Authors:
Almaz Arage Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O.Box. 1176, Ethiopia

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Thomas Layloff Consultant, USA

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Ariaya Hymete Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O.Box. 1176, Ethiopia

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Ayenew Ashenef Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O.Box. 1176, Ethiopia

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https://orcid.org/0000-0003-2505-899X
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Abstract

A rapid, selective, and precise high performance thin layer chromatographic method was developed and validated for the simultaneous analysis of paracetamol, caffeine, phenylephrine and chlorpheniramine in tablets. The chromatographic analysis was carried out on glass plates pre-coated with silica gel 60 F254 as a stationary phase. The optimized mobile phase was methanol : n-butanol : toluene : acetic acid (8:6:4:0.2 v/v). TLC chamber of 10 × 20 cm was used with saturation time of 15 min. The retardation factor (RF) for chlorpheniramine, phenylephrine, caffeine and paracetamol was found to be 0.15 ± 0.02, 0.29 ± 0.02, 0.50 ± 0.02, 0.68 ± 0.02 respectively. Detection was carried out at 212 nm. Validation study was done following ICH Q2 (R1) guideline. The regression data for the calibration plots showed good linear relationship with R 2 = 0.997 over the concentration range of 300–1,500 ng band−1 for caffeine, R 2 = 0.996 over the concentration range of 100–500 ng band−1 for phenylephrine, R 2 = 0.996 over the concentration range of 200–600 ng band−1 for chlorpheniramine, R 2 = 0.998 over the concentration range of 400–2,400 ng band−1 for paracetamol. The method was validated for precision, accuracy and recovery. Minimum detectable amounts were found to be 304.9 ng band−1, 87.88 ng band−1, 117.18 ng band−1 and 143.06 ng band−1 for caffeine, phenylephrine, chlorpheniramine, and paracetamol respectively while the limit of quantification was found to be 923.95 ng band−1, 266.32 ng band−1, 355.11 ng band−1, and 433.53 ng band−1 in the same order. The method was successfully applied to analyze two marketed tablets in a selective and reproducible manner.

Abstract

A rapid, selective, and precise high performance thin layer chromatographic method was developed and validated for the simultaneous analysis of paracetamol, caffeine, phenylephrine and chlorpheniramine in tablets. The chromatographic analysis was carried out on glass plates pre-coated with silica gel 60 F254 as a stationary phase. The optimized mobile phase was methanol : n-butanol : toluene : acetic acid (8:6:4:0.2 v/v). TLC chamber of 10 × 20 cm was used with saturation time of 15 min. The retardation factor (RF) for chlorpheniramine, phenylephrine, caffeine and paracetamol was found to be 0.15 ± 0.02, 0.29 ± 0.02, 0.50 ± 0.02, 0.68 ± 0.02 respectively. Detection was carried out at 212 nm. Validation study was done following ICH Q2 (R1) guideline. The regression data for the calibration plots showed good linear relationship with R 2 = 0.997 over the concentration range of 300–1,500 ng band−1 for caffeine, R 2 = 0.996 over the concentration range of 100–500 ng band−1 for phenylephrine, R 2 = 0.996 over the concentration range of 200–600 ng band−1 for chlorpheniramine, R 2 = 0.998 over the concentration range of 400–2,400 ng band−1 for paracetamol. The method was validated for precision, accuracy and recovery. Minimum detectable amounts were found to be 304.9 ng band−1, 87.88 ng band−1, 117.18 ng band−1 and 143.06 ng band−1 for caffeine, phenylephrine, chlorpheniramine, and paracetamol respectively while the limit of quantification was found to be 923.95 ng band−1, 266.32 ng band−1, 355.11 ng band−1, and 433.53 ng band−1 in the same order. The method was successfully applied to analyze two marketed tablets in a selective and reproducible manner.

Introduction

High performance thin layer chromatography (HPTLC) is an advanced form of thin layer chromatography (TLC) that provides superior separation power using optimized coating materials and improved sample application. It offers higher separation efficiencies, shorter analysis time, lower amounts of mobile phase, and efficient data processing. The term HPTLC is used for the technique in which substances are accurately and precisely assayed using high performance grades of silica gel. In HPTLC the sorbent material like Silica gel G 60 F254 has fine particle size (5–6 µm) distribution than conventional TLC (10–12 µm) material [1].

High Performance Thin-Layer Chromatography is the most simple separation technique today available to the analyst. It can simultaneously handle several samples even of divergent nature and composition at a time [2].

There are several advantages of using HPTLC for the analysis of compounds as compared to other techniques like HPLC which is a versatile, reproducible chromatographic technique with high sensitivity, specificity and accuracy for the estimation of drug product. It had wide application in different fields in terms of qualitative and quantitative estimation of active molecules [3].

However, in resource limited countries, the high cost of HPLC grade solvents and columns and consumption of high amount of solvent significantly affect timely release of laboratory results for appropriate action [4]. Even though the cost of HPTLC instrument is high, it has gained importance in pharmaceutical analysis because of its advantages such as advanced separation efficiency and detection limits, less cost per analysis and low analysis time, no prior treatment for solvents like filtration and degassing, low mobile phase consumption per sample and no interference from previous analysis as fresh stationery phase and mobile phase is used for each analysis [5]. Among analytical techniques for drug analysis, UV- visible spectrophotometry presents some advantages when compared to chromatographic methods, such as faster analysis, low operating costs, and low generation of wastes. However there is limitation regarding specificity, not accurate, quite sensitive to additives [6]. The main advantage of Capillary Electrophoresis (CE) over chromatographic methods is high separation [7]. Other advantages include reduction in solvent consumption and disposal, high speed of analysis and reduced cost of analysis. The main reasons for the reluctance to use CE are lack of sensitivity and poor precision of the method [8, 9]. The main advantages of Near-infrared spectroscopy are a high potential for the elucidation of molecular structures and the characteristic absorption bands can be useful for compound-specific detection [4]. It is non- invasive and non- destructive, has no sample preparation requirement, large number of molecules which could be quantified, and is very fast due to high frequency of spectrum acquisition. However there are disadvantage that include lack of sensitivity and poor precision of the method [10].

Hence, HPTLC based methods could be considered as a good alternative as they are being explored as an important tool in routine analysis for pharmaceuticals.

Paracetamol (PCM) chemically is N-(4-hydroxyphenyl) acetamide; commonly known as acetaminophen (Fig. 1a). PCM exhibit absorption maxima at 257 nm. It is used as analgesic and antipyretic. Literature reveals that HPTLC [3], UV [11, 12], HPLC [13–15] and capillary electrophoretic [15, 16] methods have been reported for simultaneous determination and validation of PCM.

Fig. 1.
Fig. 1.

A–D; Chemical structures of the APIs assayed in this Simultaneous HPTLC method

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01028

Caffeine (CAF) chemically is 3, 7-dihydro-1, 3, 7-trimethyl-1H-purine-2, 6-dione (Fig. 1b). CAF is used as CNS stimulant, mild diuretic, respiratory stimulant and an ingredient which increase the pain relieving effect. It is often combined with analgesics to treat migraine and other headache types. Literature survey reveals that UV [17], Near Infrared spectroscopy [18], HPLC [19–21], HPTLC [3] methods have been reported for simultaneous determination and validation of CAF.

Chlorpheniramine maleate (CPM) chemically is (S)-3-(4-chlorophenyl)-N,N-dimethyl-3-(pyridin-2-yl)propan-1-amine maleate (C16H19ClN2,C4H4O4) (Fig. 1c). It is used to relieve symptoms of allergy, fever and common cold. Literature survey reveals that UV [22], HPLC [23, 24], HPTLC [25] methods have been reported for simultaneous determination and validation of CPM.

Phenylephrine hydrochloride (PE) chemically is (1R)-1-(3hydroxy-phenyl)-2-(methylamino) ethanol hydrochloride (Fig .1d). PE reduces nasal congestion and acts as an effective decongestant. PE exhibit absorption maxima at 273 nm. Literature revealed that UV [22], HPLC [14, 19, 24] and HPTLC [25] methods have been reported for simultaneous determination and validation of PE.

Experimental

Chemicals and reagents

Working standards certified to contain 99.7% of Paracetamol (batch number; PC25342, expiry date; 02/2021), 99.6% of Caffeine (batch number; CB-160606, expiry date; 06/2021), 99.8% of Phenylephrine (batch number; 21L-D0931016, expiry date; 09/2021), 99.8% of chlorpheniramine (batch number; CPN091, expiry date; 04/2021), and FLU-stop® dosage form tablets (batch number; 8070123, expiry date, Jul. 2020) were all obtained as a kind gift from Ethiopian pharmaceutical manufacturing Share Company (EPHARM SC., Addis Ababa, Ethiopia). COLD-flu® was purchased from Dubai, UAE and it is labeled to contain 500 mg of paracetamol, 30 mg of Caffeine, and 5 mg of Phenylephrine (batch number; WJ7B, expiry date, Dec. 2019). HPLC grade methanol and ethyl acetate (Carlo Erba Reagents, France), formic acid, chloroform, hexane, n-butanol, ammonia, toluene, acetone, glacial acetic acid, and isopropyl alcohol (Research-Lab. Fine Chem Industries, India) were used.

Instrumentation and chromatographic conditions

The sample were spotted in the form of bands with 100 µl syringe (Hamilton-Bonaduz Schweiz), on precoated silica gel 60F254 glass plate 10 × 20 cm and 20 × 20 cm (this one had been cut to fit to 10 × 20 cm developing chamber) with 200 µm thickness (batch numbers: HX389048 and HX398477, Merck, Darmstadt, Germany) using a Camag Linomat V applicator. The plates were prewashed with methanol and activated at 110°C for 5 min prior to the sample application. The optimized mobile phase for the study was methanol : n-butanol : toluene : glacial acetic acid (8:6:4:0.2 v/v). Linear ascending development was carried out in 10 × 20 cm twin trough glass chamber (Camag, Switzerland). The optimized chamber saturation time for mobile phase was 15 min at temperature of 25°C. Saturation pad (Camag, Switzerland) was used. The length of chromatogram run was 7 cm and TLC plates were dried using hair drier (Philip lady 1,000, type HP 4312, Hong Kong). Densitometric scanning was performed on Camag TLC scanner III, using Wincats version 1.4.0 software at 212 nm. Evaluation was performed using linear regression analysis via peak areas.

Preparation of standard and sample solution

A standard solution of 5 mg mL−1 of paracetamol, 0.3 mg mL−1 of Caffiene, 0.05 mg mL−1 of Phenylepherine and 0.02 mg mL−1 of Chlorpheniramine were prepared by weighing 500 mg of PCM, 30 mg of CAF, 5 mg of PE and 2 mg of CPM and dissolving in 100 mL of methanol. Different standard dilutions were prepared over the period of method development. The solution was stored at room temperature until application to the plate.

Twenty tablets of FLU-stop were weighed and finely powdered using mortar and pestle. A portion of powder equivalent to 500 mg of PCM, 30 mg of CAF, 5 mg of PE, and 2 mg of CPM was weighed and transferred to 100 mL volumetric flask. 100 mL of methanol was added to the volumetric flask and sonicated for 20 min. To remove un-dissolved excipients the solution was filtered through a 0.45 µm filter paper (Whatman Int. Ltd, England).

Twenty tablets of Cold-flu were weighed and finely powdered using mortar and pestle. A portion of powder equivalent to 500 mg of PCM, 30 mg of CAF, and 5 mg of PE was weighed and transferred to 100 mL volumetric flask. 100 mL of methanol was added to the volumetric flask and sonicated for 20 min. To remove un-dissolved excipients solution was filtered through a 0.45 µm filter paper (Whatman Int. Ltd, England).

Selection of detection wavelength

After chromatographic development bands were scanned over the range 200 and 400 nm. It was observed that both the drugs showed considerable absorbance at 212 nm so, 212 nm was selected as the wavelength for detection.

Method validation

Linearity, limit of detection and quantification

Linearity was evaluated by applying a minimum of five concentrations in six replicates on to HPTLC plate. Concentrations were: PCM in the range of 300–1,500 ng band−1, CAF in the range of 200–1,400 ng band−1, CPA in the range of 200–600 ng band−1 and PHE 100–500 ng band−1. Calibration curve of peak area versus concentration was plotted.

Precision

Repeatability studies and intermediate precision were performed at concentrations of 800, 1,000 and 1,200 ng/spot for Paracetamol, 480, 600, and 720 ng/spot for Caffeine, 640, 800, and 960 ng/spot for Phenylephrine and 768, 960, and 1,152 ng/spot for Chlorpheniramine in triplicates.

Specificity

Specificity of the method was ascertained by analyzing standard drug and samples. The spots for paracetamol, caffeine, chlorpheniramine, and phenylephrine in sample dosage form were confirmed by comparing RF values with that of standards.

Accuracy

Accuracy of the method was evaluated by recovery studies from standard addition method. Samples of PCM, CAF, CPA, and PE were spiked with 80, 100 and 120% of standard PCM, CAF, CPA, and PE.

Robustness

Two different parameters were studied to evaluate the robustness of the proposed method. Therefore, in this method, small changes were introduced in the composition of the mobile phase (± 0.1 mL), saturation time (± 5 min), and its effects on RF values and quantification were determined. Concentration of 1,000 ng band−1 for PCM, CAF, PE, and CPA, were used.

Results and discussion

Optimization of mobile phase

In this study, chromatographic separation studies were carried out on the working standard solutions of PCM, CAF, CPA, and PE. Different mixtures of various solvents were tried and the composition of the mobile phase with a better chromatographic result having acceptable and reproducible RF value was selected. A different solvent mixture with chloroform, methanol, ammonia, ethyl acetate, hexane, formic acid, n-butanol, toluene, acetone, glacial acetic acid, distilled water, acetic acid 96%, and isopropyl alcohol also were tried.

CPA and PE are relatively non polar compared to PCM and CAF. Both substances were not eluted from the site of application when non-polar solvents like n-hexane, toluene and chloroform were used as a mobile phase. Hence studies with polar solvents such as ethyl acetate, methanol, and n-butanol were initiated.

Therefore, the non-polar solvents were combined in different ratios with relatively polar solvents. In this case, since CAF and PCM are more polar than PE and CPA and they were eluted from the site of application. CPA and PE are weakly basic because of the presence of a tertiary and secondary amine moiety in its phenyl alkyl side chain. Hence, they have highly interacted with the stationary phase especially with the un-reacted silanol groups of the silica gel. And also PE and CPA relatively non-polar compounds in the mixture will tend to form attractions with the hydrocarbon groups because of van der Waals dispersion forces. Therefore spend less time in the mobile phase and spent more time through the stationary phase [25].

Various mobile phase systems were tried for good separation of the four drugs. After several trials, a mixture of methanol : toluene : 1-butanol : glacial acetic acid (8:4:6:0.2 v/v) was chosen as the mobile phase. With this mobile phase system, complete resolution of peaks with clear baseline separation was obtained and detection was possible at 212 nm (Fig. 2). The RF values for phenylephrine, chlorpheniramine, caffeine, and paracetamol, were found to be 0.15, 0.29, 0.50, 0.68 respectively. The peaks were completely resolute.

Fig. 2.
Fig. 2.

Typical HPTLC densitogram of FLU-stop spot (Peaks 1: CPA; 2: PE; 3: CAF, and 4: PCM)

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01028

Method validation

Linearity

A linear relationship was observed for all drugs. The linearity range for CAF, CPA, PCM, and PE was found to be 400–2,400 ng band−1, 200–600 ng band−1, 300–1,500 ng band−1 and 100–500 ng band−1, respectively (Table 1).

Table 1.

Linear regression data for calibration curves of PCM, PHE, CPM, and CAF (n = 5)

Parameter CAF CPA PCM PE
Linearity range (ng band−1) 400–2,400 200–600 300–1,500 100–500
R 2 0.997 0.996 0.998 0.996
Slope 1.10 2.82 1.32 2.74
Intercept 22.3 −256.4 −22.4 −32.2
Standard Error 44.72 22.38 24.45 22.38
Significance (t-value) 11.31 30.14 51.40 30.91
Signficance (P Value) 0.0000020531 0.0000802 0.0000162 0.0000744
Linear regression equation Y = 1.104x+217.7 Y = 2.749x+22.3 Y = 2.82x−256.4 Y = 1.3248x−22.3

Precision

The developed method was found to be precise, with % RSD values for repeatability and intermediate precision studies less than 2 as recommended by ICH Q2 (R1) guideline as shown on Table 2.

Table 2.

Precision study of paracetamol; caffeine; phenylephrine and chlorpheniramine

Drug Conc. ng/spot Intraday precision Intermediate precision
Mean RSD Mean RSD
PCM 900 2,900 1.96 2,853 1.78
1,000 3,276 1.54 3,547 1.64
1,100 5,216 1.91 5,116 1.94
CAF 900 6,527 1.69 6,441 1.12
1,000 7,534 1.77 7,403 1.93
1,100 8,661 1.53 8,552 1.49
PE 720 956 1.84 963 1.91
800 1,005 1.75 949 1.76
880 1,908 1.83 1,856 1.73
CPA 576 1,124 1.77 1,090 1.76
640 1,834 1.66 1,757 1.83
704 2,054 1.35 1,954 1.94

Robustness

The % RSD of peak areas was calculated for each parameter and was found to be less than 2. A % RSD of less than 2 indicated that the method is robust (Tables 3 and 4).

Table 3.

Results in robustness study of the method (n = 6)

API drugs Conc. ng/spot Mobile phase composition (± 0.1 mL) Chamber saturation time (± 5 min)
Mean ± SD RSD Mean ± SD RSD
CPA 1,000 771.83 ± 14.83 1.92 702.10 ± 13.05 0.13
CAF 1,000 6,952.1 ± 87.86 0.981 6,834.17 ± 81.71 0.99
PE 1,000 2,466.17 ± 35,82 1.452 2,323.33 ± 26.14 1.97
PCM 1,000 4,449.5 ± 71.15 1.599 4,241.88 ± 70.35 1.65
Table 4.

Effect of small changes made on the mobile phase composition on RF values

Mobile phase (± 0.1) RF value
PCM CPA PE CAF
methanol : toluene : 1-butanol : glacial acetic acid (7.9:3.9:5.9:0.2v/v) 0.50 0.15 0.28 0.67
methanol : toluene : 1-butanol : glacial acetic acid (8.1:4.1:6.1:0.2v/v) 0.51 0.15 0.29 0.69

Small variations in all parameters except glacial acetic acid did not affect the peak areas and thus the quantification of the drug. This indicates the deliberate changes made on the method parameters had very little effect on the determination.

Accuracy (recovery studies)

Recovery study was carried out at three levels, i.e., multiple level recovery studies. The recovery of the method was evaluated by standard addition method. Sample concentration 500 ng band−1 of PCM, and CAF were spiked with 80, 100 and 120% of standard PCM, and CAF and 200 ng band−1 of CPA, and PE were spiked with 80, 100 and 120% of standard CPA, and PE (Table 5).

Table 5.

Results of Accuracy studies (n = 3)

Name of the drug Amount taken ng Amount added ng Total amount present in ng Amount recovered (ng)

working dosage standard form
% Recovery working dosage standard form
PCM 500 400 900 952.3 934.49 105.8 103.8
500 500 1,000 980.9 979.26 98.1 97.9
500 600 1,100 1,085.5 1,077.59 98.9 97.9
CAF 500 400 900 902.6 887.57 100.3 98.6
500 500 1,000 999.4 980.39 99.8 98.1
500 600 1,100 1,120.8 1,094.37 99.94 99.5
CPA 200 160 360 366.2 354.98 101.7 98.6
200 200 400 399.4 392.77 99.9 98.2
200 240 440 436.1 424.48 99.1 96.4
PE 200 160 360 356.9 338.75 99.2 94.1
200 200 400 402.5 387.71 100.6 96.9
200 240 440 438.1 420.55 99.6 95.5

Specificity

The peak purity of PCM, CAF, CPA, and PE were assessed by comparing their respective spectra at the peak start (S), peak apex (M), and peak end (E) positions of the spot. A good correlation (r ≤ 0.998) was obtained between the standard and sample spectra of PCM, CPA,CAF, and PE indicating that peaks are pure and method is specific (Fig. 3).

Fig. 3.
Fig. 3.

Typical densitogram of PCM (A), CPA (B), CAF(C) and PE (D), spots of reference standards

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01028

Sample solution stability study

Stability study of the sample solution was conducted within one week after preparation and stored in a refrigerator. The average peak areas and the RSD were calculated and presented in Table 6. The combined working standard solution was found to be stable up to 24 h at room temperature as there was no significant difference in the peak area within this time interval.

Table 6.

Stability study of sample solutions

Time of analysis Average peak area RSD Percent reduction
Paracetamol 30 min 4,490.3 1.89
6 h 4,450.8 1.82
24 h 4,400.1 1.94 0.19
3 days 3,410.6 5.54 5.33
7 days 3,001.3 6.88 5.45
Caffeine 30 min 6,900.5 1.75
6 h 6,910.2 1.85
24 h 6,942.2 1.66 0.115
3 days 6,805.1 3.99 7.56
7 days 6,700.9 5.34 6.22
Phenylepherine 30 min 2,400.8 1.35
6 h 2,490.6 1.64
24 h 2,450 1.89 0.10
3 days 2,302.5 4.21 4.54
7 days 2,200.4 5.57 5.66
Chlorpheniramine 30 min 785.5 1.78
6 h 777.8 1.92
24 h 754.9 1.67 0.12
3 days 742.6 1.77 5.28
7 days 731.4 1.56 4.96

Analysis of the tablet dosage forms (FLU-stop and cold FLU)

Sample solution of the formulations (FLU-stop and Cold Flu) in triplicates were applied on HPTLC plate, developed and scanned as described for the optimized chromatographic separation (Section “Optimization of mobile phase”). The analysis experiments were carried out during the shelf life of the tablets. For Flu Stop, the drug content was found to be 100.7% (w/w) for PCM, 101.3% (w/w) for PHE, 101.2% (w/w) for CPA, and 101.2% (w/w) for CAF as shown in Table 7. While for Cold Flu, the drug content was found to be 100.5% (w/w) for PCM, 101.3% (w/w) for PHE, and 102.3% (w/w) for CAF as shown in Table 7. Typical denistogrammes of the two formulations had been shown in Figs 2 and 4.

Table 7.

Analysis of Dosage forms (FLU-stop formulation (EPHARM SC, Ethiopia) and Cold Flu (Dubai, UAE))

Flu- Stop (Epharm SC) Cold Flu (Dubai, UAE) Assay Compliance (USP)

(90–120%)
API No of Assays Label claim (mg) Amount found (mg) Drug content % Amount found (mg) Drug content %
Paracetamol 1 500 500.3 100.06 502.3 100.4 Complies
2 500 505.9 101.20 505.9 101.2
3 500 504.3 100.86 498.8 99.8
Caffeine 1 30 31.7 105.60 30.7 102.3 Complies
2 30 29.9 99.70 29.9 99.7
3 30 30.6 102.00 30.4 101.3
Phenylephrine 1 5 4.9 98.0 5.16 103.2 Complies
2 5 5.2 104.0 5.2 104.0
3 5 5.1 102.0 4.98 99.6
Chlorphenir-amine 1 2 1.98 99.0 Complies
2 2 1.99 99.5
3 2 2.1 105
Fig. 4.
Fig. 4.

Typical densitogram of PE, PCM, and CAF spots marketed formulation of COLD-Flu

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01028

The two tablet formulations contain the correct amount of ingredients as specified by the manufacturers. The results give solid evidence that the HPTLC method developed can be utilized for routine pharmaceutical analysis work in the pharmaceutical industry, National/International Medicine Regulatory laboratories as well as independent pharmaceutical analysis laboratories.

The developed simultaneous HPTLC method had been successfully utilized for the analysis of Finished Pharmaceutical Products (FPPs). To our knowledge, there is no other analytical method that was capable of analyzing the four combined APIs simultaneously by using HPTLC. The currently available methods that are based on HPLC and Chemometric UV visible spectrophotometry methods can only capable of analyzing the two or three APIs combinations [26–31]. Only three HPLC methods are reported that simultaneously determine the four API ingredients targeted in this method development [32–34]. Besides the inherent advantages in HPTLC methods, the developed analytical method had offered advantages in terms of LOD, LOQ, and other analytical parameters determined in this study compared to the reported ones that utilize HPLC. The developed analytical method in this study will be very useful in determining the quality of common cold flu “symptom relieving” preparations which are commonly available in many countries as over the counter (OTC) products. These formulations will be prone to a targeted sub standardization and falsification formulation acts thus this method will play a critical role in circumventing it.

Conclusion

The developed HPTLC densitometric method was found to be suitable for the simultaneous determination of paracetamol, caffeine, phenylephrine hydrochloride and chlorpheniramine maleate in co-formulated tablet dosage forms containing the four APIs without any interference from the excipients and the drugs within themselves. Validation of the method proved that the method is repeatable and specific for the analysis of paracetamol, caffeine, phenylephrine hydrochloride and chlorpheniramine maleate as bulk drugs and in the pharmaceutical formulation without any interference. Advantages of the developed method are low volume of reagents, speed and simplicity of sample treatment, satisfactory precision and accuracy. Moreover, the method utilized has the merit of applying several sample spots on the HPTLC plate and up to 18 samples analysis per run.

Acknowledgments

Authors would like to thank Ethiopian Pharmaceutical Manufacturing Sh. Co. (EPHARM SC) for offering the APIs, reference standards and Flu stop tablets. Addis Ababa University, School of pharmacy is acknowledged for graduate student financial assistance to Almaz Arage. The Ministry of Innovation and Technology, Government of Ethiopia supported this research in its national innovation award scheme to Ayenew Ashenef for the project “Developing, validating and adopting simple mobile technologies in drug quality evaluation and counterfeit detection.” The HPTLC instrumentation and analytical capacity was funded by USAID through the Preventative Technologies Agreement managed by the Supply Chain Management System (SCMS) project.

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    • Search Google Scholar
    • Export Citation
  • 11.

    Joshi, R. ; Pawar, N. ; Dongre, U. ; Katiyar, S. Effective quantitation of acetaminophen, phenylephrine hydrochloride, cetirizine hydrochloride and caffeine in pharmaceutical dosage form using UV-visible spectroscopy. J. Pharm. Res. 2012, 5, 10181021.

    • Search Google Scholar
    • Export Citation
  • 12.

    Sawant, R. ; Joshi, R. ; Sawant, M. ; Lanke, P. ; Bhangale, L. Mathematical and multi wavelength spectrophotometric methods for simultaneous estimation of paracetamol, phenylephrine hydrochloride, chlorpheniramine maleate and caffeine. Int. J. Pharm. Frontier Res. 2011, 1, 3138.

    • Search Google Scholar
    • Export Citation
  • 13.

    Acheampong, A. ; Gyasi, W. O. ; Darko, G. ; Apau, J. ; Addai-Arhin, S. Validated RP-HPLC method for simultaneous determination and quantification of chlorpheniramine maleate, paracetamol and caffeine in tablet formulation. Springerplus 2016, 5(1), 18.

    • Search Google Scholar
    • Export Citation
  • 14.

    Mahajan, K. S. ; Chauhan, R. S. ; Shah, S. A. ; Shah, D. R. Development of HPTLC method for simultaneous estimation of paracetamol and flupirtine maleate in their combined tablet dosage form. J. Pharm. Appl. Sci. 2015, 2(1), 17.

    • Search Google Scholar
    • Export Citation
  • 15.

    Haj-Ali, N. D. ; Hamdan, I. I. Development of a capillary electrophoresis method for the determination of orphenadrine citrate in tablets in the presence of paracetamol. Saudi Pharm. J. 2010, 18, 233237.

    • Search Google Scholar
    • Export Citation
  • 16.

    Azhagvuel, S. ; Sekar, R. Simultaneous determination of acetaminophen, cetirizine dihydrochloride, phenylpropanolamine hydrochloride by capillary zone electrophoresis. J. Pharm. Biomed. Anal. 2007, 43, 873878.

    • Search Google Scholar
    • Export Citation
  • 17.

    Vichare, V. ; Mujgond, P. ; Tambe, V. ; Dhole, S. N. Simultaneous spectrophotometric determination of paracetamol and caffeine in tablet formulation. Int. J. Pharm. Technol. Res. 2010, 2, 25122516.

    • Search Google Scholar
    • Export Citation
  • 18.

    Muntean, D. M. ; Alecu, C. ; Tomuta, I. Simultaneous quantification of paracetamol and caffeine in powder blends for tablet by NIR. J. Spectrosc. 2017, 1, 18.

    • Search Google Scholar
    • Export Citation
  • 19.

    Bandelwar, R. ; Nikam, A. ; Sawant, S. Analytical method development and validation of phenylephrine hydrochloride, chlorpheniramine maleate, paracetamol and caffeine in bulk drug and tablet dosage form by RP-HPLC. Am. J. Pharm. Res. 2013, 3, 43304338.

    • Search Google Scholar
    • Export Citation
  • 20.

    Joshi, R. ; Pawar, N. ; Dongre, U. ; Katiyar, S. Effective quantitation of acetaminophen, phenylephrine hydrochloride, cetirizine hydrochloride and caffeine in pharmaceutical dosage form using UV-visible spectroscopy. J. Pharm. Res. 2015, 5, 10181021.

    • Search Google Scholar
    • Export Citation
  • 21.

    Renu, S. ; Mamt, K. ; Mukesha, M. ; Sunil, K. Simultaneous determination of chlorpheniramine maleate, paracetamol and phenylephrine hydrochloride in tablet dosage form by HPLC. Int. J. Drug Develop. Res. 2013, 5, 258263.

    • Search Google Scholar
    • Export Citation
  • 22.

    Wadher, S. J. ; Kalyankar, T. M. ; Panchal, P. P. Development and validation of simultaneous estimation of chlorpheniramine maleate and phenylephrine hydrochloride in bulk and capsule dosage form by ultra-violet spectrophotometry. Int. J. Chem. Technol. Res. 2013, 5, 24102419.

    • Search Google Scholar
    • Export Citation
  • 23.

    Redasani, V. K. ; Gorle, A. P. ; Badhan, R. A. ; Jain, P. S. ; Surana, S. J. Simultaneous determination of chlorpheniramine maleate, phenylephrine hydrochloride, paracetmol and caffeine in pharmaceutical preparation by RP-HPLC. Scientific Paper 2012, 1, 122.

    • Search Google Scholar
    • Export Citation
  • 24.

    Dawania, A. P. ; Barika, B. B. ; Chipadeb, V. D. ; Bakalb, R. L. ; Chandwarb, A. V. ; Kanungo . RP-HPLC-DAD method for the determination of phenylepherine, paracetamol, caffeine and chlorpheniramine in bulk and marketed formulation. Arabian J. Chem. 2014, 7, 811816.

    • Search Google Scholar
    • Export Citation
  • 25.

    Kardile, S. S. ; Potawale, S. E. ; Vidhate, S. S. ; Kashid, A. M. ; Bansode, A. S. ; Choudhury, H. ; Devale, T. L. ; Pawar, P. D. Development and validation of HPTLC method for simultaneous estimation of ambroxol hydrochloride, phenylephrine hydrochloride, chlorpheniramine maleate, paracetamol and guaiphenesin in pharmaceutical formulation. J. Chem. Pharm. Res. 2015, 7, 169177.

    • Search Google Scholar
    • Export Citation
  • 26.

    Şenyuva, H. ; Özden, T. Simultaneous high-performance liquid chromatographic determination of paracetamol, phenylephrine HCl, and chlorpheniramine maleate in pharmaceutical dosage forms. J. Chromatogr. Sci. 2002, 40(2), 97100.

    • Search Google Scholar
    • Export Citation
  • 27.

    Ahmad, I. ; Sheraz, M. A. ; Ahmed, S. ; Anwar, Z. Multicomponent spectrometric analysis of drugs and their preparations. In Profiles of Drug Substances, Excipients and Related Methodology; Academic Press, Vol.44, 2019; pp 379413.

    • Search Google Scholar
    • Export Citation
  • 28.

    Lotfi, S. ; Veisi, H. ; Karmakar, B. A convenient strategy for the electrochemical evaluation of acetaminophen and caffeine in combined drugs and biological samples over TiO2@ polymethyldopa/Pd nanocomposite functionalized glassy carbon electrodes. Measurement 2021, 186, 110156.

    • Search Google Scholar
    • Export Citation
  • 29.

    Uddin, M. N. ; Mondol, A. ; Karim, M. M. ; Jahan, R. A. ; Rana, A. A. Chemometrics assisted spectrophotometric method for simultaneous determination of paracetamol and caffeine in pharmaceutical formulations. Bangladesh J. Scientific Ind. Res. 2019, 54(3), 215222.

    • Search Google Scholar
    • Export Citation
  • 30.

    Dongala, T. ; Katari, N. K. ; Palakurthi, A. K. ; Jonnalagadda, S. B. Development and validation of a generic RP-HPLC PDA method for the simultaneous separation and quantification of active ingredients in cold and cough medicines. Biomed. Chromatogr. 2019, 33(11), e4641.

    • Search Google Scholar
    • Export Citation
  • 31.

    Nabi, A. ; Tehrani, M. S. ; Farrokhzadeh, S. ; Sadeghi, N. Separation and simultaneous determination of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate in a commercial tablet by a rapid isocratic HPLC method. Hum. Health Halal Metrics 2020, 1(2), 814.

    • Search Google Scholar
    • Export Citation
  • 32.

    Redasani, V. K. ; Gorle, A. P. ; Badhan, R. A. ; Jain, P. S. ; Surana, S. J. Simultaneous determination of chlorpheniramine maleate, phenylephrine hydrochloride, paracetamol and caffeine in pharmaceutical preparation by RP-HPLC. Chem. Industry Chem. Eng. Quarterly/CICEQ 2013, 19(1), 5765.

    • Search Google Scholar
    • Export Citation
  • 33.

    Dewani, A. P. ; Barik, B. B. ; Chipade, V. D. ; Bakal, R. L. ; Chandewar, A. V. ; Kanungo, S. K. RP-HPLC-DAD method for the determination of phenylepherine, paracetamol, caffeine and chlorpheniramine in bulk and marketed formulation. Arabian J. Chem. 2014, 7(5), 811816.

    • Search Google Scholar
    • Export Citation
  • 34.

    Sonone, R. ; Tandel, L. ; Jain, V. Novel rapid isocratic RP-HPLC method for simultaneous estimation of phenylephrine hydrochloride, paracetamol, caffeine, diphenhydramine hydrochloride. Curr. Pharm. Anal. 2021, 17(6), 792800.

    • Search Google Scholar
    • Export Citation
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    • Export Citation
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    Joshi, R. ; Pawar, N. ; Dongre, U. ; Katiyar, S. Effective quantitation of acetaminophen, phenylephrine hydrochloride, cetirizine hydrochloride and caffeine in pharmaceutical dosage form using UV-visible spectroscopy. J. Pharm. Res. 2012, 5, 10181021.

    • Search Google Scholar
    • Export Citation
  • 12.

    Sawant, R. ; Joshi, R. ; Sawant, M. ; Lanke, P. ; Bhangale, L. Mathematical and multi wavelength spectrophotometric methods for simultaneous estimation of paracetamol, phenylephrine hydrochloride, chlorpheniramine maleate and caffeine. Int. J. Pharm. Frontier Res. 2011, 1, 3138.

    • Search Google Scholar
    • Export Citation
  • 13.

    Acheampong, A. ; Gyasi, W. O. ; Darko, G. ; Apau, J. ; Addai-Arhin, S. Validated RP-HPLC method for simultaneous determination and quantification of chlorpheniramine maleate, paracetamol and caffeine in tablet formulation. Springerplus 2016, 5(1), 18.

    • Search Google Scholar
    • Export Citation
  • 14.

    Mahajan, K. S. ; Chauhan, R. S. ; Shah, S. A. ; Shah, D. R. Development of HPTLC method for simultaneous estimation of paracetamol and flupirtine maleate in their combined tablet dosage form. J. Pharm. Appl. Sci. 2015, 2(1), 17.

    • Search Google Scholar
    • Export Citation
  • 15.

    Haj-Ali, N. D. ; Hamdan, I. I. Development of a capillary electrophoresis method for the determination of orphenadrine citrate in tablets in the presence of paracetamol. Saudi Pharm. J. 2010, 18, 233237.

    • Search Google Scholar
    • Export Citation
  • 16.

    Azhagvuel, S. ; Sekar, R. Simultaneous determination of acetaminophen, cetirizine dihydrochloride, phenylpropanolamine hydrochloride by capillary zone electrophoresis. J. Pharm. Biomed. Anal. 2007, 43, 873878.

    • Search Google Scholar
    • Export Citation
  • 17.

    Vichare, V. ; Mujgond, P. ; Tambe, V. ; Dhole, S. N. Simultaneous spectrophotometric determination of paracetamol and caffeine in tablet formulation. Int. J. Pharm. Technol. Res. 2010, 2, 25122516.

    • Search Google Scholar
    • Export Citation
  • 18.

    Muntean, D. M. ; Alecu, C. ; Tomuta, I. Simultaneous quantification of paracetamol and caffeine in powder blends for tablet by NIR. J. Spectrosc. 2017, 1, 18.

    • Search Google Scholar
    • Export Citation
  • 19.

    Bandelwar, R. ; Nikam, A. ; Sawant, S. Analytical method development and validation of phenylephrine hydrochloride, chlorpheniramine maleate, paracetamol and caffeine in bulk drug and tablet dosage form by RP-HPLC. Am. J. Pharm. Res. 2013, 3, 43304338.

    • Search Google Scholar
    • Export Citation
  • 20.

    Joshi, R. ; Pawar, N. ; Dongre, U. ; Katiyar, S. Effective quantitation of acetaminophen, phenylephrine hydrochloride, cetirizine hydrochloride and caffeine in pharmaceutical dosage form using UV-visible spectroscopy. J. Pharm. Res. 2015, 5, 10181021.

    • Search Google Scholar
    • Export Citation
  • 21.

    Renu, S. ; Mamt, K. ; Mukesha, M. ; Sunil, K. Simultaneous determination of chlorpheniramine maleate, paracetamol and phenylephrine hydrochloride in tablet dosage form by HPLC. Int. J. Drug Develop. Res. 2013, 5, 258263.

    • Search Google Scholar
    • Export Citation
  • 22.

    Wadher, S. J. ; Kalyankar, T. M. ; Panchal, P. P. Development and validation of simultaneous estimation of chlorpheniramine maleate and phenylephrine hydrochloride in bulk and capsule dosage form by ultra-violet spectrophotometry. Int. J. Chem. Technol. Res. 2013, 5, 24102419.

    • Search Google Scholar
    • Export Citation
  • 23.

    Redasani, V. K. ; Gorle, A. P. ; Badhan, R. A. ; Jain, P. S. ; Surana, S. J. Simultaneous determination of chlorpheniramine maleate, phenylephrine hydrochloride, paracetmol and caffeine in pharmaceutical preparation by RP-HPLC. Scientific Paper 2012, 1, 122.

    • Search Google Scholar
    • Export Citation
  • 24.

    Dawania, A. P. ; Barika, B. B. ; Chipadeb, V. D. ; Bakalb, R. L. ; Chandwarb, A. V. ; Kanungo . RP-HPLC-DAD method for the determination of phenylepherine, paracetamol, caffeine and chlorpheniramine in bulk and marketed formulation. Arabian J. Chem. 2014, 7, 811816.

    • Search Google Scholar
    • Export Citation
  • 25.

    Kardile, S. S. ; Potawale, S. E. ; Vidhate, S. S. ; Kashid, A. M. ; Bansode, A. S. ; Choudhury, H. ; Devale, T. L. ; Pawar, P. D. Development and validation of HPTLC method for simultaneous estimation of ambroxol hydrochloride, phenylephrine hydrochloride, chlorpheniramine maleate, paracetamol and guaiphenesin in pharmaceutical formulation. J. Chem. Pharm. Res. 2015, 7, 169177.

    • Search Google Scholar
    • Export Citation
  • 26.

    Şenyuva, H. ; Özden, T. Simultaneous high-performance liquid chromatographic determination of paracetamol, phenylephrine HCl, and chlorpheniramine maleate in pharmaceutical dosage forms. J. Chromatogr. Sci. 2002, 40(2), 97100.

    • Search Google Scholar
    • Export Citation
  • 27.

    Ahmad, I. ; Sheraz, M. A. ; Ahmed, S. ; Anwar, Z. Multicomponent spectrometric analysis of drugs and their preparations. In Profiles of Drug Substances, Excipients and Related Methodology; Academic Press, Vol.44, 2019; pp 379413.

    • Search Google Scholar
    • Export Citation
  • 28.

    Lotfi, S. ; Veisi, H. ; Karmakar, B. A convenient strategy for the electrochemical evaluation of acetaminophen and caffeine in combined drugs and biological samples over TiO2@ polymethyldopa/Pd nanocomposite functionalized glassy carbon electrodes. Measurement 2021, 186, 110156.

    • Search Google Scholar
    • Export Citation
  • 29.

    Uddin, M. N. ; Mondol, A. ; Karim, M. M. ; Jahan, R. A. ; Rana, A. A. Chemometrics assisted spectrophotometric method for simultaneous determination of paracetamol and caffeine in pharmaceutical formulations. Bangladesh J. Scientific Ind. Res. 2019, 54(3), 215222.

    • Search Google Scholar
    • Export Citation
  • 30.

    Dongala, T. ; Katari, N. K. ; Palakurthi, A. K. ; Jonnalagadda, S. B. Development and validation of a generic RP-HPLC PDA method for the simultaneous separation and quantification of active ingredients in cold and cough medicines. Biomed. Chromatogr. 2019, 33(11), e4641.

    • Search Google Scholar
    • Export Citation
  • 31.

    Nabi, A. ; Tehrani, M. S. ; Farrokhzadeh, S. ; Sadeghi, N. Separation and simultaneous determination of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate in a commercial tablet by a rapid isocratic HPLC method. Hum. Health Halal Metrics 2020, 1(2), 814.

    • Search Google Scholar
    • Export Citation
  • 32.

    Redasani, V. K. ; Gorle, A. P. ; Badhan, R. A. ; Jain, P. S. ; Surana, S. J. Simultaneous determination of chlorpheniramine maleate, phenylephrine hydrochloride, paracetamol and caffeine in pharmaceutical preparation by RP-HPLC. Chem. Industry Chem. Eng. Quarterly/CICEQ 2013, 19(1), 5765.

    • Search Google Scholar
    • Export Citation
  • 33.

    Dewani, A. P. ; Barik, B. B. ; Chipade, V. D. ; Bakal, R. L. ; Chandewar, A. V. ; Kanungo, S. K. RP-HPLC-DAD method for the determination of phenylepherine, paracetamol, caffeine and chlorpheniramine in bulk and marketed formulation. Arabian J. Chem. 2014, 7(5), 811816.

    • Search Google Scholar
    • Export Citation
  • 34.

    Sonone, R. ; Tandel, L. ; Jain, V. Novel rapid isocratic RP-HPLC method for simultaneous estimation of phenylephrine hydrochloride, paracetamol, caffeine, diphenhydramine hydrochloride. Curr. Pharm. Anal. 2021, 17(6), 792800.

    • Search Google Scholar
    • Export Citation
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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s)

  • Danica Agbaba (University of Belgrade, Belgrade, Serbia)
  • Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland)
  • Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

  • R. Bhushan (The Indian Institute of Technology, Roorkee, India)
  • J. Bojarski (Jagiellonian University, Kraków, Poland)
  • B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
  • M. Daszykowski (University of Silesia, Katowice, Poland)
  • T.H. Dzido (Medical University of Lublin, Lublin, Poland)
  • A. Felinger (University of Pécs, Pécs, Hungary)
  • K. Glowniak (Medical University of Lublin, Lublin, Poland)
  • B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
  • A. Gumieniczek (Medical University of Lublin, Lublin, Poland)
  • U. Hubicka (Jagiellonian University, Kraków, Poland)
  • K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
  • H. Kalász (Semmelweis University, Budapest, Hungary)
  • K. Karljiković Rajić (University of Belgrade, Belgrade, Serbia)
  • I. Klebovich (Semmelweis University, Budapest, Hungary)
  • A. Koch (Private Pharmacy, Hamburg, Germany)
  • Ł. Komsta (Medical University of Lublin, Lublin, Poland)
  • P. Kus (Univerity of Silesia, Katowice, Poland)
  • D. Mangelings (Free University of Brussels, Brussels, Belgium)
  • E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
  • G. Morlock (Giessen University, Giessen, Germany)
  • A. Petruczynik (Medical University of Lublin, Lublin, Poland)
  • R. Skibiński (Medical University of Lublin, Lublin, Poland)
  • B. Spangenberg (Offenburg University of Applied Sciences, Germany)
  • T. Tuzimski (Medical University of Lublin, Lublin, Poland)
  • Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
  • A. Voelkel (Poznań University of Technology, Poznań, Poland)
  • B. Walczak (University of Silesia, Katowice, Poland)
  • W. Wasiak (Adam Mickiewicz University, Poznań, Poland)
  • I.G. Zenkevich (St. Petersburg State University, St. Petersburg, Russian Federation)

 

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

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2021  
Web of Science  
Total Cites
WoS
652
Journal Impact Factor 2,011
Rank by Impact Factor Chemistry, Analytical 66/87
Impact Factor
without
Journal Self Cites
1,789
5 Year
Impact Factor
1,350
Journal Citation Indicator 0,40
Rank by Journal Citation Indicator Chemistry, Analytical 72/99
Scimago  
Scimago
H-index
29
Scimago
Journal Rank
0,27
Scimago Quartile Score Chemistry (miscellaneous) (Q3)
Scopus  
Scopus
Cite Score
2,8
Scopus
CIte Score Rank
General Chemistry 210/409 (Q3)
Scopus
SNIP
0,586

2020
 
Total Cites
650
WoS
Journal
Impact Factor
1,639
Rank by
Chemistry, Analytical 71/83 (Q4)
Impact Factor
 
Impact Factor
1,412
without
Journal Self Cites
5 Year
1,301
Impact Factor
Journal
0,34
Citation Indicator
 
Rank by Journal
Chemistry, Analytical 75/93 (Q4)
Citation Indicator
 
Citable
45
Items
Total
43
Articles
Total
2
Reviews
Scimago
28
H-index
Scimago
0,316
Journal Rank
Scimago
Chemistry (miscellaneous) Q3
Quartile Score
 
Scopus
393/181=2,2
Scite Score
 
Scopus
General Chemistry 215/398 (Q3)
Scite Score Rank
 
Scopus
0,560
SNIP
 
Days from
58
submission
 
to acceptance
 
Days from
68
acceptance
 
to publication
 
Acceptance
51%
Rate

2019  
Total Cites
WoS
495
Impact Factor 1,418
Impact Factor
without
Journal Self Cites
1,374
5 Year
Impact Factor
0,936
Immediacy
Index
0,460
Citable
Items
50
Total
Articles
50
Total
Reviews
0
Cited
Half-Life
6,2
Citing
Half-Life
8,3
Eigenfactor
Score
0,00048
Article Influence
Score
0,164
% Articles
in
Citable Items
100,00
Normalized
Eigenfactor
0,05895
Average
IF
Percentile
20,349
Scimago
H-index
26
Scimago
Journal Rank
0,255
Scopus
Scite Score
226/167=1,4
Scopus
Scite Score Rank
Chemistry (miscellaneous) 240/398 (Q3)
Scopus
SNIP
0,494
Acceptance
Rate
41%

 

Acta Chromatographica
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Acta Chromatographica
Language English
Size A4
Year of
Foundation
1992
Volumes
per Year
1
Issues
per Year
4
Founder Institute of Chemistry, University of Silesia
Founder's
Address
PL-40-007 Katowice, Poland, Bankowa 12
Publisher Akadémiai Kiadó
Publisher's
Address
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Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2083-5736 (Online)

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