Pharmaceutical Compounds in our Water Supply: Causes, Consequences and Solutions Hanoz Santoke...

Pharmaceutical Compounds in our Pharmaceutical Compounds in our Water Supply:Water Supply:

Causes, Consequences and Causes, Consequences and SolutionsSolutions

Hanoz SantokeHanoz SantokeWeihua SongWeihua Song

William CooperWilliam CooperUniversity of California, IrvineUniversity of California, Irvine

OutlineOutline

• Introduction – pharmaceuticals in water, fluoroquinolones, advanced oxidation

• Methods and Materials – LINAC and mass spectroscopy

• Results and Discussion – transient spectra, rate constants, and degradation mechanisms

• Conclusions

Pharmaceuticals in Natural Bodies Pharmaceuticals in Natural Bodies of Waterof Water

• Dozens of pharmaceutical and personal care products detected in various rivers, streams and lakes

• Fluoroquinolone levels up to 0.12 g/L in various streams in the US (Kolpin 2002)

• Effluent from a Patancheru, India drug manufacturing facility contained many pharmaceuticals in the mg/L range, with six of the top eleven active pharmaceutical ingredients detected being fluoroquinolones (Larsson 2007)

Pharmaceuticals in our Drinking Pharmaceuticals in our Drinking WaterWater

• Pharmaceutical compounds, including antibiotics, anti-convulsants, mood stabilizers and sex hormones, have been detected at ppb levels in the drinking water supplies of at least 41 million Americans (Associated Press investigation, 2008)

No federal or state standards exist for pharmaceuticals in drinking water (tap or bottled)

Drinking Water Test ResultsDrinking Water Test Results

Source: Associated Press, 2008

Pathways to the EnvironmentPathways to the Environment

Human and animal excretion– High drug use in the

United States: 3.7 billion prescription and 3.3 billion non-prescription purchases per year

– Most drugs are incompletely metabolized in the body (Kummerer 2004)

Pathways to the Environment - Pathways to the Environment - continuedcontinued

• Dumped “down the drain” by consumers and medical facilities (Halling-Sorensen 1998)

• Manufacturing facilities (Larsson 2007)

Environmental ConsequencesEnvironmental Consequences

• Pharmaceutical compounds, including fluoroquinolones, are toxic to plants such as Lemna Gibba, which is commonly used as a test species for assessing aquatic toxicants (Brain 2004)

Environmental Consequences - Environmental Consequences - continuedcontinued

• Fluoroquinolones have been found to be toxic to various aquatic organisms, and their selective toxicity may impact ecosystem structure (Robinson 2005)

• A mixture of pharmaceuticals at environmental concentrations has been shown to inhibit the growth of human embryonic cells by as much as 30% (Pomati 2006)

Current Treatment TechnologiesCurrent Treatment Technologies

• Biodegradation• Nanofiltration• Activated carbon

adsorption• Ozonation• Reverse Osmosis

• Only reverse osmosis can effectively remove pharmaceuticals, but at very high cost

Advanced Oxidation/Reduction Advanced Oxidation/Reduction ProcessesProcesses

• Hydroxyl radicals – oxidizing agent

• Hydrated electrons – reducing agent

• Generated by radiating ozone or hydrogen peroxide

• Studies have shown that AOPs are very promising

(cheaper and more efficient) in removing

pharmaceutical compounds from water (Huber

2003)

What are Fluoroquinolones?What are Fluoroquinolones?

• Quinolones are a set of broad-spectrum antibiotics

• Fluoroquinolones are quinolones with a fluorine atom

attached to the central ring

• 9 fluoroquinolones are currently FDA-approved for humans

• Levofloxacin (“Levaquin”) best-selling, $1.5 billion in 2006

• Adverse effects include nerve or tendon damage, and heart

problems

• Many types of bacteria have built up resistance

Target CompoundsTarget Compounds

N

F

N

NH3C

O

OH

O

danofloxacin MW 362

N

COH

OF

F

N

HN

H3C

CH3

F

O

orbif loxacin MW 395

N

F

N

NH3C

O O

OH

enrof loxacin MW 359

O N

N

F

N

N

O

OH

O

marbofloxacin MW 362

flumequine MW 261

F

N

O

OH

O

NH

F

O

OH

O

model compound MW 207

ObjectivesObjectives

• Determine absolute bimolecular reaction rate constants

for the reactions of hydroxyl radicals and hydrated

electrons with several common fluoroquinolones

• Study degradation pathways to identify the byproducts

formed in the process.

• This information may be used to design an advanced

oxidation process to remove these compounds from

wastewater.

Degradation StudiesDegradation Studies

• Cesium-137 radiation source to prepare samples with various doses of radiation

• HPLC to measure concentrations of radiated samples

• Liquid chromatography - mass spectroscopy to identify molecular weights of byproducts and elucidate degradation mechanism

Degradation by Cesium RadiationDegradation by Cesium Radiation

Concentration of danofloxacin as a function of radiation dose

LC-MS DataLC-MS Data

Defluorination of marbofloxacin: mass chromatograms for molecular weight 360, [M-H]‒=359, at various radiation doses.

Degradation PathwaysDegradation Pathways

N

F

A

C

O

OH

O

B

D

N

F

A

C

O

OH

O

B

OH

N

HO

A

O

OH

OD

N

F

HO

C

O

OH

O

B

D

N

HO

A

C

O

OH

O

B

OH

N

F

HO

C

O

OH

O

B

OH

N

HO

HO

C

O

OH

O

B

D

HA

+ F

+

(a)

(b)

(c)

CB

Degradation Pathways LegendDegradation Pathways Legend

Transient SpectraTransient Spectra

Transient Spectra ObservationsTransient Spectra Observations

• strong absorbance in the 350 to 400 nm range

• max of each intermediate was red-shifted by around 100 nm compared to that of the parent compound, characteristic of •OH addition to the aromatic ring to form the corresponding hydroxycyclohexadienyl radical

• Flumequine has the transient spectra most comparable to the model compound

Linear AcceleratorLinear Accelerator

Linear Accelerator at Notre Dame Radiation Laboratory to calculate absolute bimolecular reaction rate constants

A few equationsA few equations

Radiolysis of water

H2O e-aq (0.27) + H• (0.06) + •OH (0.28)

+ H2 (0.05) + H2O2 (0.07) + H3O+(0.27)

Isolation of •OH • e-aq + N2O + H2O N2 + HO- + •OH• H• + N2O •OH + N2

Isolation of e-aq

• (CH3)2CHOH + •OH (CH3)2C•OH + H2O• (CH3)2CHOH + H• (CH3)2C•OH + H2

Calculation of Rate Constants: Calculation of Rate Constants: Hydroxyl RadicalHydroxyl Radical

Danofloxacin + hydroxyl radical

Pseudo-first order rate constant as a function of concentration.

0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50

1.0

1.5

2.0

2.5

3.0

3.5

Rat

e co

nst

ant

(106 s

-1)

Danofloxacin concentration (mM)

Calculation of Rate Constants: Calculation of Rate Constants: Hydrated ElectronHydrated Electron

Danofloxacin + hydrated electron

Pseudo-first order rate constant as a function of concentration.

0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

Rat

e co

nst

ant

(106 s

-1)

Danofloxacin concentration (mM)

Summary of ResultsSummary of Results

Compound·OH max

(nm)k (·OH) (M-1s-1) k (e-

aq) (M-1s-1)

-irradiation Half life (kGy)

Orbifloxacin 370 (6.94 ± .08) x 109 (2.25 ± .02) x 1010 1.56

Flumequine 360 (8.26 ± .28) x 109 (1.83 ± .01) x 1010 1.64

Marbofloxacin 400 (9.03 ± .39) x 109 (2.41 ± .02) x 1010 1.80

Danofloxacin 440 (6.15 ± .11) x 109 (1.68 ± .02) x 1010 1.85

Enrofloxacin 400 (7.95 ± .23) x 109 (1.89 ± .02) x 1010 1.38

Model compound

350 (7.65 ± .20) x 109 (1.49 ± .01) x 1010 0.05

Degradation Pathways LegendDegradation Pathways Legend

Rate Constant TrendsRate Constant Trends

• Piperazine ring provides steric hindrance, which decreases ·OH rate constant

• Electron-donating oxygen atom increases ·OH rate constant

• Cyclopropane functional group appears to reduce rate constants

ConclusionsConclusions

• Pharmaceutical residue in our drinking water is a major environmental and human health issue

• Advanced Oxidation/Reduction Processes hold great promise for the removal of pharmaceutical compounds

• This work helps us understand the reactions of fluoroquinolones with hydroxyl radicals, which will be useful in designing a pilot-scale AO/RP system

If you gave me several million years, there would be nothing that did If you gave me several million years, there would be nothing that did not grow in beauty if it were surrounded by water.not grow in beauty if it were surrounded by water.

- - Jan Erik Vold, What All The World Knows, 1970Jan Erik Vold, What All The World Knows, 1970

Thank you!Thank you! Questions?