A Review of various Analytical Methods Developed for Estimation of Paracetamol, Diclofenac sodium, and Chlorzoxazone in Single-component and Multi-component Dosage Form


Lakpa Doma Sherpa*, Bibhas Pandit, Bhupendra Shrestha

Himalayan Pharmacy Institute, Sikkim University, Majhitar, Rangpo, East Sikkim, 737136, India.

*Corresponding Author E-mail: lakpadoma117@gmail.com



Painful muco-skeletal joint disorders such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis are typically treated with a combination of paracetamol, diclofenac sodium, and chlorzoxazone. Paracetamol and diclofenac sodium are non-steroidal anti-inflammatory drugs, while chlorzoxazone is a muscle relaxant. It acts on the central nervous system and the spinal cord to reduce muscle stiffness and spasms as well as increase muscle mobility. The most commonly used pharmaceutical medicine is paracetamol, which comes in a variety of dosage forms such as injection, tablet, capsule, drops, elixirs, suspensions, and suppositories. However, due to toxicity, it may cause mortality in large dosages with extended intake. As a result, more efficient analytical approaches aimed at providing quality control of routinely used medications are required. Numerous analytical methods, both spectroscopic and chromatographic such as high-performance liquid chromatography, gas chromatography with mass spectrometry, and high-performance thin-layer chromatography have been established to estimate paracetamol diclofenac sodium and chlorzoxazone in their single-component dosage form. The simultaneous estimation of paracetamol, diclofenac sodium, and chlorzoxazone in combined dosage forms has been performed using reverse-phase high-performance liquid chromatography and high-performance thin-layer chromatography techniques. In contrast, there are very few techniques available to estimate paracetamol, diclofenac sodium, and chlorzoxazone in combination pharmaceutical dose form till date. This article is an attempt to jut out all the methods developed to estimate the above-mentioned drugs in the single or multi-component dosage form.


KEYWORDS: Paracetamol, Diclofenac sodium, Chlorzoxazone, Spectroscopy, Chromatography.




Paracetamol (PCM) also known as Acetaminophen is considered one of the widely consumed drugs for its antipyretic, analgesic, and anti-inflammatory activity,1,2 Figure 1. It's an over-the-counter (OTC) and prescription medicine used to treat moderate discomfort, lumbar pain, fever, migraines, and other non-specific symptoms3. In terms of gastrointestinal irritation, ulceration, and bleeding, it is seen to be an excellent alternative to aspirin4,5.


The suppression of prostaglandin production by Cyclooxygenase -I (COX-I) and Cyclooxygenase -II (COX-II) is responsible for PCM's antipyretic, analgesic, and anti-inflammatory properties6,7,8.


Figure 1: Chemical structure of PCM


Rheumatoid arthritis, osteoarthritis, bursitis, wound edema, ankylosing spondylitis, and pain reduction are all typical uses for diclofenac sodium (DIC)9,10. It belongs to the non-steroidal anti-inflammatory medication (NSAID) class, which also has analgesic and antipyretic properties,11 Figure 2. It has a high solubility in alcohols like ethanol and methanol12,13. It has anti-inflammatory properties because it inhibits prostaglandin production, an enzyme that is important for the formation of inflammatory responses, by inhibiting cyclooxygenase-I and II enzymes14,15.


Figure 2: Chemical structure of DIC


Chlorzoxazone (CZ) (5-chloro-2(3H)-Benz oxazolone) Figure 3, is one of the most effective skeletal muscle relaxants, particularly when combined with acetaminophen16,17. CZ works by suppressing multi-synaptic reflex arcs that are involved in the development and maintenance of skeletal muscle spasms, especially in the brain's subcortical regions and at the spinal cord level18,19.


Figure 3: Chemical structure of CZ


Pharmaceutical formulations including PCM, DIC, and CZ have been generally used in a variety of pharmaceutical formulations across the globe, either as a single dose or as a combination dosage form 20,21. There is a pressing need for analytical techniques for determining them in pharmaceutical mixes, as a result, numerous methods for estimating those medications have been devised 22. According to the literature study, no single review on multiple analytical techniques established for the quantification of PCM, DIC, and CZ has been published. As a result, this review article aims to provide an overview of the numerous analytical techniques established for estimating PCM, DIC, and CZ in single and multicomponent dose forms.


Estimation of PCM in single-component dosage form:

Due to its analgesic, antipyretic activities, PCM has been used worldwide as the first‐line treatment over any other analgesic. However, administrations more than recommended dose can lead to severe liver damage and probably death. The rising occurrence of self-imposed overdose of PCM demands more method development for PCM estimation. In 1994, Critchley et al. devised an RP-HPLC technique for quantifying PCM and its principal metabolites in bodily fluids. 0.1 M potassium dihydrogen orthophosphate: acetic acid: propane-2-01 in the ratio of (100:0.1:0.75) was used as mobile phase and UV detection was done at a wavelength of 254 nm. RSD were determined to be 0.2-1.7 % and 0.l-3.3 % for urine and plasma PCM concentrations of 5-500 µg/mL and 5-25 µg/mL, respectively23. Then, M.I.H. Helaleh et al. proposed a kinetic approach for determining the presence of PCM in various formulations and pure forms in 1999. The interaction of PCM with persulfate in an alkaline medium allows kinetics parameters to be used to successfully determine PCM24. M. de Los A. Oliva et al. in 2004 had devised a fluorescence spectrophotometric technique for PCM quantification in the tablet dosage form. Their approach used a reaction between ethyl acetoacetate and PCM to produce a coumarin molecule, with H2SO4 acting as a catalyst. At a wavelength of 446 nm, the reaction product exhibits excitation. At 478 nm, a strong fluorescence excitation spectrum for the reaction product was detected. For the equivalent of 0.1-0.4 µg/mL PCM, the calibration graph was found to be rectilinear, and the detection limit was 57 ng/mL25. A.M. Saeed has devised a UV spectrophotometric technique in 2017, for determining the amount of PCM in certainly produced tablets sold in Iraqi markets. The study was carried out using a variety of solvents, including water, water: methanol (95:5), water: methanol (90:10), water: ethanol (95:5), and water: ethanol (90:10). The linearity range of 1-30 mg/L gave the high R2 values for water, methanol, and ethanol. At 243 nm, the greatest absorption was observed. Mean % recoveries were found to be 99.0-101.2 % 26.


Estimation of DIC in single-component dosage form:

In 1995, L.A. Carreira et al. devised a spectrophotometric approach using europium (III) ion probe for the quantitative measurement of DIC in various pharmaceutical formulations as well as in bulk. The approach was developed using a very sensitive measurement of transitions of the fluorescent EU (III) probe ion at 616 nm. The non-hypersensitive response of the fluorescent EU (III) probe ion is measured at 592 nm. To calculate the proportion of bound probe ions, the intensity ratio (R =I592/I616) was utilized. A relative stability constant of 105 was found in the Eu (III) and Diclofenac (1:1) molar combination. The association between bound Eu (III) and DIC was found to be linear throughout the concentration range of (10–200) µg/mL, with a percent recovery of 100.22 % 27. L.G. Lala et al. developed a high-performance thin-layer chromatographic (HPTLC) method in 2002, for determining the concentration of DIC in biological fluid serum. It was determined that DIC was present in serum samples by extracting it with ethyl acetate, then spotting it on Silica Gel 60 F254 plates using an 80:30:1 mobile phase consisting of toluene, acetone, and glacial acetic acid, and developing the plates. DIC was discovered using a retention factor of 0.58 and a wavelength of 280 nm for densitometric analysis. Within the concentration range of 200-800 ng, the standard curve for DIC in serum was plotted and found to be linear28 By using FT-Raman spectroscopy, in 2008, S. Mazurek et al. were able to quantify DIC in solid dosage forms including tablets and capsules. Quantification of DIC was accomplished using a variety of approaches, including partial least squares (PLS), principal component regression (PCR), and counter-propagation artificial neural networks (CP-ANN). Standard curves were produced using unnormalized spectra for the tablet dosage form. The intensity of a chosen band from an internal standard was then used to normalize the spectra. Different preprocessing techniques were used for the capsule dose form. The relative standard errors of prediction (RSEP) values for the calibration and validation data sets for the tablets and capsules were determined to be in the range of 2.4-3.8 % and 0.8-1.9 % and 2.6-3.5 % and 1.4-1.7 % and the percentage recoveries for the PLS, PCR, and CP-ANN techniques were found to be 99.5-101.3%, 99.7-102.0%, and 99.9-101.2%, respectively29. Using the voltammetry technique Linear Sweep Voltammetry (LSV) and hyphenated GC-MS detection, B. Yilmaz et al. have presented a novel method to quantitatively identify diclofenac in different pharmaceutical dosage forms, in the year 2015. For LSV and GC-MS, linearity was attained in the range of (5-35) µg/mL and (0.25-5) µg/mL, respectively. The LSV and GC-MS techniques' inter-day and intra-day relative standard deviations were found to be 4.62 % and 4.39 %, respectively, and the LOQ was determined to be 4.8 µg/mL and 0.15 µg/mL30. For the measurement of DIC, Savale et al. devised a UV spectrophotometric technique, in 2017. A UV-Vis spectrophotometer (UV-1700) was used in conjunction with UV Probe software on a PC. The absorption band was measured between 200 and 800 nm. The new technique was found to be suitable for measuring DIC, with high recovery, accuracy, and linearity, and it was validated according to ICH requirements 31.


Estimation of CZ in single-component dosage form:

Chemical derivatization with several fluorogenic reagents was used by J.T. Stewart et al. to determine the fluorometric determination of CZ, in 1978. Reagents used in the study included dansyl chloride, fluorescamine, 2,4-dihydroxybenzaldehyde, and salicylaldehyde. The fluorophor produced by basic hydrolysis of CZ followed by a reaction with fluorescamine was found to be the most sensitive technique examined. Over the concentration range of 0.27-3.4 µg/mL, fluorescence was found to be linear. The analysis of CZ in a dose form and spiked human plasma and urine samples was determined to be accurate to within 1-4 % 32. In 1993, D.D. Stiff et al. have developed an HPLC method for the quantitative determination of CZ and its major metabolite 6-hydroxyCZ in plasma. The internal standard of CZ (5-fluorobenzoxazolone) was obtained from plasma by using C18 solid-phase extraction columns. For analysis of the extract a 10-µm Waters C18, µBondapak column was used with acetonitrile: tetrahydrofuran: 0.1 M ammonium acetate (22.5:5.5:72) as a mobile phase. The assay detection was done by UV at the wavelength of 283 nm which provided sensitivity and specificity sufficient to simultaneously quantify less than or equal to100 ng/mL CZ and 6-hydroxyCZ in plasma 33. C.B. Eap et al. have reported a GC-MS method for the simultaneous determination of CZ and 6-hydroxyCZ in plasma, in the year 1998. The calibration curve was plotted for CZ and 6-hydroxyCZ and was found to be linear within the range of (20 to 4000) ng/mL and (20 to 1000) ng/mL, respectively. The percentage recoveries were in the range of 65 % to 97%, with intra-day and inter-day coefficients of variation less than 9%. The LOQ was found to be 5 ng/mL 34. Porcine microsome samples may be tested for CZ and 6-hydroxy CZ using an HPLC technique developed by S.K. Cox et al, in 2003. On the YMC-Pack ODS-AQ column, chromatographic separation was carried out using a mobile phase of 0.05 percent phosphoric acid (pH-3) methanol in a ratio of 60:40. It was determined that the detector's response was linear in the range of 25-2000 ng/mL35. Then in 2012, J.C. Abbar et al. have developed an electrochemical method for the estimation of CZ. In the developed method, the electrochemical properties of CZ drugs have been studied by the use of cyclic and square wave voltammetric techniques. The experimental conditions for the estimation of CZ have been enhanced by various factors like concentration, scan rate, and pH. Within the concentration range of 8.0 x, 10-7 to 1.0 x          10-5 M CZ shows good linearity with a LOD of 4.41 x 10-8 M 36.


Estimation of PCM and DIC in combined dosage form:

In 2006, V.V. Dighe et al. developed a normal-phase HPTLC method for determining DIC and PCM in a pharmaceutical formulation and bulk drug powder. The analysis was carried out on silica gel 60 F254 HPTLC plates using a mobile phase of toluene–ethyl acetate-methanol-formic acid, 5.0 + 4.0 + 1.0 + 0.01 (v/v), at 260 nm. The responses of the DIC and PCM standards were linear in concentration ranges of 30-800 ng/μL and 300-2000 ng/μL, respectively, with aceclofenac as the internal standard. Recovery experiments were used to test the method’s accuracy, and the average recovery from the pharmaceutical formulation was determined to be 99.57 % for DIC and 100.51 % for PCM, respectively37. Then in 2018, P. Bhatt et al. have presented the development and validation of an LC-MS/MS technique for quantification of PCM and diclofenac in human plasma using gabapentin as an internal reference utilizing a Quality by Design (QbD) approach (IS). Sample preparation and extraction were carried out using the protein precipitation method, and then chromatographic analysis was performed. For PCM and diclofenac, the calibration range was found to be between 205-13060 ng/mL and 40-2555 ng/mL, respectively. The devised approach met all of the validation study criteria for PCM and diclofenac estimation, including linearity, accuracy, precision, selectivity, sensitivity, and stability38. Recently in 2020, M.M. Sebaiy et al. proposed a spectrophotometric method for determining PCM and DIC in pure form and pharmaceutical formulations. H-Point assay was utilized without prior separation for simultaneous measurement of both medications. The technique parameters were evaluated according to ICH requirements, and they were determined to be within acceptable limits in terms of accuracy, precision, repeatability, and robustness 39.


Estimation of PCM and CZ in combined dosage form:

Chemometrics-assisted spectrophotometric techniques, principal component regression (PCR), and partial least square regression (PLS-1) for determining acetaminophen and CZ in tablets have been proven by C.M. Phechkrajang et al. in 2011. A central composite design was used to construct two sets of standards mixtures and a set of calibration mixtures (CCD). PLS-1 and main component regression were used to analyze the UV absorbance spectra of the final sample’s PCR. The test set solutions for model validation were determined using the best regression models. Acetaminophen and CZ in tablets were determined using PLS-1 and PCR models 40. In 2013, E.A. Abdelaleem et al. developed and validated a TLC-densitometric method for the simultaneous determination of PCM and CZ, as well as their toxic impurities, 4-amino phenol (4AP) and 2-amino-4-chlorophenol (2ACP), which are also regarded hydrolytic degradation products and related substances of the studied drugs. Pre-activated silica gel 60 F254 TLC plates and chloroform: methanol: glacial formic anhydride (9.5:0.5:0.25) as mobile phase was used. At 225 nm UV detection was performed. Calibration curves for PAR, CZ, 4AP, and 2ACP were created using polynomial equations in the ranges of 0.3-3, 1-10, 0.06-3, and 0.04-3 mg/band, respectively41. In recent year (2020), A.F. El-Yazbi et al. have demonstrated the use of HPLC (DAD) for simultaneous estimation of PCM and CZ in the presence of five degradation products and toxic impurities, namely 4-aminophenol, 4-nitrophenol, acetanilide, 4-chloroacetanilide, and 2-amino-4-chlorophenol. The mobile phase was methanol, and the column was a Waters Symmetry C8 column (3.9 150 mm, 5 m) with gradient elution of 0.05 M phosphate buffer pH 7.5 and gradient elution of 0.05 M phosphate buffer pH 7.5. A flow rate of 1.0 mL/min was used to pump the mobile phase. To quantify PCM and CZ, the multiple wavelength detector was adjusted to 244 and 285 nm, respectively. 4-aminophenol, PCM, 4-nitrophenol, acetanilide, 2-amino-4-chlorophenol, CZ, and 4-chloroacetanilide eluted with excellent resolution at retention periods of 3.4, 5.7, 8.0, 10.1, 10.8, 13.5, and 14.4 min, respectively. For PCM and CZ, calibration curves in the ranges of 10-75 and 10-100 µg/mL were linear, with correlation coefficients of no less than 0.999842. In 2013, S.A. Patel et al. has simultaneously determined CZ and DIC by Q-absorbance ratio method, in a bulk and mixture prepared synthetically. The method uses the ratio of absorbances at two selected wavelengths, one at 281 nm (isoabsorptive point) and another at 244 nm (λ-max of CZ) by using 0.1 N NaOH. With the Linearity range of 4-22 μg/ml, analysis of both drugs was carried out. Ratio of absorbances at 281 nm and 244 nm were used to determined concentrations of the drugs. The method suitability was validated statistically and with recoveries study, for the simultaneous estimation of CZ and DIC43.


Estimation of PCM, DIC, and CZ in combined dosage form:

In 2007, A. Goyal et al. created an HPLC technique for determining PCM, CZ, and DIC in combined dosage form. A reversed-phase C8 column was used. The pH was adjusted to 4.06 with 10% orthophosphoric acid and the mobile phase was acetonitrile with 0.05M ammonium dihydrogen orthophosphate (60:40v/v). When diazepam was utilized as an internal reference, the flow rate was 1.5 mL/min. In the concentration ranges of 26-130 µg/mL, 20-100 µg/mL, and 4-20 µg/mL, respectively, the calibration curves for PCM, CZ, and DIC were determined to be linear. PCM, CZ, and DIC were found to have lower LOD of 6.51 µg, 4.97 µg, and 0.84 µg, respectively 44. Then in 2009, S.J. Pawar et al. developed an HPTLC technique to measure PCM, DIC, and CZ in the tablet dosage form. Various aliquots of sample solution were automatically spotted on Merck HPTLC plates (0.2 mm thickness) precoated with silica gel 60 F254 on the aluminum sheet as stationary phase prewashed with methanol, using mobile phase as chloroform: methanol: ammonia (20: 5: 0.2 v/v/v) with a Camag Linomat V sample applicator (Muttenz; Switzerland). A Camag TLC scanner 3 was used to scan the spots at a wavelength of 254 nm. The retention factors for PCM, DIC, and CZ were 0.53, 0.27, and 0.68, respectively. For PCM, DIC, and CZ, the LOD and LOQ were determined to be 100, 100, 500, and 300, 300, 1500 ng per spot, respectively, and the calibration curve was found to be linear in the 1000-5000 nm per spot range45. E.L. Bagary et al. (2017) designed and validated a spectrophotometric technique for the simultaneous detection of DIC, PCM, and CZ in a ternary mixture using chemometric ANN methodologies. The synthetic mixes comprising of the three drugs in methanol were produced using CLS, PCR, and partial least squares, in addition to cascade-forward backpropagation ANN (CFBP-ANN) (PLS). In the three chemometric techniques outlined, the absorbances of the synthetic mixtures in the range 267-295 nm with intervals of 0.2 nm in their zero-order spectra were selected. A sigmoid layer with 10 neurons and a linear layer of CFBP-ANN were shown to be suitable for concurrently identifying the three drugs in their ternary combination. The accuracy study's percentage recoveries were found to be in the range of 98-102 % with an RSD of 1% 46.



A Literature survey was conducted from the late 20th till recent 21st century to present a review on various analytical methods available for determination of PCM, DIC, and CZ in a single-component and in multi-component pharmaceutical dosage forms. Undoubtedly, there is numerous research articles published for estimation of PCM, DIC and CZ. But, only different types of method developed has been highlighted such as LSV, SPE-HPLC (DAD), GC-MS, HPTLC, solid-phase UV absorptiometry, gravimetric, potentiometric, fluorometric (via chemical derivatization), FTIR, cyclic and square wave voltammetry, differential pulse anodic voltammetry and derivative spectroscopy as a single component analytical techniques. Simultaneous equation, bivariate, ratio subtraction, extended ratio subtraction, TLC-densitometric, chemometrics-assisted spectrophotometric, RP-HPLC, HPTLC, TLC-densitometric, HPLC-DAD, LC-MS/MS as multi-component analytical techniques. Certainly, HPLC methods are better in terms of separation and identification. Although, UV/Vis spectroscopic method was the most commonly applied method for the routine analysis among any other methods due to its simplicity, sensitivity, availability and even less time-consuming Process. In comparison, very few methods have been reported for the simultaneous estimation of PCM, DIC, and CZ in the combined pharmaceutical dosage form. Therefore, this gives a great chance for researchers in future to develop a new simple, robust, precise and more accurate method for the routine analysis of PCM, DIC, and CZ in the combined pharmaceutical dosage form.



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Received on 07.05.2022            Modified on 20.12.2022

Accepted on 08.06.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(8):3977-3982.

DOI: 10.52711/0974-360X.2023.00653