Chemical Nature and Impurities in Paracetamol and Metronidazole:
A Review
Sonone Sumit Pravin, Shriram Vaibhav, Pawar Rutuja, Lokhande Kranti, Sabale Priyanka
Shantiniketan College of Pharmacy, Dhotre Bk., Taluka Parner, District Ahmednagar, India.
*Corresponding Author E-mail: spsonone3012@gmail.com
ABSTRACT:
Purity of any medicine is not determined solely by the quantity of active ingredient in it, but rather by what is accompanying it. These impurities, as they are called, may be introduced at some stage of production, storage or even in packaging1. Some of them might produce no effect or little, others can modify the activity of the drug, decrease its stability, or in the worst situation, result in toxic reactions among the patients. That is why impurity profiling is a highly significant component of the contemporary pharmaceutical science2.
To manage this situation, the International Council for harmonization (ICH) has developed certain guidelines including Q3A and Q3B. These principles group impurities into organic, inorganic, and residual solvents and also establish threshold levels at which impurities will be reported, identifiable or qualified. To such standards is to make sure that the medicines are safe and effective when they reach the patients3.
Two drugs that have not only found their place in all major pharmacopoeia but also have gained popularity with disease management are paracetamol and metronidazole. One of the most used pain reliever and fever suppressants is paracetamol and metronidazole is a reliable anti-microbial agent against anaerobic and protozoal infections4. The two drugs, although long in safe use, are prone to impurities, be it due to their synthetic processes, or through time degradation. Since they are medically significant and may have significant risks related to its impurities, the investigation of their chemical nature and impurity profiles becomes extremely pertinent5. This review thus combines published information on these drugs, the nature and origin of impurity, analysis procedure to identify impurity, regulation criteria on acceptable amount of impurity.
Table 1. Physicochemical Properties of Paracetamol and Metronidazole 6-7
|
Property |
Paracetamol |
Metronidazole |
|
IUPAC Name |
N-(4-hydroxyphenyl) acetamide |
2-methyl-5-nitroimidazole-1-ethanol |
|
Molecular Formula |
C8H9NO2 |
C6H9N3O3 |
|
Molecular Weight (g/mol) |
151.16 |
171.15 |
|
Appearance |
White crystalline powder |
Yellowish crystalline powder |
|
Solubility |
Slightly soluble in water; soluble in alcohol |
Slightly soluble in water; soluble in alcohol, propylene glycol |
|
Functional Groups |
Hydroxyl (-OH), Amide (-NHCOCH3) |
Nitro (-NO2), Hydroxymethyl (-CH2OH) |
Table 2. Common Impurities in Paracetamol and Metronidazole8-10
|
Drug |
Impurity |
Source/Reason |
Toxicological Concern |
|
Paracetamol |
p-Aminophenol |
Starting material / degradation |
Nephrotoxic |
|
Paracetamol |
Acetanilide |
Synthetic intermediate |
Carcinogenic potential |
|
Paracetamol |
4-Chloroacetanilide |
Byproduct during synthesis |
Harmful |
|
Metronidazole |
Hydroxymetronidazole |
Oxidation |
Reduced efficacy |
|
Metronidazole |
2-Methyl-5-nitroimidazole |
Incomplete synthesis |
Possible toxicity |
|
Metronidazole |
Acidic degradation products |
Hydrolysis in storage |
Stability issue |
2. CHEMICAL NATURE OF API: (Table-1)
2.1 Paracetamol:
The paracetamol, or acetaminophen can be referred to chemically as N-(4-hydroxyphenyl) acetamide with a molecular formula C8H9NO2. Structurally, it has a hydroxyl group and a benzene ring with an acetamide group. It is a white crystalline solid, which is not very soluble in water, but rather in alcohol. It is pharmacologically active by blocking the production of prostaglandins in the central nervous system, and this is why it is an analgesic and antipyretic6.
Figure 1. General Structures Paracetamol
2.2 Metronidazole:
The chemical name of metronidazole is 2- (2-methyl-5- nitro-1H-imidazol-1-yl) ethanol and its formula is C6H9N3O3. It has a nitroimidazole skeleton structure. The drug is in form of a crystalline white and yellowish powder, and is insoluble in a lot of water and alcohol. Within anaerobic microorganisms, the nitro group is reduced, generating reactive intermediates, which damage DNA, causing its antimicrobial activity7.
Figure 2. General Structures of Metronidazole
3. TYPES AND SOURCES OF IMPURITIES
(Table-2)
3.1 Paracetamol:
Impurities in paracetamol may originate from synthesis or degradation:
P-aminophenol and acetanilide are process related impurities that might be left behind due to unfinished reactions. The primary impurities are degradation impurities, primarily 4-aminophenol, a toxic material with a nephrotoxic potential. This impurity is usually caused by the hydrolysis or oxidative degradation8.
3.2 Metronidazole:
For metronidazole, impurities are slightly different:
Impurities related to the process are typically the remnants of the synthesis of nitroimidazole. Degradation impurities can be a result of oxidation or hydrolysis of the nitro group. Certain products of these breakdowns have caused concerns on the potential of the mutagenic effects 9.
4. Analytical Methods for Impurity Profiling:
4.1 High-Performance Liquid Chromatography (HPLC):
HPLC has been the most popular technique of identifying impurities in both drugs. It is very sensitive, reproducible and applicable to complex mixtures. As an example, reversed-phase HPLC techniques have frequently been described to measure 4-aminophenol in paracetamol formula11.
4.2 Thin Layer Chromatography (TLC):
Despite its inferior technology, TLC remains useful as a quick and cheap way of screening impurities. It is capable of displaying additional spots when a drug has been degraded giving rapid initial information 12.
4.3 Spectroscopy Techniques:
UV-Visible spectroscopy is useful in rapid determination of APIs and other impurities. Functional groups of the degradation products are determined by IR (infrared) spectroscopy. NMR spectroscopy provides specific structural data of the unknown impurities. Mass spectrometry (MS) particularly has the strength of measuring the precise molecular masses and verifying the impurity structures 13.
5. Regulatory Guidelines and Limits:
Under the ICH guidelines, impurities that are found in amounts exceeding 0.1 per cent. are normally to be identified and their safety assessed. In their official monographs, national and international pharmacopoeias (including IP, BP, and USP) also prescribe set limits of impurity. These thresholds are not merely pegged on manufacturing capacity, but also on the toxicological basis 14.
6. Comparative Analysis:
Although both the drugs have problems with impurities, the trends vary. The biggest victim of the conversion is paracetamol, which is toxic and unstable as 4-aminophenol 15. Metronidazole on the other hand is more vulnerable to hydrolytic and oxidative reactions especially to the nitro group 16. They can both be analyzed using analytical methods such as HPLC but paracetamol usually needs a closer monitoring because it has a toxic metabolite.15-16
7. Future Perspectives:
Profiling of impurities is in a continuous development. The hyphenated methods like the LC-MS/MS and HPLC-NMR are to be increasingly used, and the detection of the unknown impurities will be quicker and more precise. The use of green analytic chemistry is another trend whereby it seeks to minimize the use of toxic solvents. Pharmaceutical firms are also embracing the Quality by design (QbD) concept to prevent generation of impurities as early as during the development phase. 17-19
8. Conclusion:
Briefly, impurity profiling is a crucial element of drug development and quality control. Both paracetamol and metronidazole are safe and effective but have dangers when the impurities are not well managed. Their detection is still mostly done using analytical techniques such as HPLC, TLC and spectroscopy and regulatory guidelines are used to make sure that only safe amounts are allowed. Continued development of analytical technology will increase the possibility of identifying and categorizing impurities, which will eventually provide patient safety.
9. References:
1. Jenke DR, Stults CL, Paskiet DM, Ball DJ, Nagao LM. Materials in manufacturing and packaging systems as sources of elemental impurities in packaged drug products: a literature review. PDA Journal of Pharmaceutical Science and Technology. 2015 Jan 1; 69(1): 1-48.
2. Venkatesan P, Valliappan K. Impurity profiling: theory and practice. Journal of Pharmaceutical Sciences and Research. 2014 Jul 1; 6(7): 254.
3. Rägo L, Sillo H, Hoen ET, Zweygarth M. Regulatory framework for access to safe, effective quality medicines. Antiviral Therapy. 2014 Apr; 19(3_suppl): 69-77.
4. Samuelson J. Why metronidazole is active against both bacteria and parasites. Antimicrobial Agents and Chemotherapy. 1999 Jul 1; 43(7): 1533-41.
5. Pilaniya K, Chandrawanshi HK, Pilaniya U, Manchandani P, Jain P, Singh N. Recent trends in the impurity profile of pharmaceuticals. Journal of Advanced Pharmaceutical Technology & Research. 2010 Jul 1; 1(3): 302-10.
6. El-Obeid HA, Al-Badr AA. Acetaminophen. In Analytical profiles of drug substances 1985 Jan 1 (Vol. 14, pp. 551-596). Academic Press.
7. Price NB. Metronidazole Property.
8. Arıkan CC, Kulabaş N, Küçükgüzel İ. Synthesis and standardization of an impurity of acetaminophen, development and validation of liquid chromatographic method. Journal of Pharmaceutical and Biomedical Analysis. 2023 Jan 20; 223: 115123.
9. Yin M, Hu Y, Fan H, Wang Q, Wang M, Wang W, Shi C. Method for trace determination of N‐nitrosamines impurities in metronidazole benzoate using high‐performance liquid chromatography coupled with atmospheric‐pressure chemical ionization tandem mass spectrometry. Journal of Separation Science. 2023 Mar; 46(5): e2200225.
10. Kitenge DI, Kakumba JM, Dhimbe GB, Makola MM, Katengele JP, Kiungu WN, Kasago FM, Sita JP, Malongo TK, Kindenge JM, Kialengila DM. Impurities in Pharmaceutical Products: Review on Qc Practices in DR Congo.
11. Wyszecka-Kaszuba E, Warowna-Grześkiewicz M, Fijałek Z. Determination of 4-aminophenol impurities in multicomponent analgesic preparations by HPLC with amperometric detection. Journal of Pharmaceutical and Biomedical Analysis. 2003 Aug 8; 32(4-5): 1081-6.
12. Mwankuna CJ, Mariki EE, Mabiki FP, Malebo HM, Styrishave B, Mdegela RH. Thin layer chromatographic method for detection of conventional drug adulterants in herbal products. Separations. 2022 Dec 31; 10(1): 23.
13. Bouarroudj T, Aoudjit L, Nessaibia I, Zioui D, Messai Y, Bendjama A, Mezrag S, Chabbi M, Bachari K. Enhanced photocatalytic activity of Ce and Ag Co-doped ZnO nanorods of paracetamol and metronidazole antibiotics Co-Degradation in wastewater promoted by solar light. Russian Journal of Physical Chemistry A. 2023 May; 97(5): 1074-87.
14. Thomas R. Measuring Elemental Impurities in Pharmaceuticals: A Practical Guide. CRC Press; 2018 Jan 29.
15. Wu S, Zhang L, Chen J. Paracetamol in the environment and its degradation by microorganisms. Applied microbiology and biotechnology. 2012 Nov; 96(4): 875-84.
16. Awuchi CG, Twinomuhwezi H, Awuchi CG. Hyphenated techniques. In Analytical Techniques in Biosciences 2022 Jan 1 (pp. 125-145). Academic Press.
17. Koel M, Kaljurand M. Green analytical chemistry 2nd Edition. Royal society of Chemistry; 2019 Mar 13.
18. Sarker SD, Nahar L. Hyphenated techniques. InNatural products isolation 2006 (pp. 233-267). Totowa, NJ: Humana Press.
19. Jain S. Quality by design (QBD): A comprehensive understanding of implementation and challenges in pharmaceuticals development. Int J Pharm Pharm Sci. 2014; 6(1): 29-35.
|
Received on 29.11.2025 Revised on 18.12.2025 Accepted on 05.01.2026 Published on 10.04.2026 Available online from April 13, 2026 Asian J. Research Chem.2026; 19(2):123-125. DOI: 10.52711/0974-4150.2026.00021 İA and V Publications All Right Reserved
|
|
|
This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License. |
|