Environ. Sci. Technol. 2005, 39, 2294-2300
Accelerated Transformation and Deactivation of Erythromycin in Superheated Water. 1. Temperature Effects, Transformation Rates, and the Impacts of Dissolved Organic Matter MICHELLE N. BUTLER AND WALTER J. WEBER, JR.* Department of Chemical Engineering, Energy and Environment Program, University of Michigan, Ann Arbor, Michigan 48109-2099
The presence of antibiotics and other pharmaceuticals in the environment is of increasing concern.The stringent treatment of point discharges of antibiotic wastes holds promise as an approach for curtailing growing trends of microbial resistance. The work described in this two-part series explores the use of superheated water as a medium for the accelerated transformation and deactivation of a specific target antibiotic, erythromycin. Part 1 of the series focuses on parent compound conversion, and Part 2 examines transformation mechanisms and reaction products. This paper, Part 1, highlights the results of reactor studies performed in both batch and flow-through modes. The data presented confirm that accelerated conversion of erythromycin, based on parent compound disappearance as measured by high-pressure liquid chromatography, occurs in water under superheated conditions. Given an initial erythromycin concentration of 50 mg/L, greater than 85% apparent conversion was achieved within 30 min in the batch system at all temperatures investigated in the range from 125 to 200 °C. The presence of dissolved organic matter extracted from two natural soil materials, at concentrations of 2.5-20 mg/L, was shown to have little effect on the overall extent of transformation of erythromycin in the batch system. The rates of decomposition observed were found to be best described by a psuedo-first-order expression, one in which the rate coefficient increased linearly with increasing initial concentration of the antibiotic. First-order rate behavior was verified in subsequent flow reactor experiments. The temperature dependence of rate was also examined, and an activation energy of 68.8 kJ/mol was determined.
Introduction and Background Concerns about the increasing presence and diverse array of persistent, biologically active, organic compounds in both raw water sources and treated water supplies are escalating. This spectrum of emerging contaminants includes members of a number of different classes of drugs; for example, analgesics, antineoplastics, natural and synthetic hormones, * Corresponding author telephone: (734)763-2274; fax: (734)9364391; e-mail:
[email protected]. 2294
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and antibiotics. The latter group of pharmaceuticals is of particular concern. Exposure to antibiotic wastes can increase the likelihood of the development of resistance among microorganisms populating wastewater collection and treatment systems and potentially, in the worst case, treated water distribution networks. The investigation reported here examines the application of superheated water technology as a means for rapidly decomposing and deactivating antibiotic wastes at or near their points of generation and prior to their disposal to conventional wastewater collection and treatment works. Erythromycin, a macrolide antibiotic produced by Saccharopolyspora erythreus (formally Streptomyces erytheus), was chosen as the focus of this study. The antibiotic is used clinically for the treatment of human infectious diseases such as pneumonia, Legionnaire’s disease, and tetanus as well as in veterinary practice. It is effective against most Grampositive bacteria, particularly those with low minimum inhibitory concentrations, and is found in the environment at levels up to the micrograms per liter range (1, 2). Erythromycin is composed of a 14-membered lactone ring with two attached sugar moieties, desosamine and cladinose. Derived from propionic acid subunits, the compound has a methyl group attached to alternating carbon atoms on its ring structure and oxygen-containing functionalities at all remaining carbon atoms. The acid-base properties of the drug have important implications for both its antimicrobial activity and its chemical stability. The amino substituent carried by desosamine renders erythromycin weakly basic in nature. The antimicrobial activity of the compound is, therefore, enhanced as solution pH levels approach and exceed its acidity constant of pKa ) 8.8. The enhanced activity of the drug under alkaline conditions extends its spectrum of activity to include select Gram-negative microorganisms, such as Escherichia coli (3). Erythromycin’s susceptibility to accelerated transformation and deactivation under acidic conditions is widely recognized. Mechanisms of degradation in aqueous solutions under acidic conditions and ambient temperatures have, in fact, been well-characterized by Atkins et al. (4), Connors (5), Cachet et al. (6), Kibwage et al. (7), and Vinckier et al. (8). The reactivity of the compound under neutral and basic conditions has also been explored. Connors (5), for example, reported that the optimum stability of erythromycin is observed at pH ) 7-7.5. Selection of superheated water technology as a potential technique for investigating the accelerated transformation and deactivation of erythromycin is supported by existing literature on the solvent’s reaction chemistry. Superheated water is a universal medium for a wide variety of reactions, including hydrolysis and carbonyl condensation (9-12). Reactions observed in this “green” solvent are facilitated by changes in the physical and chemical properties of water as its temperature and pressure are increased above its boiling point at 1 atm of 100 °C and gradually approach a critical point of 374 °C and 218 atm. As water is heated above its boiling point, while maintained in the liquid form by increasing pressure, it begins to lose much of the hydrogen bonding structure that inhibits organic solubility. Weakening of this structure is thought to induce the release of protons (9, 10). An increase in the dissociation constant (Kw) by nearly 3 orders of magnitude at temperatures greater than 250 °C allows water to participate in reactions as both acid and base. Changes in polarity are linked to those that occur in ionization. As temperature increases, the dielectric constant 10.1021/es049398f CCC: $30.25
2005 American Chemical Society Published on Web 02/09/2005
of water, which is indicative of changes in polarity, drops dramatically from 80 at ambient temperature to 27 at 250 °C. The latter value is comparable to that of polar organic solvents such as acetone at room temperature, making superheated water a powerful solvent for organic compounds. For example, increasing the temperature of water from 25 to 200 °C has been reported to result in a 10-fold increase in the solubility of benzene and a 30-fold enhancement of m-xylene solubility (13). Because of this enhancement in the solubility of organics and noted changes in the hydrogen bonding structure of water, superheated/subcritical water technology is now being explored as a tool for the rapid degradation of organic micropollutants. Both the dechlorination of PCBs and decomposition of biosolids in this media have recently been investigated (14-16). The technology has also been used to extract contaminates from solid matrixes (17-21), The work presented here relies on the inherent potential of water under superheated conditions to treat, with some degree of specificity, pharmaceuticals such as erythromycin that are subject to pH-dependent instabilities.
Experimental Methods Preparation of Solutions. Stock and dilute solutions of erythromycin A (Sigma-Aldrich Co.) were prepared in distilled deionized water (Millipore). The concentrations of these solutions are reported at ambient conditions throughout the remainder of this paper. Erythromycin solutions that were used as inlet streams to the reactor system were stored for up to 48 h before being discarded. Analytical standards were stored at 4 °C for 1 week. The aqueous solutions of natural organic matter employed in this study were prepared from two diagenetically young soil materials. The first of these materials is designated as Chelsea Soil because it was collected from a location near Chelsea, MI. It consists primarily of humic-type organic matter. After collection, Chelsea Soil was sieved to obtain a particle size fraction of less than 1 mm for use in the preparation of dissolved organic matter (DOM) solutions. The second young soil-like material, referred to as Canadian Peat, was produced at a facility in Quebec and obtained from Premier Grower Services (Red Hill, PA). Canadian Peat consists entirely of recently deposited plant organic matter and was sieved to obtain a particle size fraction of less than 2 mm prior to use. DOM solutions were prepared by equilibrating 50 g of solid material in distilled deionized water for a period of 1 week. The aqueous supernatants were then filtered through 0.7-µm Millipore glass fiber filters. The total organic carbon (TOC) contents of filtered solutions were measured using a Shimadzu model TOC-500 total carbon analyzer, in which high-temperature combustion is used to quantify the amount of organic carbon present in a sample. Standard solutions with the desired range of carbon equivalents were prepared from potassium hydrogen phthalate and used to calibrate the instrument for analysis. Stability Tests. To evaluate baseline erythromycin stability under ambient and storage conditions, 50 mg/L aqueous solutions of the antibiotic were prepared in Erlenmeyer flasks and stored at the desired test temperature. Changes in the structure of erythromycin and the appearance of unspecified reaction products were observed daily using both HPLC and infrared spectroscopy analyses. The tests revealed that erythromycin remains undegraded for up to 5 days when stored at a temperature of 19 °C and for up to 7 days when refrigerated at a temperature of 4 °C. Batch Reactor Operation. Figure 1 is a schematic of the experimental system. Inlet solutions were sparged with helium (Cryogenic Gases) for 1-2 h prior to delivery into the reactor system through a Valco check valve, Swagelok tee,
FIGURE 1. Superheated water reactor system. and inlet valve port PT-1. The reaction vessel was a 300-mL capacity LC series stainless steel benchtop bomb manufactured by Pressure Products Industries, Inc. (Erie, PA). Stainless steel tubing and Swagelok fittings were used to assemble the system. The reactor was jacketed by an electric heater and fitted with an in-line mixer designed to enhance liquid and gas dispersion. The mixer operated at 850 rpm, per recommendation of the manufacturer. An external control device manufactured by Pressure Products Industries provided digital displays of system pressure, temperature, and mixing speed as well as directing safety features, such as the automatic shutdown of rotating parts. Internal system temperatures were measured by a thermocouple inserted within a well in the reaction vessel. The label T in Figure 1 designates the position of this thermocouple. System pressure was measured via a mounted gauge and a transducer, designated by the letter P in Figure 1. In preparation for each experiment in which the system was operated in batch reactor mode, all inlet lines were flushed with solutions intended for delivery during the run. The reaction vessel was closed after flushing, and a calibrated torque wrench was used to tighten the bolts on the lid to 20 ft-lb, as directed by the manufacturer. Once sealed, the threeway valve at port PT-3 was used to fill the reactor with helium. A vacuum pump, also connected to the three-way valve at port PT-3, was used to evacuate the reactor. This process was repeated twice before each run. Inlet solutions were pumped into the reactor using two Alltech model 426 high-pressure isocratic pumps. A desired volume of degassed Millipore water was transferred from reservoir A by pump a into the reactor through the inlet valve at PT-1. This valve was then closed and the water heated until the temperature setpoint was reached. The inlet valve was opened and a concentrated solution of erythromycin delivered to the reactor by pump b from reservoir B. The inlet valve was once again closed. This point in time was designated t ) 0 in all experimental runs in batch reactor mode. Both pumps were operated at or near the maximum flow rate of 10 mL/min. The pumping time used during each sequence was determined by both the stock solution concentration and the desired initial reaction concentration. For example, for a desired initial erythromycin concentration of 50 mg/L, pump a delivered pure water at a flow rate of 9 mL/min for 25 min. After the temperature setpoint was reached, pump b delivered a 500 mg/L erythromycin solution at a flow rate of 10 mL/min for 2.5 min. The total volume of liquid in the reactor under these conditions was 250 mL. Because of pressure limitations, the reaction vessel was never completely filled. The system was always operated under autogenous pressure. A small piece of stainless steel tubing (0.005 in. i.d.) was connected to outlet port PT-2 via a Swagelok fitting to allow for instantaneous reactor sampling. Three-milliliter samples of the liquid contained in the vessel were collected at desired VOL. 39, NO. 7, 2005 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 2. Effects of temperature on erythromycin decomposition (Co ) 50 mg/L). time intervals. Changes in system pressure were recorded at each sampling time point. The samples were immediately transferred upon collection to a dry ice bath for 1.5 min to prevent any further reaction and then refrigerated for subsequent analysis. Reactor samples were stored for no more than 3 days before being analyzed. Once the reaction was completed, all heating elements were turned off, and an internal cooling coil was used to cool the system and relieve system pressure. Flow Reactor Operation. Operation of the reactor system in flow-through mode involved pumping a single aqueous solution of erythromycin continuously through PT-1 into the reaction vessel. Flow through the reactor outlet was directed through a back-pressure regulator connected to the outlet port PT-3 by a span of 0.125-in. i.d. stainless steel tubing, rather than through a section of 0.005-in. i.d. tubing as described for batch reactor operation. This setup allowed not only for ease of reactor sampling but also for control of system pressure. For flow-through operations, the time at which the temperature setpoint, as measured by an internal thermocouple, was reached was designated as t ) 0. The reactor was allowed to run for 2 h after this time before sampling was begun. Two 3-mL samples were collected from each individual run for chromatographic analysis. High-Pressure Liquid Chromatography. Quantitative measurements of parent compound concentrations in the reactor effluent were made using high-pressure liquid chromatography (HPLC) with evaporative light scattering detection. HPLC analysis was performed using an Alltech Econosil guard cartridge coupled with a 2.5 cm × 4.6 mm Jones Apex silica column (5 mm particle size). Analyses were carried out on a Hewlett-Packard 1090 series liquid chromatograph with a thermo separations membrane degasser and a Sedex model 75 evaporative light scattering detector (ELSD). The ELSD was operated at a gain of 10 and a temperature of 50 °C. The solvent media used was a 90% methanol (HPLC grade, Fisher Scientific) and 10% 0.2 M ammonium acetate (HPLC grade, Fisher Scientific) solution. This mobile phase flowed through the column at a rate of 1.3 mL/min resulting in an erythromycin retention time (tR) of 5.2 min. Chromatograms were collected at an average column temperature of 25 °C. The sample injection volume 2296
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was 25 mL, and the total run time was 6.5 min. The limit of quantification for erythromycin was approximately 2 mg/L.
Results and Discussion The effect of temperature on erythromycin decomposition was determined on the basis of parent compound disappearance as measured by HPLC. Residual erythromycin concentrations as percentages of the initial concentration are plotted in Figure 2 as functions of time at reaction temperatures of 125-200 °C. Duplicate runs are designated by “a” in the legend of the figure. Because the reactor was evacuated prior to use, system pressure readings listed in the legend of Figure 2 are approximately 1 atm lower than theoretical values of water’s vapor pressure at corresponding reaction temperatures. Greater than 85% conversion of erythromycin was achieved after 1 h at all reaction temperatures within the test range. An unexpected “cycling” problem was observed at 175 and 200 °C. Virtually complete disappearance of erythromycin at initial times was followed by an apparent recurrence of the compound at t ) 25 and 4 min, respectively. This reappearance may be attributed to one or more of three system phenomena; a reversible reaction, redissolution of volatilized erythromycin from the gas phase into the liquid phase, and inadequate mixing. The properties of the compound essentially eliminate the second explanation, phase redistribution, and it was dismissed from further consideration. While it is conceivable that a reversible step is included in the reaction pathway, reversibility would not be expected to result from increased temperature, particularly at the high levels of temperature at which apparent reappearance was observed. Preliminary investigations of reactor hydraulics at temperatures of 125 and 150 °C via bromide tracer studies indicated that for batch mode operation complete mixing of the solute was not attained until approximately 12 min after its introduction. Given these results, an overestimation of initial conversion created by the inability to achieve instantaneous mixing is the most plausible of the explanations considered. The effects of incomplete mixing were more apparent as reaction temperature increased, resulting in an initial flush of water with low erythromycin concentrations and resulting inaccuracies in the prediction of true conver-
FIGURE 3. First-order representation of concentration-time data. sion. To minimize the uncertainties created by observed reactor conditions, all subsequent experiments using the batch configuration were performed in the temperature range within which reactor behavior was well-characterized, 125150 °C, and only data collected after a reaction time of 12 min are presented. The work described above has significant implications for the design of the superheated water reactor. It indicated that problematic reactor behavior could be eliminated and/ or further delineated by introducing inlet streams directly into the liquid phase/reaction media or by introducing desired reactants and a conservative tracer simultaneously. Future work utilizing these modifications will allow the authors to extend the scope of this work to a broader range of reaction temperatures. Transformation Rate Analysis. The material balance relationship for a reaction occurring in a given reactor can be interpreted directly as a reaction rate equation only if the reactor is in fact “closed” and “completely mixed” (22). Completely mixed batch reactors (CMBRs) are, therefore, usually the preferred type of reactor for conducting reaction rate studies. An integrated material balance equation for a CMBR, incorporating a first-order rate expression for a reaction in which concentration decreases, yields the following expression for the corresponding first-order rate coefficient, k:
k)-
()
Ct 1 ln t Co
(1)
in which Ct and Co are the concentrations of the reactant at reaction times of t ) t and t ) 0, respectively. A plot of Ct vs t for a set of rate data that can be described by eq 1 should yield a linear data trace having a slope of k. Figure 3 is a first-order representation of the concentration-time data obtained at T ) 125 °C and four different initial erythromycin concentrations. The correlation coefficient (R 2) values that correspond to linear regressions of data sets generated at various initial erythromycin concentrations are also included on this figure. Importantly, the regressions applied to the data in Figure 3 were not forced though the origin, a treatment of the data that would have neglected the impacts of mixing on initial reactor performance and apparent reaction rate. Rate coefficients estimated from the experimental data are plotted in Figure 4 as functions of initial erythromycin concentration. The essentially linear dependence of these
FIGURE 4. Rate coefficient dependence on initial erythromycin concentration.
TABLE 1. First-Order Reaction Rate Coefficients Determined from Flow Reactor Data T (°C)
Ceffluent (mg/L)
k (min-1)
100 125 150
32.2 ( 0.35 13.2 ( 0.20 5.87 ( 0.05
0.018 ( 0.006 0.092 ( 0.002 0.251 ( 0.003
rate coefficients on initial concentration implies that they are lumped parameters and thus more appropriately termed psuedo-first-order coefficients. A number of investigators have reported that the decomposition of erythromycin under ambient conditions can be described by psuedo-first-order rate expressions, including Connors (5), Pasean et al. (23), and Volmer and Hui (24). Connors (5) found that this type of expression describes erythromycin degradation in acidic media, while Pasean et al. (23) reported similar rate behavior in various buffer solutions under basic conditions. Table 1 lists the values of the psuedo-first-order reaction rate coefficients estimated from continuous flow reactor data for an initial erythromycin concentration of 50 mg/L, a fluid residence time in the reactor of 30 min, and three different reaction temperatures. These coefficients are of the same order of magnitude as those obtained from the batch reactor studies. As an indication of whether deviations in the data obtained at specific reaction temperatures could be attributed to random error, the difference between the mean reaction VOL. 39, NO. 7, 2005 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 5. Transformation of erythromycin in DOM solutions at 125 °C (Co ) 50 mg/L).
FIGURE 6. Transformation of erythromcyin in DOM solution at 125 °C (Co ) 30 mg/L). rate coefficients obtained at temperatures of 100 and 125 °C and at 125 and 150 °C were tested against the null hypothesis using the Student’s t test statistic for independent samples. Differences observed between both sets of data were statistically significant at a level of 0.01. Flow reactor data collected at the reaction temperatures shown in Table 1 was further analyzed to obtain the activation energy (Ea) for the observed reaction. The value of Ea is given by the slope of a plot of ln k versus 1/T multiplied by the universal gas constant, R. This plot is based on the linearized form of the Arrhenius relationship given by eq 2. The Arrhenius equation describes the dependence of the rate coefficient on temperature:
k ) Ae-Ea/RT
(2)
The experimentally determined value of Ea ) 68.8 kJ/mol compares well with that of Ea ) 77.8 kJ/mol reported by Connors (3) for the first-order decomposition of erythromycin 2298
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at ambient temperatures, indicating that similar reaction dynamics exist across a board range of temperatures. This finding further suggests that comparison of the data generated in this study with data from studies conducted at room temperature can provide a basis for evaluation of the hypothesis that decomposition of erythromycin is accelerated under superheated conditions. Impacts of Dissolved Organic Matter. Limited attention has been paid to how common environmental factors, other than pH, may interfere with demonstrated pathways of erythromycin decomposition. Given the ubiquitous nature of dissolved organic matter (DOM) in natural aquatic systems, the effect of DOM on erythromycin transformation was also examined. These investigations were intended as a first step in demonstrating the ability of superheated water to selectively attack polar residues carried by antibiotics in the presence of more complex matrixes. Erythromycin was reacted in batch mode in water amended with DOM at the
total organic carbon (TOC) concentrations specified in Figure 5. At 125 °C, the initial rate of erythromycin conversion decreased as TOC concentration increased, suggesting that DOM may competitively inhibit erythromycin decomposition in superheated water. Although the data is not presented here, inhibitory effects observed at early reaction times became less significant at 150 °C, an anticipated result of the increased activity of water at higher reaction temperatures. The presence of the DOM amendment did not ultimately affect the final extent of conversion of erythromycin, however. After a reaction time of approximately 30 min, the data for all of the DOM-amended systems converged with data generated using erythromycin-only control systems at the corresponding reaction temperature. To ensure that sequestration of erythromycin by DOM was not being camouflaged by the large gap in concentration between the TOC in the medium and the initial erythromycin concentration, a second experiment in which the concentrations of the two solutes were of the same order of magnitude was performed. These data are presented in Figure 6. In superheated water containing 21 mg/L TOC and an initial concentration of 30 mg/L erythromycin, the presence of the DOM had no apparent impact on the overall extent of conversion of erythromycin. These data further support the conclusion that erythromycin can be effectively decomposed in superheated water despite the presence of equivalent concentrations of natural organic matter. Additional investigations are necessary to better characterize the nature of observed interactions between DOM and erythromycin. The investigations presented in this paper support the hypothesis that, at the pressures and temperatures at which superheated processes are operated, selective and accelerated decomposition of erythromycin that takes advantage of the chemical properties of pure water, without a reliance on the addition of chemical oxidants, can occur. These experiments have also helped to identify several areas of further study. Superheated water is an ideal reaction medium when the treatment objective is the elimination of key chemical functionalities rather than complete mineralization, as is the case in the targeted elimination of antimicrobial activity. Identification of functional groups of importance for degradation of this compound in superheated water may help extend some of the chemistry observed for erythromycin to other semi-synthetic compounds within the macrolide class. The second paper in this series explores the nature of the chemical transformations observed in the current reactor system (25). Superheated water technology is also uniquely suited for use in the pretreatment of small-volume wastes that can be coupled with energy waste streams, like the unit-specific wastewaters produced during manufacturing. The pharmaceutical industry, where processing is often carried out in batches that produce small quantities of highly concentrated, homogeneous wastes containing primarily active substances, is just one example of an attractive market for this remedial technique. For this reason, the authors chose to utilize relatively high concentrations of erythromycin that would allow reaction rates and reactor behavior to be more easily quantified. Additional investigation at environmentally relevant concentrations must be weighted by an analysis of treatment costs and the potential risk/selective pressure exerted by these compounds in more traditional waste treatment scenarios.
Acknowledgments The authors acknowledge the invaluable laboratory support provided by University of Michigan undergraduate students Tikoshia Davis, Douglas Chenoweth, and Kendra Carter. Special thanks go to Laboratory Director Tom Yavaraski for
his assistance in development of the analytical components of this study. Development of the superheated water reactor system and its operating protocols was supported in part by companion Grants DMI-9985423 and R828246 from the National Science Foundation and the U.S. Environmental Protection Agency, respectively. Fellowship support to M.N.B., a graduate student in the Departments of Chemical Engineering and Civil and Environmental Engineering, was provided by the University of Michigan’s Horace H. Rackham Graduate School and the National Science Foundation.
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Received for review April 21, 2004. Revised manuscript received December 21, 2004. Accepted December 22, 2004. ES049398F
