Kinetics Study of Paracetamol Production from Para-Aminophenol and Acetic Anhydride

https://doi.org/10.22146/jrekpros.64551

Rifki Wahyu Kurnianto(1*), Muhammad Fahrurrozi(2), Hilda Ismail(3), Raden Rara Endang Lukitaningsih(4), Indah Tri Nugraha(5), Pudjono Pudjono(6), Rochmadi Rochmadi(7), Ari Sudarmanto(8), Ratna Asmah Susidarti(9)

(1) Department of Chemical Engineering, Faculty of Engineering, Universitas Gadjah Mada, Jl Grafika No. 2 Kampus UGM, 55281 Yogyakarta
(2) Department of Chemical Engineering, Faculty of Engineering, Universitas Gadjah Mada, Jl Grafika No. 2 Kampus UGM, 55281 Yogyakarta
(3) Faculty of Pharmacy, Universitas Gadjah Mada, Jl Sekip Utara Kampus UGM, 55281 Yogyakarta
(4) Faculty of Pharmacy, Universitas Gadjah Mada, Jl Sekip Utara Kampus UGM, 55281 Yogyakarta
(5) Department of Chemical Engineering, Faculty of Engineering, Universitas Gadjah Mada, Jl Grafika No. 2 Kampus UGM, 55281 Yogyakarta
(6) Faculty of Pharmacy, Universitas Gadjah Mada, Jl Sekip Utara Kampus UGM, 55281 Yogyakarta
(7) Department of Chemical Engineering, Faculty of Engineering, Universitas Gadjah Mada, Jl Grafika No. 2 Kampus UGM, 55281 Yogyakarta
(8) Faculty of Pharmacy, Universitas Gadjah Mada, Jl Sekip Utara Kampus UGM, 55281 Yogyakarta
(9) Faculty of Pharmacy, Universitas Gadjah Mada, Jl Sekip Utara Kampus UGM, 55281 Yogyakarta
(*) Corresponding Author

Abstract


In the last decade, Indonesia intensifies the efforts to reduce pharmaceutical imports. One of the initiatives is establishing a paracetamol production facility to start operating in 2024. Kinetics study is needed as a basis to design the paracetamol reactor. This study investigated the optimal temperature, reactant mole ratio, and agitation speed in the reactor for paracetamol production. In this study, aqueous solution of para-aminophenol was reacted with acetic anhydride. The mole ratio of para-aminophenol to acetic anhydride was varied to 1:1, 1:1.2, 1:1.5, and 1:2 while the temperature was varied to 80 °C, 90 °C, and 110 °C. However, due to uncontrolled heat of the reaction and limitation of the mixture’s boiling point, the actual reaction temperatures were 86 °C, 90 °C, and 108 °C. In addition, the agitation speed of 250 RPM and 350 RPM were also studied. Thin layer chromatography (TLC) and densitometry were used to determine the concentration of paracetamol in the reacting mixture. The optimum temperature, reactant mole ratio, and agitation speed in this study were 108 °C, 1:1.5, and 350 RPM, respectively. In addition, a reaction performed under those operating parameters gave the reaction rate constant of 1.95 L mol-1 min-1.

Keywords: acetic anhydride; kinetics; para-aminophenol; paracetamol; pharmaceutical industry

 

A B S T R A K

Dalam sepuluh tahun terakhir ini, Indonesia bertekad mengurangi impor bahan baku farmasi. Salah satu upaya yang dilakukan adalah membangun fasilitas produksi parasetamol yang akan mulai beroperasi pada tahun 2024. Studi kinetika diperlukan sebagai dasar perancangan reaktor parasetamol. Oleh karena itu, penelitian ini mengkaji kondisi operasi optimal pada reaksi produksi parasetamol yang akan dibutuhkan sebagai dasar perancangan pabrik. Pada percobaan ini, para-aminofenol direaksikan dengan anhidrida asetat dengan media air. Rasio mol para-aminofenol terhadap asetat anhidrida divariasikan 1:1 1:1,2, 1:1,5, dan 1:2 sedangkan temperatur divariasikan 80 °C, 90 °C, dan 110 °C. Akan tetapi, karena panas reaksi yang tidak dikontrol dan batasan berupa titik didih dari campuran reaksi, temperatur aktual reaksi menjadi 86 °C, 90 °C, dan 108 °C. Selain itu, kecepatan putaran pengadukan juga divariasikan pada angka 250 RPM dan 350 RPM. Kromatografi lapis tipis (KLT) dan densitometri digunakan untuk menentukan konsentrasi parasetamol dalam campuran reaksi. Temperatur, rasio mol reaktan, dan kecepatan putaran pengadukan yang optimum pada penelitian ini masing-masing adalah 110 °C, 1:1,5, dan 350 RPM. Selain itu, reaksi yang dilakukan dengan kondisi operasi tersebut menghasilkan konstanta laju reaksi 1,95 L mol-1 menit-1.

Kata kunci: anhidrida asetat, industri farmasi, kinetika, para-aminofenol, parasetamol


Keywords


acetic anhydride, kinetics, para-aminophenol, paracetamol, pharmaceutical industry

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References

Abdullaev, M.G., Abdullaeva, Z.S., Klyuev, M. V., Kafarova, S.S. and Gebekova, Z.G., 2014, Kinetics of the production of p-acetaminophenol and p-hydroxyphenylsalicylamide by reductive acylation of p-nitrophenol on palladium-containing anionites, Pharm. Chem. J., 47 (11), 610–611.

Amin, M. and Iqbal, M.S., 2015, Solvent Free Synthesis of Acetaminophen, US Patents No. US9006488B1

Bhattacharya, A., Purohit, V.C., Suarez, V., Tichkule, R., Parmer, G. and Rinaldi, F., 2006, One-step reductive amidation of nitro arenes: Application in the synthesis of AcetaminophenTM, Tetrahedron Lett., 47 (11), 1861–1864.

BPS-Statistics Indonesia., 2016, Foreign Trade Statistical Bulletin: Import December 2016.

BPS-Statistics Indonesia., 2019, Foreign Trade Statistical Bulletin: Import December 2019.

Caldeira, R.L.F. de., 2010, An Assessment of Cross-Contamination Issues in the Context of Chemical and Pharmaceutical Processes Using a Continuous Oscillatory Baffled Reactor, PhD Thesis, Heriot-Watt University, United Kingdom

Du, Y., Chen, H., Chen, R. and Xu, N., 2004, Synthesis of p-aminophenol from p-nitrophenol over nano-sized nickel catalysts, Appl. Catal. A Gen., 277 (1–2), 259–264.

Jiang, M. and Ni, X.W., 2018, Effects of water and temperature on reaction mechanism and crystal properties in a reactive crystallization of paracetamol, Chem. Eng. Process. - Process Intensif., 131, 20–26.

Jie, D., Yongjun, L. and Jianguo, L., 2003, Process for prepraring p-acetpamidophenol, China patents No CN1434026A.

Jing, Z., 2014, Process for synthesizing paracetamol, China patents No CN105622449A.

Joncour, R., Duguet, N., Métay, E., Ferreira, A. and Lemaire, M., 2014, Amidation of phenol derivatives: A direct synthesis of paracetamol (acetaminophen) from hydroquinone, Green Chem., 16 (6), 2997–3002.

Kumar, R., Jain, S. and Jain, N., 2013, Synthesis and evaluation of acetaminophen derivatives as analgesic, antipyretic and anti-inflammatory agents, Sch. Res. Libr., 5 (3), 73–78.

Lee, H.L., Lin, H.Y. and Lee, T., 2013, The impact of reaction and crystallization of acetaminophen (Paracetamol) on filtration and drying through in-process controls, Org. Process Res. Dev., 17, 1168−1178.

Mane, S.N., Gadalkar, S.M. and Rathod, V.K., 2018, Intensification of paracetamol (acetaminophen) synthesis from hydroquinone using ultrasound, Ultrason. Sonochem., 49, 106–110.

Min, K. Il, Choi, J.S., Chung, Y.M., Ahn, W.S., Ryoo, R. and Lim, P.K., 2008, p-Aminophenol synthesis in an organic/aqueous system using Pt supported on mesoporous carbons, Appl. Catal. A Gen., 337 (1), 97–104.

Ministry of Research and Technology of the Republic of Indonesia., 2020, Prioritas Riset Nasional, pp. 1–13.

Pyka, A., Wiatr, E., Kwiska, K. and Gurak, D., 2011, Validation thin layer chromatography for the determination of naproxen in tablets and comparison with a pharmacopeil method, J. Liq. Chromatogr. Relat. Technol., 34 (10–11), 829–847.

Ralph, J., Karlen, S. and Mobley, J., 2019, Synthesis of paracetamol (acetaminophen) from biomass-derived p-hydroxybenzamide, US Patents No US10286504B2

Rode, C. V., Vaidya, M.J. and Chaudhari, R. V., 1999, Synthesis of p-aminophenol by catalytic hydrogenation of nitrobenzene, Org. Process Res. Dev., 3 (6), 465–470.

Rode, C.V., Vaidya, M.J. and Chaudhari, R.V., 2002, Single step hydrogenation of nitrobenzene to p-aminophenol, EU Patents No EP1229018A1

Sawalha, R., 2018, Integrated synthesis and crystallization for the continuous manufacturing of paracetamol, Master Thesis, Graz University of Technology, Austria

Van de Straat, R., De Vries, J., Groot, E.J., Zijl, R. and Vermeulen, N.P.E., 1987, Paracetamol, 3-monoalkyl- and 3,5-dialkyl derivatives: Comparison of their hepatotoxicity in mice, Toxicol. Appl. Pharmacol., 89 (2), 183–189.

UNDESA., 2019, World Population Prospects 2019, Dep. Econ. Soc. Aff. World Popul. Prospect. 2019.



DOI: https://doi.org/10.22146/jrekpros.64551

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