk drug and nanoemulsion formulation formed after spiking with 50%, 100% and 150% of additional drug afforded recovery of 98.79-99.61%, as listed in [Table 2].
Table 2: Accuracy, as recovery studies (n=6)


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Robustness

The SD of peak areas was calculated for each parameter and RSD was found to be less than 2%. The low values of %RSD as shown in [Table 3] indicated robustness of the method.
Table 3: Robustness testing (n=6)


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Specificity

The peak purity of repaglinide was assessed by comparing the spectra at peak start, peak apex and peak end positions of the spot, i.e., r2 (S, M) = 0.9997 and r2 (M, E) = 0.9979. Good correlation (r2 = 0.9998) was also obtained between standard and sample spectra of repaglinide.

Sensitivity

The signal-to-noise ratios 3:1 and 10:1 were considered as LOD and LOQ, respectively. The LOD and LOQ were found to be 0.023 and 0.069 ng spot−1 , respectively.

Nanoemulsion analysis for repaglinide

A single spot at Rf 0.38 was observed in the chromatogram of the drug samples extracted from prepared formulation. There was no interference from the excipients commonly present in the formulation. The drug content was found to be 99.39 ± 0.35% with a %RSD of 0.62 for six replicate determinations. It may therefore be inferred that degradation of repaglinide had not occurred in the prepared nanoemulsion formulations that were analyzed by this method. The good performance of the method indicated the suitability of this method for routine analysis of repaglinide in pharmaceutical dosage form.

Forced degradation of repaglinide

Acid and base-induced degradation

The chromatogram of the acid-degraded sample for repaglinide showed peak at Rf 0.19 and 0.43 [Figure 2]a. The chromatogram of the base-degraded sample showed peak at Rf value of 0.20, 0.25, 0.29 and 0.51 [Figure 2]b. The areas of the degraded peaks were found to be lesser than the area of standard drug concentration (400 ng spot−1 ) indicating that repaglinide undergoes degradation under acidic and basic conditions.
Figure 2: Forced degradation study; (a) Chromatogram of acid-treated RPG (peak 1: Degraded, Rf: 0.19; peak 2: Repaglinide, Rf: 0.38; peak 3: Degraded. Rf: 0.43); (b) Chromatogram of base-treated RPG (peak 1: Degraded, Rf: 0.20; peak 2: Degraded, Rf: 0.25; peak 3: Degraded, Rf: 0.29; peak 4: Repaglinide, Rf: 0.38; peak 5: Degraded, Rf: 0.51)

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Photo-UV degradation

The photo-degraded sample showed one additional peak at Rf 0.22 when drug solution was left in daylight for 3 days. The drug was degraded when exposed to UV irradiation for 10 days and showed additional peaks at Rf value of 0.53.

Dry and wet heat degradation

The samples degraded under dry heat and wet heat conditions [Figure 3]a and b showed additional peaks at Rf 0.16, 0.46 and 0.51, respectively. The spots of degraded products were well resolved from the drug spot.
Figure 3: Chromatograms of (a) dry heat-degraded RPG (peak 1: Degraded, Rf: 0.16, peak 2: Repaglinide, Rf: 0.38, peak 3: Degraded, Rf: 0.45); (b) wet heat-degraded RPG (peak 1: Repaglinide, Rf: 0.38, peak 2: Degraded, Rf: 0.51)

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Peroxide-induced degradation

The sample degraded with 30% v/v hydrogen peroxide showed additional peaks at Rf value of 0.41, 0.46 and 0.62 [Figure 4]a. The spots of degraded products were well resolved from the drug spot.
Figure 4: Chromatogram of (a) hydrogen peroxide-treated RPG (peak 1: Repaglinide, Rf: 0.38, peak 2: Degraded, Rf: 0.41, peak: 2 Degraded, Rf: 0.46, peak 3: Degraded, Rf: 0.62); (b) impurity profiling (peak 1: Impurity, Rf: 0.06. peak 2: Repaglinide, Rf: 0.38)

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Detection of the related impurities

The spots other than the principal spot (repaglinide) from the sample solution were not as intense as the principal spot from the standard solution. The sample solution showed one additional spot at Rf 0.06 [Figure 4]b. However, the peak area of the additional spot was found to be much less as compared to the peak area of the principal spot from the standard solution.

Degradation kinetics

In basic medium, a decrease in the concentration of the drug with increasing time was observed. At the selected temperatures (50, 70 and 90°C), the degradation process followed pseudo first-order kinetics. Apparent first-order degradation rate constant and half-life were obtained from the slopes of the straight lines at each temperature. Data obtained from first-order kinetics treatment was further subjected to fitting in Arrhenius equation [K = Ae -Ea/RT ], where K is rate constant, A is frequency factor, Ea is energy of activation (Cal mol -1 ), R is gas constant (1.987 cal deg -1 mol -1 ) and T is absolute temperature ( oK). A plot of (2 + log Kobs ) values versus (1/T × 10 3 ) the Arrhenius plot was obtained [Figure 5], which was found to be linear in the temperature range of 40-90°C. The degradation rate constant at room temperature (K25°) is obtained by extrapolating the resulting line in the Arrhenius plot to 25°C [Figure 6] and was found to be 12.4 × 10−2 h−1 and calculated t1/2 and t 0.9 are 5.59 and 0.848 h respectively.
Figure 5: Pseudo first-order plot for the degradation of RPG with 1M NaOH at various temperatures using HPTC method. Ct, concentration at time t; C0, concentration at time zero

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Figure 6: Arrhenius plot for RPG degradation in 1M NaOH and its extrapolation for predicting the degradation at room temperature (25°C)

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   Conclusion Top


The HPTLC technique developed for RPG was found specific, accurate and stability-indicating. Statistical analysis proves that the method is repeatable and selective for the analysis of repaglinide as bulk drug and in nanoemulsion formulations without any interference from the excipients. The method can be used to determine the purity of the drug available from various sources by detecting the related impurities. The above results showed the suitability of the proposed method for basic-induced degradation kinetic study of repaglinide. The degradation rate constant, half-life and shelf life of repaglinide can be predicted. As the method separates the drug from its degradation products, it can be employed as a stability-indicating one.



 
   References Top

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7.Gumieniczek A, Berecka A, Hopkala H. Quantitative analysis of repaglinide in tablets by reversed-phase thin-layer chromatography with densitometric UV detection. J Planar Chromatogr-Mod TLC 2005;18:155-9.  Back to cited text no. 7
    
8.El-Ries MA, Mohamed GG, Attia AK. Electrochemical determination of the antidiabetic drug repaglinide. Yakugaku Zasshi 2008;128:171-7.  Back to cited text no. 8
    
9.Ferenczi-Fodor K, Vigh Z, Nagy-Turak A, Renger B, Zeller M. Validation and quality assurance of planar chromatography procedures in pharmaceutical analysis. J AOAC Int 2001;84:1265-76.  Back to cited text no. 9
    
10.Ferenczi-Fodor K, Vigh Z. Planar Chromatography: A retrospective view from the third Millennium (Sz. Nyiredy Edt.), Budapest: Springer Scientific Publisher; 2001. p. 336-52.  Back to cited text no. 10
    
11.ICH Guidelines Q2A. Validation of analytical procedure: Methodology, In: International Conference on Harmonization, Geneva; 1994.  Back to cited text no. 11
    
12.ICH Guidelines Q2B. Validation of analytical procedure: Methodology, In: International conference on Harmonization, Geneva; 1996.  Back to cited text no. 12
    
13.Faiyazuddin M, Ahmad S, Iqbal Z, Talegaonkar S, Ahmad FJ, Bhatnagar A, et al. Stability indicating HPTLC method for determination of terbutaline sulfate in bulk and from submicronized dry powder inhalers. Anal Sci 2010;26:467-72.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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