INTRODUCTION:

Aceclofenac is chemically [[[2-[(2, 6-Dichlorophenyl) amino] phenyl] acetyl] oxy] acetic acid, is a non-steroidal anti-inflammatory drug (NSAIDS). It is used for the relief of pain and inflammation in several types of arthritis. Diclofenac is chemically [2-[(2, 6-Dichlorophenyl] amino] phenyl] acetic acid, also used as anti-inflammatory and analgesic drug and is a major metabolite and/or degradation product of aceclofenac. Paracetamol is chemically N-(4-hydroxy phenyl) acetamide and is used as analgesic and antipyretic drug in the treatment of pain and fever. Para-aminophenol is a major metabolite and/or degradation product of paracetamol¹. The combination tablets containing 100 mg of aceclofenac and 500mg of paracetamol have been used for acute painful condition in osteoarthritis and rheumatoid arthritis.

The literature survey revealed that aceclofenac in pure form and/or presence of its degradation product, diclofenac was reported by Voltametry², Densitometry³, Colourimetry⁴, Spectrophotometry⁵, HPLC^3-8, LC-MS⁹ and UPLC-QTOF-MS.^10,11 The determination of paracetamol in pure form and/or in presence of its degradation product, para-aminophenol, was reported by Voltametry¹², Electrochemical method¹³, Spectrophotometry^14-17, Flow-Injection Spectrophotometry¹⁸, Spectrofluorimetry¹⁹ and HPLC.^20-23

Simultaneous determination of aceclofenac and paracetamol has been reported by several analytical methods. Such methods includes Densitometric TLC^24-26, Spectrophotometry^27-30, HPLC,^31-37 Stability-Indicating HPLC,^38-40 HPTLC,^41,42 UPLC-PDA,^43-45 HPLC-MS⁴⁶ and UPLC/Q-TOFMS.^47-49 A fixed dose combination (FDC) is a formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses. Combination therapy mechanisms of action represents a type of incremental innovation that has extended the range of therapeutic options in the treatment of almost every human disease. Several difficulties are arise during formulation development, manufacturing and regulations of FDC products. In the era of developed and modified chromatographic techniques, the HPLC-UV is still the simplest, most reliable, easy handling and worldwide used technique in the various stages of drug development. The technique is particularly very simple when analysis is carryout simultaneously for several compounds. Method development by HPLC-UV for two or more compounds and their related impurities becomes very complex if the solubility and the pka values vary greatly and the UV profiles are not similar. Hence to be analyzed by other sophisticated techniques such as LC-MS, UPLC-PDA, UPLC/Q-TOF-MS⁵⁰.

In the presented review article, author has described the various analytical methods for determination of aceclofenac and paracetamol individually and simultaneously.

1. Determination of Aceclofenac:

Several analytical methods have been reported for determination of aceclofenac as individual drug in pure form, its tablet formulations or with its degradation products or alongwith its major metabolites ie diclofenac. Such methods are Voltametry², Densitometry³, Colourimetry⁴, Spectrophotometry⁵, HPLC^3-8, LC-MS⁹ and UPLC-QTOF-MS.^10,11 The details of types of analytical methods, sample matrix, detection and references are summarized in Table 1.

Table 1: Determination of aceclofenac and/or its degradation products

Analytical Methods	Sample Matrix	Detection	Reference
Voltametry	Modified Carbon Paste Electrodes	Voltametric technique	2
Spectrophotometry and Densitometry	Pure form and Pharmaceutical formulations	UV Detection	3
Colourimetry	Pure form and Pharmaceutical formulations	Absorption of coloured complex at 665.5 nm	4
UV Spectrophotometry	Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	UV Detection at 252 nm for aceclofenac and 248 nm for diclofenac	3
UV Spectrophotometry	Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	UV Detection at 245 nm	5
HPLC	Pure form and Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	274 nm for aceclofenac and for diclofenac 283 nm	3
	Pure form and Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	UV Detection	4
	Pure form and Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	UV Detection at 275 nm	5
	aceclofenac and diclofenac from human plasma samples	UV Detection	6
	aceclofenac and three of its metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) in human plasma in pharmacokinetic study	UV Detection at 282 nm	7
	Stability-indicating HPLC, alongwith degradation product i.e. diclofenac	UV Detection at 275 nm	8
LC-MS	LC-MS/MS aceclofenac and its three metabolites (4'-OH-aceclofenac, diclofenac, and 4'-OH-diclofenac) in human plasma	Q- ESI-MS m/z 352.9 to 74.9 for aceclofenac 296.1 to 251.7 diclofenac	9
UPLC-QTOF-MS	Pure form and Pharmaceutical formulations, alongwith degradation product i.e. diclofenac	Q-time-of-flight Mass spectrometer using the MS/MS transitions m/z 354.07 to 215.07 for aceclofenac, 296.23 to 214.06 for diclofenac	10, 11

2. Determination of Paracetamol:

Several analytical methods have been reported for determination of paracetamol as individual drug in pure form, its tablet formulations or with its degradation products or alongwith its major metabolites ie para-aminophenol such method includes Voltametry¹², Electrochemical method¹³, Spectrophotometry^14-17, Flow-Injection Spectrophotometry¹⁸, Spectrofluorimetry¹⁹ and HPLC.^20-23 The details of types of analytical methods, sample matrix, detection and references are summarized in Table 2.

Table 2: Determination of paracetamol and/or its degradation products

Analytical Methods	Sample Matrix	Detection	Reference
Voltametry	Tablet formulation	Voltametric	12
Electrochemical	Blood and Pharmaceutical Formulations	Electrochemical	13
UV Spectrophotometry	Pure Form and in Tablets	UV Detection at 670 nm	14
	Pure form and degradation product i.e. p-aminophenol	UV Detection	15
	Pure form and degradation product i.e. p-aminophenol	UV Detection 223.8 nm	16
	Pure form and degradation product i.e. p-aminophenol	UV Detection 601 nm	17
Flow-Injection Spectrophotometry	Tablets and Oral Solutions	UV Detection at 430 nm	18
Spectrofluorimetry	Pharmaceuticals and Biological Fluids	spectrofluorimetric	19
HPLC	Acetaminophen and Its degradation Product in tablets	UV Detection	20
	Paracetamol and related compounds in tablets	UV Detection at 244 nm	21
	paracetamol and its related compounds in bulk drugs and pharmaceutical formulations	Photo diode array (PDA) detection at 215 nm	22
	Paracetamol in Pharmaceutical Formulations and Environmental Water Samples	UV Detection at 243 nm	23

3. Simultaneous Determination of Aceclofenac and Paracetamol:

Table 3: Determination of aceclofenac and paracetamol and/or their degradation products

Analytical Methods	Sample Matrix	Detection	Reference
Densitometric TLC	Bulk Drugs and in Combined Tablet	UV Detection at 270nm	24
	Bulk Drugs and in Combined Tablet	UV Detection at 274nm	25
	Bulk Drugs, Tablets, Human plasma	UV Detection at 263nm	26
UV Spectrophotometry	Bulk Drugs and in Combined Tablets	UV Detection at 273nm for aceclofenac and 244 nm for paracetamol	27
	Bulk Drugs and in Combined Tablets	UV Detection at 276nm for aceclofenac and 249 nm for paracetamol	28
	Bulk Drugs and in Combined Tablet Dosage Forms	UV Detection at 274.5nm for aceclofenac and 244 nm for paracetamol	29
	Bulk Drugs and in Combined Tablet Dosage Forms	Additivity of UV- absorbances at 276 nm for aceclofenac and 282 nm for paracetamol	30
HPLC	Bulk Drugs and in combined dosage forms.	UV Detection at 265 nm	31
	Bulk Drugs and in combined dosage forms.	UV Detection at 274 nm	32
	Bulk Drugs and in combined dosage forms.	UV Detection at 265 nm	33
	Bulk Drugs and in combined dosage forms.	UV Detection at 275 nm	34
	Bulk Drugs and in combined dosage forms.	UV Detection at 275 nm	35
	pharmaceutical dosage form	UV Detection at 270 nm	36
	Bulk Drugs and in combined dosage forms.	UV Detection at 276 nm	37
Stability-Indicating HPLC	Pure form, Tablets and Degradation products	UV Detection at 276 nm	38
	Tablets and in microsphere formulations	UV Detection at 276 nm	39
	Pure form, FDC Tablets and Degradation products i.e Diclofenac, Para-aminophenol	UV Detection at 275 nm	40
HPTLC	Bulk drugs and FDC Tablets	UV Detection at 254 nm	41
HPTLC	Pure and Pharmaceutical Dosage Form	UV Detection at 254 nm	42
UPLC-PDA	Bilayer Matrix FDC Tablet	PDA Detector at 275 nm	43
	Sustained Release Matrix FDC Tablet	PDA Detector at 275 nm	44
	Pure form, FDC Tablets and Degradation products i.e Diclofenac, Para-aminophenol	PDA Detector at 275 nm	45
LC-MS	Human plasma	Electrospray-Mass spectrometry	46
UPLC-QTOF-MS	Human plasma applied to pharmacokinetic study of combined tablets	Q-TOF mass spectrometer MS/MS transitions m/z 354.07 to 215.07 for aceclofenac, and 152.07 to 110.06 for paracetamol	47-49

Author has reported the UPLC-QTOF-MS^47-49 method for quantitative determination and structural identification of aceclofenac and paracetamol. Quadrupole time-of flight mass spectrmeter was operated via positive ionization mode and both the drugs have strong responses in the positive ionization mode and they form protonated molecules in the full scan mass spectra. Therefore, the positive ions, [M+H]⁺ at m/z 354.07 for aceclofenac, and m/z 152.07 for paracetamol, were selected as the precursor ions. Moreover, under the selected MS/MS conditions the precursor ions were fragmented to major product ions at m/z 215.07 for aceclofenac, and m/z 110.06 for paracetamol. The product ion spectra of aceclofenac suggested that the fragmentation of molecules occurs from carboxylic group and loss of carbon dioxide results in the formation of one common production, which was identified as C₆H₃C_l2NHC₇H₅⁺ at m/z 250.05, is further fragmented in to another product ion, C₆H₄ClNC₇H₅⁺ with higher intensity at m/z 215.07. Spectra of paracetamol was due to the fragmentation of molecule from acetamide group and loss of neutral molecule, namely ketene (CH₂=C=O) results in the formation of major product ion at m/z 110.06. On the basis of product ion spectrum, the fragmentation patterns of drugs were established. The proposed fragmentation mechanisms of aceclofenac, and paracetamol are presented in Figures 1 and Figures 2, respectively.

Figure 1: Fragmentation mechanism of Aceclofenac by Q-TOF-MS/MS technique.

Figure 2: Fragmentation mechanism of Paracetamol by Q-TOF-MS/MS technique

CONCLUSION:

In this review article, author has described the various analytical methods for determination of aceclofenac and paracetamol individually and simultaneously. The details of different types of analytical methods, sample matrix, detection techniques are summarized in tabulation. The presented review is useful for overall and comparative study of various analytical methods reported for determination of aceclofenac and paracetamol.

ACKNOWLEDGMENT:

The author is thankful to Dean and In-charge of Instrumentation Facilities, Faculty of Pharmacy, Hamdard University, New Delhi, India, for providing opportunities to work on UPLC-Q-TOF-MS system.

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Received on 17.09.2023 Modified on 01.12.2023

Asian J. Pharm. Ana. 2024; 14(3):175-179.

DOI: 10.52711/2231-5675.2024.00031