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

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 min.


Introduction
Currently, Indonesia is reported to import Paracetamol, also known as acetaminophen, is commonly used as analgesic and antipyretic drug (Mane et al., 2018;Sawalha, 2018) and is produced more than 100,000 tons per year universally (Joncour et al., 2014). Apart of being used directly, some scientists tried to improve paracetamol by modifying the molecules. Van de Straat et al. (1987) concluded that 3,5dialkyl substitution resulted in lower chance of inducing hepatotoxicity. It was also found that substituting acetic acid to the molecule can significantly enhance the antipyretic and analgesic effect (Kumar et al., 2013).
Furthermore, activation energy (Ea) and frequency factor (A) are calculated using linear regression from Equation (3).   L.mol -1 .min -1 respectively. such as water content. Jiang and Ni (2018) concluded that the weight ratio between acetic acid and water of 7:3 produced the solubility for the reaction while in this study, we used a weight ratio of 1:1.85.

Effect of Reactant Mole Ratio
In addition to the temperature variation,     Table 3 shows that the reaction rate constant was increasing as the PAF to AA mole ratio was increased from 1:1 to 1:5.
However, the reaction rate constant decreased when the mole ratio was further increased to 1:2. This exception might be due to the presence of side reaction between acetaminophen and excess acetic anhydride to form 4'-acetoxyacetanilide (Jiang and Ni, 2018). Therefore, both Figure 2 and Table 3 show that the optimum PAF to AA mole ratio in this experiment was 1:1.5.

Effect of Agitation speed
The third parameter that was studied in this experiment was agitation speed. The success of PAF and AA reaction relies on perfect dissolution of PAF in the reaction mixture and hence, agitation speed is crucial to enhance the dissolution rate. In this experiment, the agitation speed of 250 RPM was compared with the agitation speed of 350 RPM. The experiment was done at the temperature of 90 °C with PAF to AA mole ratio of 1:1. The conversion of PAF in this experiment is presented in Figure 5 and the reaction rate constant is summarized in Table   4. It was shown in both Figure 5 and Table 4 that the agitation speed of 350 RPM produced higher reaction rate than the agitation speed of 250 RPM by reaching 100% conversion faster and producing higher reaction rate constant.  The complete process of PAF and AA reaction consisted of two consecutive steps, i.e., PAF dissolution into the water followed by the homogeneous reaction between PAF and AA in the aqueous phase. Hence, the kinetic model presented in Eq. (1) assumed a homogeneous reaction. The result in Figure 5 indicated that mixing intensity determined Finally, all the optimum parameters that were concluded in the prior experiments were lumped together and were carried out in one run. Therefore, in the last run, the reaction with PAF to AA mole ratio of 1:1.5 was carried out at the temperature of 108 °C with 350 RPM agitation speed. The conversion of PAF in this run is presented in Figure 6. At these combined optimum conditions, the reaction rate constant value was 1.95 L mol -1 min -1 (R 2 = 0.755), which was 37.7% higher than the highest rate constant obtained at highest temperature but unoptimized reactant mole ratio ( Table 1). The complete 100% conversion was also reached in less than 5 minutes. The reaction time was much less than the reaction times in Figure 3, 4, and 5 to reach the 100% conversion. This finding is very beneficial to improve the profitability of the paracetamol production. Prospect. 2019.