Solubility and degradation of paracetamol in subcritical water

In this study, solubility and degradation of paracetamol were examined using subcritical water. The effect of temperature and static time was investigated during the solubility process in subcritical water at constant pressure (50 bar). The experimental results showed that temperature and static time have crucial effects on the degradation and solubility degrees. The maximal solubility of paracetamol was obtained at 403 K as (14.68±0.74)×103. An approximation model for the solubility of paracetamol was proposed. O2 and H2O2 were used for the degradation of paracetamol. The maximum degradation degree was found as 68.66±1.05 % and 100±0.00 % using O2 and H2O2, respectively.


INTRODUCTION
In recent times, pharmaceuticals have been detected in surface water, ground water, drinking water and sewage effluents due to their intensive usage. 1,2The presence of pharmaceuticals in drinking water and aquatic environments endangers human health and causes various health problems. 3][6] Paracetamol (acetaminophen, N-(4-hydroxyphenyl)acetamide) is a major analgesic and antipyretic agent and is widely used as an intermediate agent in the azo dyes industries and photographic chemicals worldwide. 7,8Although paracetamol, used as fever reduction drug and for pain relief, is relatively safe at lower doses, it has various hazards, such as gastrointestinal disease, liver failure, hepatotoxic potential, and centrilobular necrosis in the liver. 9,1000 E M İ R E et al.
Paracetamol has been found in sewage treatment plant with concentration up to 6 and 10 ppb in natural waters. 7,11,12Thus, efficient degradation techniques are required to avoid potential risks of contaminated waters polluted by pharmaceuticals, particularly by paracetamol.4][15] Moreover, subcritical water oxidation, with or without oxidants, is an effectual method for the degradation of hazardous compounds that exist in aquatic environments. 16,177][18] Hydrogen peroxide is a relatively innocuous oxidation agent that decomposes to O 2 and H 2 O at room temperature.It produces reactive hydroxyl radicals (HO • ) which are able to efficiently degrade most organic pollutants present in wastewaters. 19,20Although oxygen is not as effective as hydrogen peroxide, it has been employed in many studies concerned with wastewater treatments due to its environmentally friendly nature. 21Thus, hydrogen peroxide, and oxygen were used as oxidizing agents in the present study.
In addition, the solubility of pharmaceuticals is essential for their removal from contaminated sites.Dissolving hazardous organic compounds in subcritical water appears to be an effective method for remediating contaminated water. 22any literature studies focused on using several methods for determining the solubility of paracetamol in various solvents. 7These methods were often toxic and required an additional solvent removal step.Herein, subcritical water was used as a unique alternative and environmentally friendly method that offers many advantages. 23n the literature, there are several investigations about the solubilities of pharmaceuticals in single and binary solvent mixtures, which is important for pharmaceutical industry.Approximation model equations are useful to predict the solubilities of the pharmaceuticals over a wide range of temperatures.These equations are obtained using experimental data for the pharmaceuticals.Various physicochemical parameters affect the approximation models, such as pressure, pH, salt and co-solvent concentration, dissolution enthalpy, entropy, etc.Moreover, the decomposition temperature of pharmaceuticals obtained through these models seems to be important. 14,24,25Thus, the mentioned models are recommended as useful for determining appropriate operating parameters by performing a limited number of experiments in decontamination treatments.
Paracetamol was degraded using O 2 and H 2 O 2 in subcritical water.The solubility characteristics of paracetamol in subcritical water were investigated.In addition, an approximation model for the solubility of paracetamol was obtained using reported models for organic molecules.Solubility experiments procedures A syringe pump system and a self-made oven system were used for the solubility experiments, as described in a previous work. 26An empty cylindrical HPLC column was filled with 0.25 g of paracetamol.Both ends of the column were covered with 0.45 µm mesh size frits and the cell was tightened to prevent leakage.The filled column was placed in a Teknosem TF R400 model oven.The syringe pump system was used to deliver water in the pressure mode fixed to 50 bar.Fractions (3 mL) were collected at 5, 10, 15 and 30 min after 60 min equilibration at each temperature.Solubility experiments were performed in triplicate to ensure accuracy of the experimental solubility data and were performed at six different temperatures ranging from 293 to 433 K.

Degradation experiments procedures
A self-made system, a so-called reactor, was used for the degradation experiments, as shown in a previous work. 27The reactor was filled with 120 mL of 5 ppm aqueous paracetamol solution.Degradation experiments were performed at four different temperatures ranging from 373 to 433 K.The samples were collected at 5, 15, 30 and 60 min.The pressure was maintained at 30 bar with nitrogen to keep the water in liquid form, and 0.035 mL of H 2 O 2 were used as oxidizing agent in each degradation experiment.In the other batch of degradation experiments, the pressure was maintained at 30 bar with oxygen, which also acted as an oxidizing agent in this case.

HPLC analysis
Paracetamol was analyzed using a mobile phase consisting of a mixture of 28 vol.% of methanol and 3 vol.% of glacial acetic acid in water at a flow rate of 1.5 mL min -1 at ambient temperature.A UV-DAD detector was used at a wavelength of 275 nm.Paracetamol standards were prepared in deionized water.

Effect of temperature on solubility
Experimental mole fraction solubilities (x 2 ) of paracetamol in subcritical water obtained at different temperatures are summarized in Table I.It is clearly seen that the temperature has a significant effect on the solubility as stated in previous studies. 15,28owever, the mole fraction solubility of paracetamol decreased dramatically to x 2 < 10 at 413 K due to possible degradation of paracetamol at higher temperature.

Effect of static time on solubility
The highest mole fraction solubility of paracetamol was obtained at 403 K as 12.78±0.51,14.36±0.59,14.44±0.46and 14.68±0.74, in static times of 5, 10, 15 and 30 min, respectively.The static time is an effectual parameter for the solubility of organic molecules, as stated in previous papers. 23It was found that a static time above 10 min had a minor effect on the rates so that an adequate time was provided to the system to attain equilibrium.

Approximation models
Miller et al. proposed a new equation (Eq.( 1)) for the solubility of polycyclic aromatic hydrocarbons in subcritical water. 13The mole fraction solubility at elevated temperatures can be predicted using the mole fraction solubility obtained at ambient temperature (T 0 ) as shown in Eq. (1): 13 ( ) ( ) where x 2 (T) demonstrates the mole fraction solubility at any temperature (T), x 2 (T 0 ) demonstrates the ambient mole fraction solubility and T 0 demonstrates ambient temperature.
The authors developed the equation by adding a cubic term to the base equation, Eq. ( 1), as is shown in Eq. ( 2): ( ) ( ) Mathis et al. developed Eq. ( 3), which was employed for determining the solubility of liquid apolar organic compounds in subcritical water, as follows: Kayan et al. developed an approximation model, Eq. ( 4), for the solubility of benzoic and salicylic acids, which Yabalak et al. successfully applied for the solubility of sebacic acid: 15,23 ( ) Kapalavavi et al. developed a new model, Eq. ( 5), for the solubility of paraben in subcritical water: 28 As is shown in Table I, none of the five equations could correctly predict the mole fraction solubility of paracetamol.Thus, a new modified approximation model (Eq.6) was obtained, which correctly predicts the mole fraction solubility of paracetamol: The developed model ensures a comprehensive prediction for the solubility of paracetamol at most of the temperatures compared with experimental ones, as illustrated in Table I.

Degradation of paracetamol with O 2
The degradation process was performed in subcritical water medium under O 2 atmosphere.Using O 2 in subcritical water medium offers a powerful and eco--friendly method that is widely used in the water recycling process and other environmental treatments. 29,30Dissolving oxygen in subcritical water initiates the formation of hydroxyl and other reactive radicals that participate in the reaction process, thereby increasing the degradation degree. 31egradation experiments were realized at four selected temperatures, specifically at 373, 393, 413 and 433 K, as demonstrated in Table II.The degradation degree of paracetamol during 60 min were determined as 52.20±1.42% without using oxidant at 433 K, and 68.66±1.05% using the same conditions but under 30 bar of O 2 pressure.The effect of static time on degradation degree was investigated at four selected times (5, 10, 30 and 60 min), as shown in Table III.Increasing the static time from 5 to 60 min increased the degradation degree of paracetamol from 64.45±1.11% to 68.66±1.05% at 433 K. High static time might have enhanced the interaction of O 2 and other radicals formed by O 2 with paracetamol, thereby increasing the degradation degree.

Degradation of paracetamol with hydrogen peroxide
Hydrogen peroxide is a unique alternative oxidant to air or pure oxygen in degradation of organic compounds to carbon dioxide and water. 32,33While H 2 O 2 is reduced to H 2 O and O 2 at room conditions, both of H 2 O and O 2 do not have any effect on degradation degrees. 34,35It decomposes to form highly reactive hydroxyl radicals in subcritical water medium. 36,37Once hydroxyl radicals are produced, they initiate chain reactions in which reactive radicals are formed. 38enerally, temperature and static time play an important role in the degradation process. 16High temperature enhances the decomposition rate of H 2 O 2 to the aforementioned reactive radicals, thereby increasing the degradation rate of the target molecules.Adequate static time is essential for the effective interaction of oxidative species and the target molecules. 16egradation experiments were performed at four selected temperatures, i.e., 373, 393, 413 and 433 K, as shown in Table IV.The degradation degree of paracetamol in 60 min was determined as 52.20±1.42% without using an oxidant at 433 K and 100±0.00% under the same conditions using 0.035 mL H 2 O 2 , under nitrogen pressure fixed at 30 bar, as shown in Table IV.In addition, increasing static time from 5 to 60 min increased the degradation degree of paracetamol from 93.81±0.14% to 98.28±1.94% at 373 K, as shown in Table V.

CONCLUSIONS
This study demonstrated that subcritical water has a remarkable effect on the degradation and solubility of paracetamol.It was found that the static time is an effective parameter along with temperature in both the degradation and solubility processes.
The experimental solubility results show a good consistency with the developed approximation model (Eq.( 6)).The mole fraction solubility of paracetamol was determined as (14.68±0.74)×10 3 at 30 min static time and 403 K.
Furthermore, O 2 has a significant impact on the degradation degrees of paracetamol, enhancing the degrees by up to 18 %.While 100 % degradation was obtained using H 2 O 2 , the attained degradation of 68 % using O 2 should not be underestimated due to its environmentally friendly nature.
Paracetamol was supplied by Sigma-Aldrich, glacial acetic acid and H 2 O 2(35 vol.%, ρ = 1.13 g cm -3 ) were from Merck, and methanol from J. T. Baker.Deionized water (18 MΩ cm at 25 °C) was obtained from a Millipore Milli-Q Advantage A10.The HPLC column ACE 5 C18 (250 mm×4.6 mm id) was supplied by Mac-Mod (USA).An empty HPLC column (150 mm×4.6 mm i.d.) was used as an extraction cell.A Teledyne ISCO 260 D series syringe pump system (USA) was used for delivering water and providing pressure.O 2 and N 2 gases were supplied from Linde gas (Turkey).An Agilent 1200 model HPLC apparatus was used for the HPLC analyses.

TABLE I .
Comparison of experimental mole fraction solubility (x 2 ×10 3 ) of paracetamol in subcritical water obtained in a static time (t) of 30 min according to Eqs. (1)-(6) defined later aThe experiments were performed in triplicate

TABLE II .
Effect of temperature on the degradation degrees of paracetamol using O 2 in 60 min

TABLE III .
Effect of static time on the degradation degrees of paracetamol using O 2 at 433 K

TABLE IV .
Effect of temperature on the degradation degrees of paracetamol using H 2 O 2

TABLE V .
Effect of static time on the degradation degree of paracetamol using H 2 O 2 at 373 K