{Solubility and degradation of paracetamol in subcritical water} J. Serb. Chem. Soc. 82 (1) 99–106 (2017) UDC 615.2paracetamol+546.212:542.92: JSCS–4950 544.351.3 Original scientific paper 99 Solubility and degradation of paracetamol in subcritical water ZUHAL EMİRE, ERDAL YABALAK*, ÖZKAN GÖRMEZ and AHMET MURAT GİZİR Mersin University, Faculty of Arts and Science, Department of Chemistry, Çiftlikköy Campus, TR-33343, Mersin, Turkey (Received 20 May, revised 29 August, accepted 16 September 2016) Abstract: In this study, solubility and degradation of paracetamol were exam- ined using subcritical water. The effect of temperature and static time was investigated during the solubility process in subcritical water at constant pres- sure (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, res- pectively. Keywords: subcritical water medium; approximation model; paracetamol; degradation; solubility. INTRODUCTION In recent times, pharmaceuticals have been detected in surface water, ground water, drinking water and sewage effluents due to their intensive usage.1,2 The presence of pharmaceuticals in drinking water and aquatic environments endan- gers human health and causes various health problems.3 Thus, the treatment of water contaminated with pharmaceuticals, such as anticonvulsants, antipyretics, antidepressants, cytostatic drugs, chemotherapy agents and antibiotics, has become a serious problem.4–6 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.7,8 Although para- cetamol, 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.9,10 * Corresponding author. E-mail: yabalakerdal@gmail.com doi: 10.2298/JSC160520079E 100 EMİRE et al. Paracetamol has been found in sewage treatment plant with concentration up to 6 and 10 ppb in natural waters.7,11,12 Thus, efficient degradation techniques are required to avoid potential risks of contaminated waters polluted by pharma- ceuticals, particularly by paracetamol. Conventional methods, such as chemical coagulation, biological remediation, adsorption and advanced oxidation pro- cesses, have been applied for the treatment of wastewaters containing various contaminants.13–15 Moreover, subcritical water oxidation, with or without oxi- dants, is an effectual method for the degradation of hazardous compounds that exist in aquatic environments.16,17 Using subcritical water with oxidizing agents, such as oxygen, permanganate, hydrogen peroxide, etc., various potential pollu- tants that are difficult to oxidize with conventional methods can be efficiently oxidized.16–18 Hydrogen peroxide is a relatively innocuous oxidation agent that decomposes to O2 and H2O at room temperature. It produces reactive hydroxyl radicals (HO•) which are able to efficiently degrade most organic pollutants pre- sent in wastewaters.19,20 Although oxygen is not as effective as hydrogen per- oxide, it has been employed in many studies concerned with wastewater treat- ments due to its environmentally friendly nature.21 Thus, 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.22 Many literature studies focused on using several methods for determining the solubility of paracetamol in various solvents.7 These 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.23 In 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. More- over, the decomposition temperature of pharmaceuticals obtained through these models seems to be important.14,24,25 Thus, the mentioned models are recom- mended as useful for determining appropriate operating parameters by perform- ing a limited number of experiments in decontamination treatments. Paracetamol was degraded using O2 and H2O2 in subcritical water. The sol- ubility 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.23 SOLUBILITY AND DEGRADATION OF PARACETAMOL 101 EXPERIMENTAL Reagents and apparatus Paracetamol was supplied by Sigma–Aldrich, glacial acetic acid and H2O2 (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. O2 and N2 gases were supplied from Linde gas (Turkey). An Agilent 1200 model HPLC apparatus was used for the HPLC analyses. Solubility experiments procedures A syringe pump system and a self-made oven system were used for the solubility expe- riments, as described in a previous work.26 An 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 Tekno- sem 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 tem- peratures 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.27 The reactor was filled with 120 mL of 5 ppm aqueous para- cetamol 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 H2O2 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 stan- dards were prepared in deionized water. RESULTS AND DISCUSSION Effect of temperature on solubility Experimental mole fraction solubilities (x2) 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.15,28 However, the mole fraction solubility of paracetamol decreased dramatically to x2 < 10 at 413 K due to possible degradation of paracetamol at higher tem- perature. 102 EMİRE et al. TABLE I. Comparison of experimental mole fraction solubility (x2×10 3) of paracetamol in subcritical water obtained in a static time (t) of 30 min according to Eqs. (1)–(6) defined later T / K Exp.a x2±SD (30 min) Eq. (1) Eq. (2) Eq. (3) Eq. (4) Eq. (5) Eq. (6) 293 1.52±0.01 1.52 1.52 1.52 1.52 1.52 1.52 298 1.77±0.00 1.69 2.29 0.25 4.91 1.69 1.74 303 2.06±0.00 1.88 2.55 0.31 5.97 1.88 1.98 373 10.06±1.37 6.10 8.27 2.83 52.75 6.55 9.44 383 10.92±1.13 6.97 10.76 3.58 67.49 7.71 11.39 393 11.37±0.85 7.91 14.35 4.47 85.26 9.09 13.65 403 14.68±0.74 8.91 19.72 5.48 106.47 10.73 16.26 aThe experiments were performed in triplicate 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±0.46 and 14.68±0.74, in static times of 5, 10, 15 and 30 min, respectively. The static time is an effectual parameter for the sol- ubility of organic molecules, as stated in previous papers.23 It 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 poly- cyclic aromatic hydrocarbons in subcritical water.13 The mole fraction solubility at elevated temperatures can be predicted using the mole fraction solubility obtained at ambient temperature (T0) as shown in Eq. (1):13 ( ) ( )02 2 0ln ln T x T x T T  ≈     (1) where x2(T) demonstrates the mole fraction solubility at any temperature (T), x2(T0) demonstrates the ambient mole fraction solubility and T0 demonstrates ambient temperature. The authors developed the equation by adding a cubic term to the base equa- tion, Eq. (1), as is shown in Eq. (2): ( ) ( ) 3 0 0 2 2 0ln ln 15 1 T T x T x T T T    = −     +    (2) Mathis et al. developed Eq. (3), which was employed for determining the solubility of liquid apolar organic compounds in subcritical water, as follows:14 3 0 0 2 2 0 0 ln ( ) ln ( ) 2 1 T T T x T x T T T  − = + −       (3) SOLUBILITY AND DEGRADATION OF PARACETAMOL 103 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 ( ) 02 2 0ln 1.85 1 )ln ( T x T x T T  = −    (4) Kapalavavi et al. developed a new model, Eq. (5), for the solubility of paraben in subcritical water:28 ( ) 0 02 2 0 0.5(ln ln 11 ) T T x T Cx T T T  + − −  =   (5) 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: ( ) 02 2 0 0 0 8 / 5ln ln TT x T x T T T T =  − +     (6) 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 O2 The degradation process was performed in subcritical water medium under O2 atmosphere. Using O2 in subcritical water medium offers a powerful and eco- -friendly method that is widely used in the water recycling process and other environmental treatments.29,30 Dissolving oxygen in subcritical water initiates the formation of hydroxyl and other reactive radicals that participate in the react- ion process, thereby increasing the degradation degree.31 Degradation experiments were realized at four selected temperatures, spe- cifically at 373, 393, 413 and 433 K, as demonstrated in Table II. The degrad- ation 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 O2 pressure. TABLE II. Effect of temperature on the degradation degrees of paracetamol using O2 in 60 min T / K 433 (without O2) 373 393 413 433 Degradation, % 52.20±1.42 10.13±1.98 42.62±1.88 64.11±1.71 68.66±1.05 104 EMİRE et al. 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 O2 and other radicals formed by O2 with paracetamol, thereby increasing the degradation degree. TABLE III. Effect of static time on the degradation degrees of paracetamol using O2 at 433 K t / min 60 (without O2) 5 10 30 60 Remaining amount, ppm 2.18±0.08 1.77±0.06 1.68±0.09 1.62±0.07 1.57±0.05 Degradation degree, % 52.20±1.42 64.45±1.11 66.31±1.81 67.61±1.31 68.66±1.05 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.32,33 While H2O2 is reduced to H2O and O2 at room conditions, both of H2O and O2 do not have any effect on degradation degrees.34,35 It decomposes to form highly reactive hydroxyl radicals in subcritical water medium.36,37 Once hydroxyl radicals are produced, they initiate chain reactions in which reactive radicals are formed.38 Generally, temperature and static time play an important role in the degradation process.16 High temperature enhances the decomposition rate of H2O2 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.16 Degradation 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 H2O2, under nitrogen pressure fixed at 30 bar, as shown in Table IV. TABLE IV. Effect of temperature on the degradation degrees of paracetamol using H2O2 T / K 373 393 413 433 Degradation degree, % 98.28±1.94 100±0.00 100±0.00 100±0.00 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. TABLE V. Effect of static time on the degradation degree of paracetamol using H2O2 at 373 K t / min 5 10 30 60 Remaining amount, ppm 0.31±0.01 0.30±0.01 0.21±0.02 0.09±0.10 Degradation degree, % 93.81±0.14 94.07±0.11 95.73±0.30 98.28±1.94 SOLUBILITY AND DEGRADATION OF PARACETAMOL 105 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 dev- eloped approximation model (Eq. (6)). The mole fraction solubility of paracet- amol was determined as (14.68±0.74)×103 at 30 min static time and 403 K. Furthermore, O2 has a significant impact on the degradation degrees of paracetamol, enhancing the degrees by up to 18 %. While 100 % degradation was obtained using H2O2, the attained degradation of 68 % using O2 should not be underestimated due to its environmentally friendly nature. Acknowledgements. This work was funded by the Mersin University Research Fund (Project No. BAP-FBE KB (ZE) 2014-1 YL). The authors thank Sengul AKSU and Umut Ufuk DEMİRHAN (MEU. Linguistics Department) for regulation of the English grammar. И З В О Д РАСТВОРЉИВОСТ И РАЗГРАДЊА ПАРАЦЕТАМОЛА У ПОДКРИТИТИЧНОЈ ВОДИ ZUHAL EMİRE, ERDAL YABALAK, , ÖZKAN GÖRMEZ, A. MURAT GİZİR Mersin University, Faculty of Arts and Science, Department of Chemistry, Çiftlikköy Campus, TR-33343, Mersin, Turkey Испитани су растворљивост и разградња парацетамола коришћењем подкритичне воде. Проучен је утицај температуре и времена стајања на процес растварања при конс- тантном притиску (50 bar). Експериментални резултати показују да температура и време стајања имају пресудан утицај на разградњу и растворљивост. Максимална растворљивост од (14.68±0.74)×103 за парацетамол постигнута је на 403 K. Предложен је апроксимативан теоријски модел за растворљивост парацетамола. При разградњи пара- цетамола коришћени су кисеоник и H2O2. Максимални степен разградње од 68,66±1,05 и 100±0,00 % постигнут је разградњом помоћу O2, односно H2O2. (Примљено 20. маја, ревидирано 29. августа, прихваћено 16. септембра 2016) REFERENCES 1. C. R. Gadipelly, V. K. Rathod, K. V. Marathe, J. Mol. Catal., A: Chem. 414 (2016) 116 2. C. Gadipelly, A. Pérez-González, G. D. Yadav, I. Ortiz, R. Ibáñez, V. K. Rathod, K. V. Marathe, Ind. Eng. Chem. Res. 53 (2014) 11571 3. L. Yang, L. E. Yu, M. B. Ray, Water Res. 42 (2008) 3480 4. M. Magureanu, N. B. Mandache, V. I. Parvulescu, Water Res. 81 (2015) 124 5. J. Liu, Q. Sun, C. Zhang, H. Li, W. Song, N. Zhang, X. Jia, Desalin. Water Treat. 57 (2016) 11386 6. K. Ikehata, N. J. Naghashkar, M. G. El-Din, Ozone Sci. Eng. 28 (2006) 353 7. R. A. Granberg, A. C. Rasmuson, J. Chem. Eng. 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Khataee, Desalination 270 (2011) 15. << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments true /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. 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