Microwav Assisted Green Synthesis of Paracetamol, Aspirin and their Pharmacokinetic Studies

Microwav Assisted Green Synthesis of Paracetamol, Aspirin and their Pharmacokinetic Studies

Ganesh N Yallappa, Rajendra Prasad S1, Ganesh N. Yallappa2*, NatarajaG3, Megha G4, Dhanyashree S.V.5, Leela P6, Manukumar G. T7

1Department of Chemistry, Davangere University,Davangere, India 2*,3Department of Chemistry, Jain Institute of Technology, Davangere, India 4,5,6,7 Department of Chemistry, Davangere University,Davangere, India

Abstract: The research looks at a new way to make Paracetamol and Aspirin using green chemistry concepts via solvent free reaction and under microwave irradiation. The synthesis was carried out from salicylic acid and 4- aminophenol, acetic anhydride, and no catalyst. The reaction time for both the molecules was low. The yield of Paracetamolis 92.0% and Aspirin is 82.0%. The reaction progression was confirmed by TLC. The structure of the compounds was confirmed by FT-IR and Melting point. Upon literature studies, our work was focussed on the biological metabolismof these synthesized compounds. The compounds were tested for pharmacological studies. We reported the pharmacokinetics and their side effects during the metabolism in the human body. The results were interpreted.

Key Words: Paracetamol, Aspirin, Microwave method, Green Chemistry, Pharmacokinetics.

1. INTRODUCTION

   Today, Paracetamol is a widely used drug in many nations and pharmaceutical formulations. Its composition drugs are used to treat and/or relieve minor aches and pains [1] and are used for cold and flu Infections due to their antipyretic activity[2].

   It is also used to treat and relieve severe pain like post- operative pain [3] and palliative care for cancer patients. Therefore, we planned for the synthesis of this drug by green chemistry. Microwave method is a suitable method for green synthesis. 4-amino phenol treated with acetic anhydride inacidic media to form paracetamol [4-5].

   Figure 1 shows the chemical structures of Paracetamol (PAR) and Aspirin (ASA).

   The scope for this drug led to the manufacture of active pharmaceutical ingredients and statistics showing that over 1, 45,000 tonnes of paracetamol were synthesized every year. Green chemistry is a challenging task to

   follow the synthetic procedures. It is an Engineering idea of pollution prevention and zero waste. It also promotes the adoption of cost favor andenvironmental friendly methods.

   The literature study shows that Aspirin is a very scope drug in the field of medical science [6-7]. After literature survey, we planned to work on the synthesis of Aspirin. Aspirin is known as Salicylates. It is a common drug used for minor aches, pains and fevers. It shows anti- inflammatory activity. In this work, we synthesized the drug by salicylic acid under microwave irradiation [8]. After the synthesis, we tested its pharmacokinetics and for side effects. The metabolism studies have been done.

2. MATERIALS AND METHODS

   All required Chemicals are purchased from Davangere Scientifics. The reaction was carried in Microwave Oven (Convention) (20L, 23,500MHz). The TLC was checked in UV-Chamber and Iodine Chamber. The molecules were characterized by FT-IR (Bruker) in SJMIT, Chitradurga. Pharmacokinetic studies in SS research centre.

   A. Experimental Section:

   General Procedure for the synthesis of Paracetamol: The solid 4-amino Phenol (10 Mmol) was added with aceticanhydride (10 Mmol) in an acidic medium. The sealed reaction mixture was kept in microwave oven for the reaction to proceed. The progress of the reaction was confirmed byTLC. After the reaction, the solution turns to white solid precipitate. The crude solid was recrystallized by ethanoland water. The product was purified by washing with waterfor 2-3 times, filtered and dried.

   General Procedure for the synthesis of Aspirin: The Salicylic acid solution (10 Mmol) was added with acetic anhydride (10 Mmol) in an acidic medium. Microwave oven was subjected to the reaction by inserting the reaction mixture into it. The confirmation of the reaction was done by TLC. After the reaction completion, the solution turns to white solid. The crude white was recrystallized by ethanol and water. The product was purified by water wash for 2-3 times. The solution was filtered and dried (Fig-2).

   Fig-2: Synthesis of Paracetamol and Aspirin

3. SPECTRAL DATA FT-IR

   FT-IR (KBr): cm-1 3000 (O=C-OH, carboxylic), 1757 (-O-

   C=O, Ester) (Fig-4).

4. PHARMACOKINETICS AND SIDE EFFECTS: PARACETAMOL

The maximum single-dose of acetaminophen for pain or fever is 1,000 mg every 4 hours as needed, up to a maximum daily intake of 4g. The therapeutic concentrations range from 5 to 20 mg/ml (Table-1). The plasma maximum concentration (Cmax) is 12.3 g/ml after oral administration of 1,000 mg acetaminophen, the area under the curve over 6 h AUC (06) is 29.4 g/h/ml, and the AUC extrapolated to infinity (AUC0) is 44.4 g/h/ml (Bertolini et al., 2006) [9-11].

The elimination half-life (t1/2) is 2.53 hours, and the time to peak concentration (Tmax) is 1.0 hour. These findings demonstrate that intravenous acetaminophen delivery results in higher peak plasma levels and occurs sooner than oral dosing [12-15].

Aspirin

Table-1: Pharmacokinetic parameters

Oral Bioavailability (F)	65%
Clearance (CL)	33 L
Volume of distribution (Vd)	9.0L
Half-life (t1/2)	0.25h

CONCLUSION:

Both Paracetamol and Aspirin synthesized by Green Chemistry. Pharmacokinetic studies were evaluated and reported their side effects. Overall studies concluded that drugs can be synthesized by green route under microwave method. Also, drugs are having cytotoxic effects for human.

Fig-3: FT-IR of Paracetamol

FT-IR (KBr) cm-1: 3325 (-OH stretching), 3162-3035 (CH3 stretching), 1665 (C=O, Amide), 1609 (C=C) (Fig-3)

Aspirin

Fig-4: FT-IR of Aspirin

ACKNOWLEDGMENT

All authors express thanks to JIT- Davangere and Davangere University-Davangere for the support of this work.

REFERENCES:

[1] S. Eyers, M. Weatherall, S. Jefferies and R. Beasley. "Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis". Clinical and Experimental Allergy. Vol 41 (4), pp 4829, April 2011.

[2] G. Fan G, B. Wang, C. Liu, and D. Li. "Prenatal paracetamol use and asthma in childhood: A systematic review and meta- analysis". Allergol Immunopathol (Madr). Vol 45 (6), pp 528

533, 2017.

[3] R. Masarwa, H. Levine, E. Gorelik, S. Reif, A. Perlman, and I. Matok. "Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta- Regression Analysis of Cohort Studies". Am J Epidemiol. Vol 187 (8) pp 18171827, August 2017.

[4] J. Deen, L. Von Seidlein. "Paracetamol for dengue fever: no benefit and potential harm?". Lancet Glob Health. Vol 7 (5), pp e552e553, May 2019.

[5] Y. Ji, R.E. Azuine, Y. Zhang, W. Hou, X. Hong, G. Wang, A. Riley, C. Pearson, B. Zuckerman, X. Wang "Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism

Spectrum Disorder in Childhood". JAMA Psychiatry. Vol 77 (2): pp 180189, (February 2019).

[6] D. Dominik, S. Wolfgang, S. Schwarzer. Microwave Synthesis of a Prominent LEDPhosphor for School Students: Chemistrys Contribution to Sustainable Lighting. J. Chem. Edu., Vol 96 (12), pp 3018-3024, 2019.

[7] V.I. Isaeva, A.L. Tarasov, V.V Chernyshev and L.M. Kustov. Control of morphology and size of microporous framework MIL- 53 (Al) crystals by synthesis procedure. Mendeleev Commun., Vol 25, pp 466467, 2019.

[8] Ganesh N Yallappa, D. Nagaraja, U. Chandrashekhar. Nano- catalyzed Green synthesis of Pyrazole derivatives & its biological activity as EAC receptor antagonists. Pharmacophore Vol 28(3), pp 28-32, 2019.

[9] I. Torjesen. "Covid-19: ibuprofen can be used for symptoms, says UK agency, but reasons for change in advice are unclear". BMJ. Vol 369: pp 1555, April 2020.

[10] Ebrahimi, P. et al. Prevalence rate of laboratory defined aspirin resistance in cardiovascular disease patients: A systematic review and meta-analysis. Casp. J. Intern. Med. 11, 124134, 2020.

[11] H.M. Kedir, E.A. Sisay, A.A Abiye. Enteric-coated aspirin and the risk of gastrointestinal side effects: a systematic review. Int J Gen Med., Vol 14, pp 475763, 2021.

[12] L. McEvoy, D.F. Carr, M. Pirmohamed. Pharmacogenomics of NSAID-Induced Upper Gastrointestinal Toxicity. Front Pharmacol. Vol 12, pp 684162, 2021.

[13] K. Dizon, M. Battistella. A retrospective study of antithrombotic therapy use in an outpatient haemodialysis unit. J Clin Pharm Ther. Vol 46(5), pp 1387-1394, 2021.

[14] T. Weltermann, C. Schulz, L. Macke. Effect of frequently prescribed drugs on gastric cancer risk. Best Pract Res Clin Gastroenterol.Vol 50-51, pp 101741, march 2021.

[15] M. Christiansen, E.L. Grove, A.M. Hvas. Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives. Semin Thromb Hemost. Vol 47(7), pp 800-814, 2021 Oct.