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Pharmaceutical compounds are typically produced in batch processes leading to the presence of a wide variety of products in wastewaters which are generated in different operations, wherein copious quantities of water are used for washing of solid cake, or extraction, or washing of equipment. The presence of pharmaceutical compounds in drinking water comes from two different sources: production processes of the pharmaceutical industry and common use of pharmaceutical compounds resulting in their presence in urban and farm wastewaters. The wastewaters generated in different processes in the manufacture of pharmaceuticals and drugs contain a wide variety of compounds. Further, reuse of water after removal of contaminants, whether pharmaceuticals or otherwise, is required by industry. In view of the scarcity of water resources, it is necessary to understand and develop methodologies for treatment of pharmaceutical wastewater as part of water management. In this review, the various sources of wastewaters in the pharmaceutical industry are identified and the best available technologies to remove them are critically evaluated. Effluent arising from different sectors of active pharmaceutical ingredients (API), bulk drugs, and related pharmaceutics, which use large quantities of water, is evaluated and strategies are proposed to recover to a large extent the valuable compounds, and finally the treatment of very dilute but detrimental wastewaters is discussed. No single technology can completely remove pharmaceuticals from wastewaters. The use of conventional treatment methods along with membrane reactors and advanced posttreatment methods resulting in a hybrid wastewater treatment technology appear to be the best. The recommendations provided in this analysis will prove useful for treatment of wastewater from the pharmaceutical industry.
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Pharmaceutical Industry Wastewater: Review of the Technologies
for Water Treatment and Reuse
Chandrakanth Gadipelly,
AntíaPe
́rez-González,
Ganapati D. Yadav,*
,
Inmaculada Ortiz,
Raquel Ibáñez,
Virendra K. Rathod,
and Kumudini V. Marathe
Department of Chemical Engineering, Institute of Chemical Technology, Mumbai 400 019, India
Department of Chemical and Biomolecular Engineering, University of Cantabria, Cantabria 39005, Spain
ABSTRACT: Pharmaceutical compounds are typically produced in batch processes leading to the presence of a wide variety of
products in wastewaters which are generated in dierent operations, wherein copious quantities of water are used for washing of
solid cake, or extraction, or washing of equipment. The presence of pharmaceutical compounds in drinking water comes from
two dierent sources: production processes of the pharmaceutical industry and common use of pharmaceutical compounds
resulting in their presence in urban and farm wastewaters. The wastewaters generated in dierent processes in the manufacture of
pharmaceuticals and drugs contain a wide variety of compounds. Further, reuse of water after removal of contaminants, whether
pharmaceuticals or otherwise, is required by industry. In view of the scarcity of water resources, it is necessary to understand and
develop methodologies for treatment of pharmaceutical wastewater as part of water management. In this review, the various
sources of wastewaters in the pharmaceutical industry are identied and the best available technologies to remove them are
critically evaluated. Euent arising from dierent sectors of active pharmaceutical ingredients (API), bulk drugs, and related
pharmaceutics, which use large quantities of water, is evaluated and strategies are proposed to recover to a large extent the
valuable compounds, and nally the treatment of very dilute but detrimental wastewaters is discussed. No single technology can
completely remove pharmaceuticals from wastewaters. The use of conventional treatment methods along with membrane
reactors and advanced posttreatment methods resulting in a hybrid wastewater treatment technology appear to be the best. The
recommendations provided in this analysis will prove useful for treatment of wastewater from the pharmaceutical industry.
1. INTRODUCTION
The global demand for quality water, whether for purposes of
drinking, sanitation, irrigation, and industrial use, has been on a
continuous rise, and there has been overwhelming concern in
recent years about water treatment and reuse requiring the
strictest standards (Figure 1).
1
The pharmaceutical industry is
beset with high-value, low volume multiproduct plants on one
hand which are mostly batch operations wherein the euent is
mixed and treated. There are some dedicated batch, semibatch,
and continuous process plants producing bulk drugs. These
plants use dierent types of reactants, (homogeneous) catalysts,
solvents, solids, and water, handled in special equipment. In
these types of units, the major cost of the drug depends on the
type of impurity rather than on the purity of the drug. Thus,
separation processes play a very vital role in this industry. The
so-called environmental quotient or E-factor for the pharma-
ceutical industry is anywhere between 50 and 100 kg/(kg of
desired product) since these processes are multistep operations
(anywhere between 5 and 30 steps) with several noncatalytic
routes using copious quantities of (volatile organic compound
(VOC)) solvents or crazymixtures of close boiling solvents.
Further, ultrapure water is used in the pharmaceutical sector to
give multiple washings to the solid cake or to use as extractant
or as solvent per se. This water is not reused due to strict
regulations as dened in drug master le (DMF) etiquettes
approved by the authorities. The presence, outcome, and
toxicity of pharmaceutical residues in the aquatic environment
pose diculties. Therefore, recovery of high-value API and
pharmaceutical drugs from dilute streams, instead of treatment,
ought to be considered while dealing with this issue. Many of the
frequently used generic drugs such as antibiotics, analgesics,
antihistamines, and antituberculosis (anti-TB) drugs, etc., are used
on the same scale as pesticides and other organic micro-
pollutants, but they are not subjected to the same level of scrutiny
for possible environmental eects. The total spread and
repercussions of the presence of these moieties in the environment
are therefore mostly unknown and ill-dened. Although these
compounds have been detected in a wide variety of environmental
samples including sewage, surface waters, groundwater, and
potable water, their concentrations generally range from a few
parts per trillion to parts per billion levels. It is therefore very often
considered unlikely that pharmaceuticals will have a detrimental
eect on the environment. However, in the absence of validated
analytical methods, proper monitoring information, and associated
data about the fate and toxicity of the pharmaceutical compounds
and/or their metabolites in the aquatic environment, it is dicult
to make a correct risk assessment.
The purpose of the current review is to take stock of euent
arising from dierent sectors of active pharmaceutical ingredients
(API), bulk drugs, and related pharmaceutics, which use large
quantities of water, to propose strategies to recover to a large
extent the valuable compounds, to demonstrate the economic
benet of recovery, and nally to discuss the treatment of very
Received: March 26, 2014
Revised: June 19, 2014
Accepted: June 20, 2014
Published: June 20, 2014
Review
pubs.acs.org/IECR
© 2014 American Chemical Society 11571 dx.doi.org/10.1021/ie501210j |Ind. Eng. Chem. Res. 2014, 53, 1157111592
dilute but detrimental wastewaters. Some important drug
manufacture ow sheets are included to show how and why
the waste is generated and whether some steps could be combined
to reduce the cost. There are instances where adequate data are
not available or the industry would not share such information for
being targeted by pollution control authorities. We also believe
that there is tremendous scope to develop new strategies for some
of the old problems from the perspective of green chemistry and
waste minimization principles.
2. PHARMACEUTICAL PROCESS WASTEWATER
Water is a critical raw material in pharmaceutical and chemical
manufacturing operations; consistent and high-quality water
supplies are required for a range of operations including production,
material processing, and cooling. The various categories of water
which need treatments as part of water management are potable
water, process water, feedwater for utilities, water recycling,
wastewater, water coming from byproduct treatment, water used
for odor treatment, water from desalination, and water for irrigation.
We will restrict this review to pharmaceutical water, wherein
it is widely used as a raw material, ingredient, and solvent in the
processing, formulation, and manufacture of pharmaceutical
products, APIs and intermediates, compendia articles, and
analytical reagents. Table1 provides the complete compositions
of the wastewater generated in pharmaceutical industries.
Process water quality management is of great importance in
pharmaceuticals manufacturing and is also a mandatory require-
ment for the sterilization of containers or medical devices in
other healthcare applications including water for injection.
Process wastewaters are a term used to dene wastewater in any
industry coming from the processes occurring in the industry.
Process wastewaters thus cover any water which at the time of
manufacturing or processing comes in contact with the raw
materials, products, intermediates, byproducts, or waste products,
which are handled in dierent unit operations or processes.
In fact, the wastewater coming out of pharmaceutical units
varies in content and concentration, and thus a unique
treatment is not attempted since the volumes are small and
dierent products are manufactured from the same battery of
reactors and separators. Water reuse provides savings through
the reduction of waste disposal costs and feedwater requirements,
Figure 1. Ratio of treated to untreated wastewater reaching water bodies from 10 regions across the globe. More than 90% of the water is discharged
untreated. Reprinted with permission from ref 2. Copyright 2014 GRID-Arendal (T). Adaptation from ref 3. Copyright 2010 UNEP/GRID-Arendal
and Hugo Ahlenius.
Table 1. Composition of Pharmaceutical Wastewaters
chemical processes wastewaters fermentation processes wastewaters
param minmax value av composition param minmax value av composition
COD, mg/L 37532500
a
c
,
e
j
8854 COD, mg/L 18012380
k
w
4670
BOD5, mg/L 2006000
a
c
,
f
h
,
j
2344 BOD5, mg/L 256000
k
p
,
r
,
s
,
u
,
v
2150
BOD5/COD ratio 0.10.6
a
c
,
f
h
,
j
0.32 BOD5/COD ratio 0.20.6
k
p
,
r
,
s
,
u
,
v
0.4
TOC, mg/L 8604940
b
,
e
,
j
2467 TKN, mg/L 190760
m
,
o
,
p
440
TKN, mg/L 165770
a
c
,
h
383 NH4+-N, mg/L 65.5190
p
,
u
128
NH3N, mg/L 148363
a
c
244 pH 3.311
k
u
,
w
7
TDS, mg/L 6759320
d
,
f
,
i
6.9 TDS, mg/L 130028000
m
,
r
,
s
12950
pH 3.99.2
a
c
,
e
,
g
,
j
TSS, mg/L 577130
m
,
n
,
p
t
1200
conductivity, μS/cm 160044850
n
,
r
,
t
17800
anions
x
anions
x
Cl, mg/L 7604200
a
c
,
g
,
i
2820 Cl, mg/L 1822800
k
,
l
,
p
,
r
,
t
1500
SO42, mg/L 8901500
a
c
,
i
1260 SO42, mg/L 1609000
k
m
,
o
,
p
,
r
,
t
2100
a
Reference 115.
b
Reference 116.
c
Reference 47.
d
Reference 78.
e
Reference 106.
f
Reference 128.
g
Reference 119.
h
Reference 46.
i
Reference 100.
j
Reference 121.
k
Reference 95.
l
Reference 45.
m
Reference 97.
n
Reference 49.
o
Reference 65.
p
Reference 51.
q
Reference 67.
r
Reference 44.
s
Reference 126.
t
Reference 98.
u
Reference 64.
v
Reference 52.
w
Reference 127.
x
Other anions are also likely to be present depending on type of
process. Data are scarce to enumerate.
Industrial & Engineering Chemistry Research Review
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osetting operational costs associated with the waste reuse
process.
2.1. Fate of APIs, Pharmaceuticals, and Drugs in the
Environment. A wide variety of sources can deliver
pharmaceutical chemicals, APIs, and drugs to streams, ground-
water storage, and aquifers. During dry weather, such sources
might include failing septic tanks or other on-site waste-
treatment systems, leaking sewer lines, permitted and accidental
discharges, illicit and unpermitted dumping, sanitary-sewer/
storm-sewer cross-connections, and unmanaged or poorly
managed pet and livestock wastes. Chemicals, used every day
in homes, industry, and agriculture, can enter the environment
in wastewater. These chemicals include human and veterinary
drugs (including antibiotics), hormones, detergents, disinfec-
tants, plasticizers, re retardants, insecticides, and antioxidants.
1
2.2. Health Hazard of Discharged Pharmaceuticals.
Pharmaceutically active compounds, APIs, are of emerging
concern because of their intrinsic biological activity, which can
lead to fatal consequences.
47
It is estimated that approximately
half of the pharmaceutical wastewaters produced worldwide are
discarded without specic treatment.
8,9
The presence of the so-
called endocrine disrupting compounds (EDCs) in aquatic
systems has caused considerable fear since they are known to
disrupt the human endocrine system.
10
The presence of
pharmaceutical products in the environment has eects such
as development of antibiotic resistant microbes in the aquatic
environment,
11
retardation of nitrite oxidation and methagenosis,
and the potential increased toxicity of chemical combinations and
metabolites.
12
Recent studies have found that pharmaceutical
products (PhPs) in water streams can cause adverse eects such
as feminization in sh
13
and alligators.
14
PhPs can also aect the
behavior and migratory patterns of salmon. The pharmaceutical
diclofenac was found to be the direct cause of near-extinction of
the vulture population in India.
15
Pharmaceuticals end up into the environment from humans
or animals via urine or faeces, through the sewage system, and
into the inuent of wastewater treatment plants as partially
active metabolites or in unmetabolized form.
7,16
In addition to
human consumption waste, disposal of pharmaceuticals which
are being used in agriculture, industry, and medical treatment
also contribute to the entry of pharmaceuticals into fresh water
bodies.
17
Veterinary pharmaceuticals on the other hand
contaminate directly soil via manure and surface and ground
waters by runofrom elds.
18
But, recently it has been
documented that various pharmaceutical production facilities
were found to be sources of much higher concentrations of
pharmaceuticals to the environment than those caused by the
usage of drugs.
19
The major pathway for PhPs to enter the
environment is through discharges of pharmaceutical industries
wastewater to the wastewater treatment plants (WWTP) and
then from municipal euent, but the extent to which
pharmaceuticals and personnel care products (PPCPs) are
removed by treatment processes is not well understood, and
many of the compounds released are nonbiodegradable and
therefore are not eciently removed by conventional (primary,
secondary, and tertiary) treatment technologies, leading to an
unfavorable accumulation in the aquatic environment.
20
Pharmaceutical manufacturing processes are batch and multi-
stage processes thus leading to generation of a huge quantity of
euent wastewater.
1
Also, the investigations show that PhP
production and administration will continue to increase with
the development and advancement of lifestyle and longevity
globally.
2123
2.3. Wastewater Treatment Options. A lot of research
papers have been published on the treatment of PhPs, EDCs,
and pharmaceuticals and household consumer products
(PHCPs) in the past decade mainly dealing with the euent
from tertiary WWTPs. Table 2 lists the costs of various
wastewater treatment technologies. However, treatment
options at the source not only could reduce costs and
environmental impact but also provide potential recovery of
compounds. Although much research has been done in this
context and many reviews have been published in recent years,
they lack a complete scenario of the pharmaceutical wastewater
composition and treatment technologies.
17,2428
The pharmaceutical industry requires consistent, high-quality
water for production and wastewater treatment to meet the
demands of ever-stricter regulatory discharge limits. To meet
these challenges, companies must question conventional
thinking and typical approaches and explore new technologies
and solutions to remain competitive. Thus, in the current
review, attempts have been made to (1) understand the nature
of the pharmaceutical waste originating at the industry site, (2)
categorize the dierent industrial processes to classify their
waste, and (3) access the eectiveness of advanced processes
and hybrid technologies for the removal of pharmaceuticals
from the aqueous systems.
3. OVERVIEW OF PHARMACEUTICAL
MANUFACTURING PROCESSES AND WASTEWATER
COMPOSITIONS
3.1. Prole of the Pharmaceutical Industry. The
pharmaceutical manufacturing industry encapsulates the
manufacture, extraction, processing, purication, and packaging
of chemical and biological materials, as solids and liquids to be
used as medication of humans and animals. Wastewaters in a
pharmaceutical manufacturing industry usually originate from
the synthesis and formulation of the drugs. Most of the APIs
distributed worldwide are manufactured by chemical synthesis
using organic, inorganic, and biological reactions. Since the
reactors and separators used in a multiproduct pharmaceutical
industry are not designed per the capacity but typically
oversized or used ineciently, the quantity of wastewaters
generated is increased. There are a number of subprocesses
occurring in a pharmaceutical industry, and it is a dicult task
to characterize each and every product waste. A more
elaborated classication based on raw materials, nal products,
and uniqueness of plants has been attempted. The classication
is done on the basis of the similarities of chemical processes and
treatments as well as certain classes of products. Based on the
processes involved in manufacturing, pharmaceutical industries
can be subdivided into the following ve major subcategories:
29
(1) fermentation plants; (2) synthesized organic chemicals
plants; (3) fermentation/synthesized organic chemicals plants
(generally moderate to large plants); (4) natural/biological
product extractions (antibiotics/vitamins/enzymes, etc.); (5)
drug mixing, formulation, and preparation plants (tablets,
capsules, and solutions, etc.).
Table 3 summarizes the dierent pharmaceutical processes
and the classication based on it.
The pharmaceutical industry uses an array of complex batch-
type processes and technologies for the manufacture of its
products. Figures 26 are schematic diagrams of the dierent
stages in the manufacture of a drug. The present section will
deal with the brief outline of all of the stages mentioned.
Industrial & Engineering Chemistry Research Review
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3.2. Pharmaceutical Manufacturing Processes.
3.2.1. Chemical Synthesis Process. Chemical synthesis
processes use organic and inorganic chemicals in batch
operations to produce drugs with dened pharmacological
action or intermediates. A schematic diagram of the chemical
synthesis process is shown in Figure 2. Mainly, a series of
chemical reactions are carried out in multipurpose reactors. The
products are isolated by using dierent separation processes
such as liquidliquid extraction, leaching (solidliquid
extraction), crystallization, and ltration. The product is then
usually dried, milled, and sent for further processing to the
formulation unit. The chemical synthesis process is usually a
multistep process with a lot of intermediates and byproducts.
Because of a large number of steps, the atom economy in
chemical synthesis is compromised including generation of a lot
of waste of material and energy. Apart from the reactors, there
are heat exchangers and other process vessels continuously
operating. The product usually in the mother liquor is
transferred internally using process vessels and pipelines and
thus the process becomes more complex leading to a
widespread use of raw water at every step. Very rarely, the
process water is used to minimize impurities except in a few
cases where the ltrate could be and has been reused. The
water washing of cakes of crystallized or precipitated solids
from organic solvents leads to considerable release of volatile
solvents into water and also into the air.
Wastewaters from chemical synthesis operations are diverse
due to many operations and reactions taking place in the reactor as
well as at dierent stages. Almost every stage produces mother
liquor that contains unreacted reactants, products, coproducts/
byproducts, and residual products in the organic solvent base.
Acids, bases, halides, nitrates, sulfates, cyanides, and metals may
also be generated. Usually, the spent solvent recovery leads to
solvent wastewater at the scrubber stage after evaporation.
Wastewater is generated at the purication steps comprising
solvents, nished products, cleaning water, and spills. This sewage
has a high toxicity level; thus, it requires immediate treatment
rather than release into WWTP. Wastewaters from synthesis
processes typically have high biological oxygen demand (BOD),
chemical oxygen demand (COD), and total suspended solids
(TSS) levels and pH ranging from 1 to 11.
29
A typical synthetic organic medicinal chemical production
process can be summarized as shown in Figure 3, which shows
the production of oxyphenonium bromide with the dierent
waste streams resulting from the process.
3.2.2. Fermentation Process. Fermentation is a biochemical
process involving the use of Bakers yeast, lactic acid bacillus,
bacillus sp., and various other microorganisms to produce a
chemical product. A batch fermentation process involves three
steps: seed inoculum and preparation, fermentation, and
product recovery. Inoculum preparation is done with necessary
conditions and the required microorganism, and then the whole
mixture is transferred to the steam sterilized fermenter.
Nutrients, inorganic salts, and other materials are added to
the fermentation tank. The process is usually a batch step. The
temperature is controlled by heat exchangers and coolers. The
fermentation broth then undergoes a series of steps such as
ltration, solvent extraction, precipitation by metal salts, ion
exchange, and addition of disinfectants such as phenolic
compounds.
The fermentation process generates a large amount of waste
such as spent aqueous fermentation broth and dead cell waste.
As in most of the aqueous-phase fermentations the bacteria do
Table 2. Summary of Wastewater Treatment Technologies and Cost Comparison
a
name of the technology treatment method treatment capacity capital cost ($/KLD) O & M ($/(KLD/year)) reuse of treated wastewater
DWWT
b
sedimentation, anaerobic digestion, ltration and phyto-remediation 1000 KLD
c
$580$1200 $15$25 horticulture biogas generation
soil biotechnology sedimentation, ltration, biochemical process 5 KLD to tens of
MLD
c
$160$250 $15$25 horticulture cooling systems
biosanitizer/ecochip biocatalyst: breaking the toxic/organic contents 100 mg/KLD chip cost $160 excluding
construction cost not available in situ treatment of water bodies,
horticulture
soil scape lter ltration through biologically activated medium 1250 KLD $300$500 $30$35$ horticulture
ecosanitation zero
discharge toilets separation of fecal matter and urine individual to
community level $650$850 (excluding the cost of
toilet construction) not available ushing horticulture composting
Nualgi technology phyco-remediation (use of micro-/macroalgae): xCO
2, remove
nutrients, and increase DO in water 1 kg treats up to ML $6/MLD
c
$150$160/MLD
c
in situ treatment of lakes/ponds,
increase in sh yield
bioremediation decomposition of organic matter using Persnickety 713 (biological
product) 1 billion CFU/mL $3750$5000/MLD
c
$3000$5000/MLD
c
in situ treatment of lakes/ponds
green bridge
technology
ltration, sedimentation, biodigestion, and biosorption by microbes
and plants 50200 KLD/m2$4$8 $1 in situ treatment of water bodies
a
Costs have been estimated on the basis of the year of implementation of listed case studies. The current cost involved may vary. (Adapted from ref 129.) KLD = kiloliters per day. MLD = megaliters per
day.
b
DWWT = decentralised wastewater treatment.
c
Cost of the technologies for lakes and water bodies remediation have been indicated in per MLD per year.
Industrial & Engineering Chemistry Research Review
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not survive at higher concentrations of the product because of
inhibition of the bacteria due to accumulation of the product.
The waste stream has a large quantity of unconsumed raw
materials such as the nutrient broth, metal salts, starch, nitrates,
and phosphates with high COD, BOD, and TSS with pH values
ranging from 4 to 8. Steam and small amounts of industrial
chemicals (phenols, detergents, and disinfectants) maintain the
sterility in the process plant and thus their leftovers also add to
the aqueous waste stream. A considerable quantity of metal
and halogen impurities is also found due to usage for the
precipitation of the product from the mother liquor. Large
amounts of solvents are also used for the purication of the
desired product, and during the recycling of the solvents
aqueous waste having miscible organic solvents is generated.
A good example of the fermentation process in the pharma-
ceutical industry is antibiotic production of penicillin (Figure 4).
The process gives a clear outline of the wastewater streams
generated at the various outlets and the prospective of applying
recovery and treatment technologies at the site of the generation
of wastewater.
3.2.3. Natural/Biological Extraction Process. Large
amounts of natural (plant and animal) materials are processed
to extract the active pharmaceutical ingredient from the source.
In each step, a large volume of water input is required and the
product recovery decreases until the nal product is reached.
Solvents are used on a large scale to remove the lipophilic
matter and to extract the desired product. The pH adjustment
of the extract solutions makes use of substantial amounts of
acids and bases. Also, metal addition for precipitation and
phenolic compounds for disinfection add to the number of
components in the process leading to further treatment
problems. Thus, the nal yield of the product is low. Typically
hexane is used as solvent for natural product or herbal
extraction, which is released into the air and also the water.
These days processes based on supercritical carbon dioxide
(scCO2) are developed to contain organic impurities in the
nal product as well as to reduce euent. Spent raw material
and solvents, wash water, and spills are the primary sources of
wastewater. Organic and inorganic chemicals may be present as
residues in these waste streams. Also, the usage of a variety of
low-boiling organic solvents generates wastewater with solvents.
Usually, wastewaters have low BOD, COD, and TSS, with
relatively neutral pH values ranging from 6 to 8 (Figure 5).
3.2.4. Compounding/Formulation Process. Drug products
obtained from the three processes mentioned before are then
processed to usable forms such as tablets, ointments, syrups,
and other dosage forms. The process uses steps such as milling,
mixing, grinding, compression, and packaging (Figure 6). Many
types of llers, binders, avoring agents, preservatives, and
antioxidants are added during the compounding process. The
process plant is common to almost all drug manufacturing
processes. Very hygienic conditions are required during the
process thus making rampant use of steam sterilization and
phenolic compounds.
After the production, APIs produced by batch processes must
be converted to dosage forms and this part is carried out in a
separate batch of mixing/compounding and formulations
processes. Thus, various methods such as ller addition, dilution
of APIs, binding, and tablet operation machines are involved. Also,
various physical operations such as grinding, sieving, ltration,
washing, drying, encapsulation, and nally packing are a common
practice. All of the mentioned steps add to the wastewater sources
in the pharmaceutical industry.
On the contrary, these manufacturing processes may be
discrete batch, continuous, or a combination thereof depending
on the volume of production and the value of the product.
Antibiotics, steroids, and vitamins are produced by fermenta-
tion, whereas many other common pharmaceuticals are
prepared by chemical synthesis process. Many drugs were
derived from natural materials, but due to low recovery and
cost eciency this process is less observed.
3.3. Water Consumption in Pharmaceutical Bulk
Manufacturing Process. A wide variety of products are
made in the chemical and pharmaceutical manufacturing
Table 3. Classication of Dierent Processes Based on Routes of Bulk Pharmaceutical Manufacture
chemical synthesis fermentation natural product extraction
antibiotics ; antihistamines; cardiovascular agents; central
nervous system (CNS) stimulants; CNS depressants,
hormones vitamins
antibiotics; antineoplastic
agents; therapeutic nutrients;
vitamins; steroids
antineoplastic agents (chlorambucil, daunomycin, melphalan,
mitomycinc); enzymes and digestive aids; CNS depressants;
hematological agents; insulin; vaccines
Mixing or Compounding/Formulation Stage
This process is common to all the bulk processes having some API waste along with solvents and packaging waste materials.
Figure 2. Process ow sheet diagram for the chemical synthesis process. Adapted from ref 29. Copyright 1998 U.S. EPA.
Industrial & Engineering Chemistry Research Review
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industries, typically requiring large volumes of chemicals,
materials, and substances that are used throughout process
operations. The mixtures of pharmaceuticals, hormones, and
other wastewater contaminants can occur at low concentrations
in streams that are susceptible to various wastewater sources,
and the volumes will vary from industry to industry or site to
site for the same compound. Waste streams generated in these
industries can be heavily laden with contaminants, toxins,
nutrients, and organics, presenting unique challenges in terms
of treatment in view of stringent regulations. It is important
that for reuse in both validated and nonvalidated systems the
treated wastewater quality must exceed the feedwater quality
for high operational eciency, water quality, and product
safety. Thus, it may be possible to expand production capacity
without exceeding water discharge limits, drastically reduce raw
water requirements and waste disposal cost of operation, and
reduce specic organics while leaving other inorganic species
intact (Figures 7 and 8).
Figures 7 and 8 highlight the water consumption pattern in a
chemical and a fermentation process manufacturing unit. If
observed clearly, it can be seen that approximately 50% of the
water input is going out as waste. Also, deep analysis of the
water balance shows that the fermentation process consumes
more process water as compared to the synthetic route. Thus,
the need to devise methods of reclaiming and reuse of water is
mandatory. There is an ample scope for water reuse by usage of
advanced treatment technologies at the site of generation of
wastewater rather than treatment at the euent treatment plant
(ETP) and disposal site.
3.4. Solvent Use and Water Requirement. Several
solvents are employed as vehicles in the pharmaceutical
manufacturing process to dissolve gaseous, solid, or viscous
reactants, products, and impurities. They are used in the chemical
synthesis process to dissolve reactants in a homogeneous phase to
overcome mass and heat transfer eects. Some solvents are also
used to control the reaction temperature. A variety of pollutants
released during the manufacture of pharmaceutical products are
the reaction and purication solvents.
32,33
These include benzene,
phenol, toluene, halogenated solvents, and cyanide. Although EPA
has banned or put restriction on use of some 23 solvents including
some VOCs and chlorinated solvents, some are still used by the
pharmaceutical industry since the relevant drugs cannot be
manufactured by using other solvents; for instance, methylene
chloride (Table 3). The major nonconventional solvents used in
industry are methanol, ethanol, isopropanol, acetone, and ethyl
acetate. Also, many heteroaromatics such as pyridine or piperidine
contribute to this list as they are inert in the reaction process.
Many industries have their solvents recovery systems for
purication of contaminated solvents consisting of distillation
columns and solventsolvent evaporation systems in which a
Figure 3. Process ow diagram for synthesis of oxyphenonium bromide (antrenyl). Adapted from ref 30. Copyright 19881989 CPCB.
Industrial & Engineering Chemistry Research Review
dx.doi.org/10.1021/ie501210j |Ind. Eng. Chem. Res. 2014, 53, 115711159211576
Figure 4. Streptomycin production and its recovery and purication from the fermentation broth. Adapted from ref 30. Copyright 19881989
CPCB.
Figure 5. Process ow sheet diagram for natural/biological extraction
process. Adapted from ref 29. Copyright 1998 U.S. EPA.
Figure 6. Process ow sheet diagram for the compounding/
formulation process. Adapted from ref 29. Copyright 1998 U.S. EPA.
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second solvent is used to separate impurities.
36
These
operations result in aqueous wastewaters being fully or partially
saturated with residual solvents. For instance, in 2007, 119000
tons of Irelands hazardous waste generation was organic
solvent and of this, 55400 tons was exported for recovery or
disposal. This waste arose primarily from the pharmaceutical
sector (Table 4).
A thorough review of published literature suggested that
chemical synthesis and fermentation processes are among the
pharmaceutical sectors with larger water consumption and
wastewater generation, and thus, this work is focused on the
wastewater treatment dealing with these two processes
exclusively. Tables 5 and 6 give an outline of the composition
of the actual wastewater from the chemical synthesis process and
fermentation process pharmaceutical manufacturing industries.
4. TREATMENT OF PHARMACEUTICAL WASTEWATER
The pharmaceutical industry employs a wide array of
wastewater treatment and disposal methods.
34
Wastewaters
generated from these industries vary not only in composition
but also in quantity, by plant, season, and even time, depend-
ing on the raw materials and the processes used in the
manufacturing of various pharmaceuticals. Plant location also
brings in a variable related to the quality of available water.
Hence it is very dicult to specify a particular treatment system
for such a diversied pharmaceutical industry. Many alternative
treatment processes are available to deal with the wide array of
waste produced from this industry, but they are specic to the
type of industry and associated wastes. However, the analysis of
published information in the public domain shows that six
Figure 7. Water balance for a chemical synthesis process manufacturing plant producing paracetamol (ratio of consumption of process water to total
water = 0.5). Adapted from ref 31. Copyright 2007 CPCB.
Figure 8. Water balance for a fermentation process manufacturing plant producing penicillin (ratio of consumption of process water to total water =
0.08). Adapted from ref 31. Copyright 2007 CPCB.
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general approaches are employed to treat pharmaceutical
wastewaters which are (i) recovery of individual APIs or
drugs which are likely to be present in wash waters and
solvents, (ii) physicalchemical treatment by sedimentation or
oatation, (iii) aerobic/anaerobic biological treatment in
membrane bioreactors or bioaeration, (iv) inactivation of active
substances by UV oxidation in conjunction with O3or H2O2,
(v) sterilization and decontamination of infectious and
bioactive substances from biotechnology, and (vi) new hybrid
technologies specic to the pharmaceutical industry. An
attempt is made here to discuss some of these issues with
reference to general methodology and specic examples.
4.1. Recovery Processes. Pretreatment and recovery of
various useful byproducts, such as solvents, acids, heavy metals,
and various important APIs, which nd their way into the
waste streams comprise a very important waste control strategy
for pharmaceutical plants. In the fermentation plants, the
fermentation broth contains large amounts of solvent and
mycelia. The solvents exhibit very high BOD strength, and also
some of the solvents are not biologically degradable.
Recovery of the pharmaceutical product can reduce or even
eliminate waste disposal costs of the primary unit process and
raw water requirements of the secondary unit process, quickly
osetting waste-treatment operational costs and improving the
economics of the process. The recovered waste stream can be
used elsewhere in the process, and the water could be used for
boiler feed or cooling towers and other operations thereby
reducing consumption of precious raw water and drastically
reducing operating costs. In fact, hot waste streams after
processing can be used for other heat exchangers (heat
pinching) or as boiler feed thereby reducing water and energy
costs.
In general, pharmaceuticals have molecular weights higher
than 250 Da and can be recovered by using eective membrane
technologies provided that the product is alone in the stream.
Indeed, a lot of economic benet can be realized by using
reverse osmosis, nanoltration, and ultraltration. The ltrate
can then be subjected to further processing as given in what
follows.
Nanoltration is the most recent developed pressure driven
membrane separation process, and its applications have been
increasing rapidly in the past decade. It has been widely used in
aqueous systems such as the concentration of antibiotic
aqueous solutions.
35,36
As an example, recovery of amoxicillin
based on its physical characteristics and release in the
environment is important. Amoxicillin (MW = 365.40 Da) is
a widely used antibiotic in human and veterinary medicine for
the treatment and prevention of respiratory, gastrointestinal,
urinary, and skin bacterial infections due to its pharmacological
and pharmacokinetic properties. In human medicine amoxicillin
is commonly used in combination with clavulanic acid, a
penicillinase inhibitor in veterinary use. It is used in many
domestic and food animals, including cats, dogs, pigeons,
horses, broiler chickens, pigs, goats, sheep, preruminating calves
(including veal calves), and cattle. In dogs and cats, amoxicillin
is used in respiratory and urinary infections and in soft tissue
wounds caused by Gram-positive and Gram-negative patho-
genic bacteria.
38
So the quantity of amoxicillin released into the
atmosphere and in sewage, wastewater, and potable waters
could be quite high. Nanoltration (NF) can be used to
separate and recover amoxicillin from pharmaceutical waste-
water in order to palliate the amoxicillins harm to the environment
and also improve economics. Separation of amoxicillin from
pharmaceutical wastewater by NF membrane has also been
investigated by Shahtalebi et al.
39
The rejection of the amoxicillin
by the selected NF membrane was adequate and in most cases
exceeded 97% whereas COD reached a maximum of 40% rejection
and permeation ux was over 1.5 L/(min·m2). The stable
permeation ux and high rejection of amoxicillin indicated the
potential of NF for the recovery of amoxicillin from pharmaceutical
wastewater.
Nanoltration can be useful in recovering more than 80% of
the complex waste stream with a quality better than feedwater
quality for high operational eciency and product safety. This
is a sort of process intensication which permits increased
production capacity without exceeding water discharge limits,
drastically reducing raw water requirements and waste disposal
cost while reducing specic organics and, at the same time,
leaving other inorganic species intact.
The assessment of pollution due to toxic heavy metals in the
industrial wastewater euents collected from the Taloja
industrial belt of Mumbai revealed that dye, paint, pharma-
ceutical, and textile industries are some of the major industries
contributing to the heavy metal pollutants in the surrounding
aquatic environment. For instance, the concentration of Cd and
Ni was found maximum in euent samples collected from
pharmaceutical industries amounting to 35.8 and 33.6 mg/L,
respectively.
40
Studies at the University of Alicante showed development of
electrochemical processes for the recycling and recovery of
metals (Pb, Zn, Ni, ...) from their secondary process. The use of
electrochemical processes allows obtaining metals of a higher
purity, and it supposes a much less polluting alternative than
the classic pyrometallurgy, since it avoids the emission of gases,
sulfur, and metal particles.
41
Table 4. Solvents Used in Pharmaceutical Manufacturing
Process
chemicals
priority
pollutant
under the
clean water act chemicals
priority
pollutant
under the
clean water act
acetone ethylene glycol
acetonitrile formaldehyde
ammonia (aq.) formamide
n-amyl acetate furfural
amyl alcohol n-heptane
aniline n-hexane
benzene ×isobutyraldehyde
2-butanone (MEK) isopropyl ether
n-butyl acetate methanol
n-butyl alcohol methyl amine
chlorobenzene ×methyl cellulose
chloroform ×methylene chloride ×
chloromethane ×methyl isobutyl
ketone
cyanide ×N-methylpyridine
cyclohexane petroleum naptha
o-dichlorobenzene ×phenol ×
diethyl amine PEG-600
diethyl ether n-propanol
dimethyl sulfoxide pyridine ×
N,N-
dimethylformamide tetrahydrofuran
1,4-dioxane toluene ×
ethyl acetate triethylamine
ethanol xylene
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Table 5. Chemical Synthesis Based Pharmaceutical Wastewater Treatment Technology
no. technology and its features matrix comments ref
1 sulfate anion radical oxidation (Fe and Co sulfate
salts used with hydrogen peroxide and ozone)
simulated aniline-based pharmaceutical product waste: diclofenac and
sulfomethaxazole, both 1000 mg/L
DCF and SMX followed second-order kinetic degradation, with
N-centered radical mechanism: very ecient method as sulfate
radicals is more selective than hydroxyl radicals
Ahmed et al.
117
2 dissolved air precipitation with solvent sublation simulated water: mineral oil layer with organic solvents (toluene, methylene
chloride, benzene, chlorobenzene, hexane, butyl acetate)
Removal eciencies for a mixture of contaminants can dier from a
case of single contaminants due to dierences in their physical
properties such as Henrys constant and interfacial partitioning
coecient. A higher removal of toluene was observed.
Bayati et al.
118
3 electrocoagulation (EC) followed by heterogeneous
photocatalysis (TiO2; iron electrodes were used as
cathode and anode)
BOD:COD, 0.11, caused by the high COD value (such alow index indicates the
presence of refractory substances, probably stable organic compounds, which
can hardly undergo biological degradation): COD, 1753 mg/L; BOD, 200
mg/L; sulfate, 893.7 mg/L; phosphate, 17.0 mg/L; N-ammonical, 220.4 mg/L;
organic nitrogen, 344.0 mg/L; nitrite, 383.9 mg/L
This allowed the removal eciency of 86% COD and 90% turbidity;
the initial removal with EC is 70% which is enhanced to 76% by the
use of UV/H2O2. Combination works best for wastewater with a
high concentration of refractory chemicals.
Boroski et al.
115
4 up-ow anaerobic sludge blanket (UASB) + micro-
aerobic hydrolysis acidication reactor (NHAR) +
two-stage aerobic process, cyclic activated sludge
system (CASS) and biological contact oxidation
tank (BCOT)
amoxillin (69.2105.4 mg/L) manufacture wastewater from dierent stages of
the plant: COD, 401613093 mg/L; total N, 156.4650.2 mg/L
The combined process leads to total reduction in COD levels at every
stage of the process and above 90% COD removal eciency and is
best suited for chemical synthesis based wastewater euents.
Chen et al.
47
5 two-phase anaerobic digestion (TPAD) system and
a subsequential membrane bioreactor (MBR)
TPAD system comprised of a continuous stirred
tank reactor (CSTR) and an up-ow anaerobic
sludge blanket-anaerobic lter (UASBAF), work-
ing as the acidogenic and methanogenic phases
product manufacture and wash water waste comprised of organic compounds
such as the GCLE intermediate, cefdinir, pingyangmycin, riboavin sodium
phosphate, and glibenclamide: COD, 500060000 mg/L; BOD5, 75010800
mg/L; TN, 560980 mg/L; TP, 51.41120.4 mg/L; TOC, 35936287
mg/L; NH3N, 36.31260.6 mg/L; suspended solids,
6002000 mg of COD/L; many solvents and sulfate, 11281627 mg/L;
chloride ion, 23243570 mg/L; pH, 6.07.0
The combined pilot plant removed 99% COD, and the MBR reduced
the pH in the neutral range. The combination of TPAD-MBR can
be successfully applied to chemical synthesis based wastewater.
Chen et al.
116
6 adsorption: granular activated carbon (a series of
columns of GAC were used)
major impurity mercury and organomercury compounds: TDS, 675 mg/L; pH,
8.9
Removal eciency was 99% of total mercury and 90% of copper. The
treatment system was also eective for removal of turbidity (99%),
color (99%), and phenols (96%) from the wastewater.
Cyr et al.
78
7 electrochemical treatment (boron doped diamond
BDD anode for corrosion stability)
organics (aromatic and aliphatic compounds), solvents (methanol and ethanol),
and high concentration of chloride ions: COD, 12000 mg/L; TOC:COD,
0.27; pH, 8.5; TSS, 5000 mg/L; TOC, 1600 mg/L
The process was capable of achieving satisfactory levels of TOC
removal at short treatment times. With adequate combinations of
both variables (current density and ow rate), almost 100% of TOC
content can be removed.
Domi ́
nguez et al.
106
8 continuous heterogeneous catalytic wet peroxide
oxidation (CWPO) process using a
Fe2O3/SBA-15 nanocomposite catalyst
pH, 5.6; COD, 1901 mg of O2/L; TOC, 860 mg/L; BOD, 38 mg of O2/L;
HCO3, 112 mg/L; NO3, 500 mg/L; NH4, 4.8 mg/L; Cl1, 3380 mg/L;
suspended solids, 40.6 mg/L; BOD/COD, 0.20; av oxidation state (AOS),
0.70
Fe2O3/SBA-15 extruded catalyst exhibits high eciency, TOC
removal of 5060%, and ecient COD degradation. After initial
treatment water can be treated biologically.
Melero et al.
119
9 acidogenic reactor (USAB sludge from an alcohol
industry was used with high glucose as initial feed
and then varying pharmaceutical wastewater)
COD, 4000060000 mg/L; TKN, 800900 mg/L; phosphate, 36 mg/L;
volatile SS/TSS, 0.60.7 mg/L; alkalinity (as CaCO3), 9001000; pH, 78;
also traces of bacampicilline and sultampicilline tosylate
ecient acidication method for chemical synthesis based waste;
COD removal 1025% throughout; acidication conversion of 44%
of the inuent waste
Otkem et al.
120
10 hybrid up-ow anaerobic sludge blanket reactor COD, 4000060000 mg/L; TKN, 800900 mg/L; phosphate, 36 mg/L;
volatile SS/TSS, 0.60.7 mg/L; alkalinity (as CaCO3), 9001000; pH, 78;
also traces of bacampicilline and sultampicilline tosylate
This allowed 6065% removal eciency for chemical synthesis
wastewater having organic content. SMA test showed no inhibitory
action. Biomass was economical. USAB reactor showed stability for
high organic contaminants
Otkem et al.
66
11 conventional treatment: activated sludge reactor
using sequencing batch reactor
COD, 250500 mg/L; BOD, 130280 mg/L; ammonia as N, 80200 mg/L;
total N, 90240 mg/L; total phosphorus, 12 mg/L; pH, 8.89.6
Nitrogen removal eciency of 99% was achieved at 23 °C. The nitrite
reduction eciency of the reactor can be used for wastewater with
high ammonia content. Nitrogen removal can be controlled and cost
reduction can be achieved.
Peng et al.
46
12 hybrid up-ow anaerobic sludge blanket reactor wastewater conditions: TDS, 85009000 mg/L; TSS, 28003000 mg/L; COD,
1300015000 mg/L; BOD, 70007500 mg/L; volatile fatty acids, 600750
mg/L; alkalinity (as CaCO3), 25003000; chlorides, 200250 mg/L; nitrates,
120170 mg/L; sulfates, 300450 mg/L; phosphates, 100120 mg/L;
phenol, 2530 mg/L; 2-methoxy phenol, 2025 mg/L; 2,4,6-trichlorophenol,
2025 mg/L; dibutyl phthalate, 3040 mg/L; 1-bromonaphthalene, 510
mg/L; antipyrene, 510 mg/L; carbamazepine, 1015 mg/L; pH, 7.07.5;
BOD:COD, 0.450.6 (amenable to biological treatment)
Best option for high organic wastewater. Removal eciency: COD,
6575%; BOD, 8090%. The bio gas production rate is high, thus
an economically feasible process
Sreekanth et al.
70
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The ultraltration process has also been eectively used for
the recovery of organic compounds from several synthetic
media resulting from fermentation process wastewater.
Bezawada et al.
42
used ultraltration for recovery of alkaline
protease from spent fermentation broth. Alkaline protease
accounts for 60% of the total enzymes sales and is a very
important material for the fermentation industry. The recovery
of alkaline protease using ultraltration process with an
optimum transmembrane pressure of 90 kPa and feed ux of
714 L/(h/m2) showed a recovery of 83% of the protease activity.
4.2. Wastewater Treatment of Dilute Streams. The
dilute streams from the manufacturing units are mainly treated
by biological treatment methods as they convert most of the
waste into gases and sludge can be disposed oharmlessly.
Available treatments include the activated sludge process, trickling
ltration, the powdered-carbon-fed activated sludge process, and the
anaerobic hybrid reactor. Apart from the foregoing conventional
treatment processes there are several other oxidation processes,
membrane techniques, and advanced oxidation processes.
43
Based
upon an extensive literature survey of the research carried out on
actual pharmaceutical waste treatment, a listing has been made of
the treatment technologies available in Table 2.
To have a clear understanding of the various techniques used
in the treatment and disposal of various types of wastes
produced in the pharmaceutical industry, the treatment
processes can be divided into the following four categories
and subcategories:
(1) biological treatment process;
(a) aerobic treatment
(b) anaerobic treatment
(2) advanced treatments;
(a) membrane technology
(b) activated carbon
(c) membrane distillation
(3) advanced oxidation processes
(a) ozone/hydrogen peroxide treatment
(b) Fenton oxidation
(c) photocatalysis
(d) electrochemical oxidation/degradation
(e) ultrasound irradiation
(f) wet air oxidation
(4) hybrid technologies
4.2.1. Biological Treatment. Biological treatment methods
have been traditionally employed for dealing with pharmaceut-
ical wastewater.
44
The biological treatment of pharmaceutical
wastewater includes both aerobic and anaerobic treatment
systems. Apart from the previously mentioned two processes,
Afzal et al.
45
investigated an ecient degradation by using
Pseudomonas aeruginosa (P. aeruginosa) and P. pseudomallei
where the former showed a higher degradation rate and COD
and BOD removal which indicated that the strains work well
for phenolic wastewaters from fermentation processes.
4.2.1.1. Aerobic Treatment. Aerobic treatment is one of the
common technologies applied which include the activated sludge
(AS) process, extended aeration activated sludge process, AS with
granular activated carbon, and membrane bioreactors.
4650
Activated Sludge Process. The activated sludge process is
the most common aerobic treatment which has been found to
be ecient for various categories of pharmaceutical waste-
waters.
51
The conventional activated sludge (CAS) treatment is
a low-cost method which depends mainly on two parameters,
the temperature and the hydraulic retention time (HRT). Apart
no. technology and its features matrix comments ref
13 catalytic wet air oxidation: homogeneous catalyst,
Cu salt; heterogeneous catalyst, MnFe compo-
site; temperature variation study
pH, 2.65.2 (organic matter content); COD, 712 g/L; BOD, 57 g/L With the increase in the temperature and catalyst loading (Cu salt),
higher COD removal was achieved within a 1 h interval.
Zheng
121
14 multistage loop membrane bioreactor COD, 12009600 mg/L; BOD5, 5002500 mg/L; NH4N, 50200 mg/L;
TN. 105400 mg/L; intermediates (6-APA, 7-ACA, GCLE), cefazolin,
cefoperazone sodium, cephalosporins ampicillin, penicillin G sylvite,
amoxicillin, ampicillin sodium, and poly(ethylene oxide); ethylene; glycerin
The removal rate was constant at 90% with pH constant. The
technology is not suitable for wastewater having a lot of organic
contaminants.
Chen et al.
47
15 photofenton followed by lime or NaOH coagulation wash waters from the production plant and mixture of spent chemicals from
ointment production already treated by adsorption, occulation, and ltration:
COD, 413 mg/L
8696% COD removal and biodegradability increase after 120 min
oxidation at H2O2:Fe2+ molar ratio, 10:1; lime coagulation, 0.5 g/L
Kulik et al.
96
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Table 6. Fermentation Process Based Pharmaceutical Wastewater Treatment Technology
no. technology and its features matrix comments ref
1 photocatalysis (TiO2)+H
2O2; a single baffled
reactor for the process.
pH, 8.2; phenol, 380 mg/L; chlorides, 182 mg/L; sulfates, 160 mg/L; COD, 1082
mg/L; BOD, 170 mg/L; BOD:COD, 0.15
Addition of H2O2to the system increases degradation rate from 75 to 95%.
Also, phenol removal rate enhanced from 40% to 45%. The combination of
H2O2to the photo catalytic system enhanced the effluent removal rate.
Adishkumar and
Kanmani
95
2 biodegradation using bacterial strains
(Pseudomonas aeruginosa and Pseudomonas
pseudomallei)
aqueous phenol waste, 1053 mg/L; COD, 5097 mg/L; BOD, 1100 mg/L; chloride,
1152 mg/L; sulfate, 2280 mg/L; pH, 48
Efficient degradation of phenol by two strains at higher concentration. P.
aeruginosa showed higher degradation rate and COD and BOD removal and
can be used for phenolic treatment.
Afzal et al.
45
3 photocatalysis (Fenton + photo-Fenton +
ozonation)
penicillin formulation effluent: av COD, 1395 mg/L; TOC, 920 mg/L 1020% COD removal after 60 min. Poor improvement in biodegradability Arslan-alaton and
Dogruel
90
4 ozonation (pretreatment) + biological activated
sludge reactor combination in series
penicillin formulation effluent: av filtered COD, 830 mg/L; soluble COD, 615
mg/L; pH, 6.9; amoxicillin trihydrate; lactamase inhibitor; potassium clavulanate
Preozonation enhanced the biodegradability of the effluent. Efficiency of the
process for COD, around 90% removal with the organic content. The
combination of preozonation and biodegradation is the best option for
pharma effluent.
Alaton et al.
93
5 Fentonbiological process: first Fenton coagu-
lation and then biological treatment by
activated sludge
COD, 410013023; TSS, 20330 mg/L; oil grease, 17.4600 mg/L; traces of
salicylic acid, chlorompenicol, and paracetamol; TOC, 4679.4 mg/L; sulfate, 788
mg/L
More than 95% COD removal was observed. Fenton pretreatment reduced the
COD and toxicity level thus making it suitable for biological treatment. Also,
many organic compounds were degraded.
Badawy and Wa-
haab
97
6 chemical oxidation ozonation and ozonation
coupled with treatment with hydrogen per-
oxide
antibiotic formulation waste was made synthetically by characterizing the actual
industrial waste: antibiotic I (ceftriaxone sodium, cephalosporine group); human
antibiotic II (penicillin VK and penicillin group; contain only active substances);
veterinary antibiotic enrofloxacin, quinolone group are prime constituents. COD
up to 1400 mg/L
Preozonation helps to reduce the COD level to a great extent and H2O2
enhances the process to the maximum. Also, the biodegradability character-
istic of the waste also increases. Thus, ozonation can be successfully applied as
a pretreatment.
Balcıoǧlu and
Otker
91
7 membrane bioreactor technology (hollow fiber
membrane)
pH, 6.69.4; SS, 60360 mg/L; COD, 80011800 mg/L; BOD, 1006350 mg/L MBR system is capable of removing 95% and 99% of COD and BOD,
respectively.
Chang and
Chang
49
8 up-flow anaerobic stage reactor (UASR) soluble COD, 7000 ±800 mg/L; soluble BOD5, 3500 ±500 mg/L; sulfates, 2500
±500 mg/L; total Kjeldahl nitrogen (TKN), 364 ±50 m/L; pH, 5.26.8; tylosin
concentration, 10220 mg/L
75% of soluble COD removal with 95% reduction in tylosin concentration was
observed. The anaerobic biological reactor can be efficiently applied to such
antibiotic wastewater.
Chelliapan and
Sallis
65
9 up-flow anaerobic stage reactor (UASR) tylosin and avilamycin; soluble COD, 70007800 mg/L; soluble BOD 35007500
mg/L; sulfates:25007500 mg/L; total Kjeldahl nitrogen (TKN): 364750
mg/L; pH: 5.26.8; and tylosin concentration, 20200 mg/L
UASR can be used effectively as an option for pretreatment of pharmaceutical
wastewaters that contain Tylosin and Avilamycin macrolide antibiotics. COD
reduction of 7075%; Tylosin can be degraded efficiently in anaerobic
environments
Chelliapan
69
10 ozonation (pretreatment) + biological activated
sludge treatment by synthetic biomass with
30% COD
penicillin formulation waste with wash waters: COD, 710 mg/L; soluble COD, 690
mg/L; TOC, 200 mg/L; BOD, 15 mg/L; pH, 6.85; with chlorides and sulfates
ozonation removed 34% COD and 24% TOC and then the water showed
efficient COD removal by biodegradability using activated sludge.
Cokgor et al.
94
11 activated sludge reactor in batch and continuous
flow
process waste: COD, 14886818 mg/L; BOD, 9504050 mg/L; TSS, 56656
mg/L; TDS, 13717314 mg/L; chloride, 1005000 mg/L; iron, 14 mg/L;
phenol, 116.7210 mg/L; pH, 1.874.4
More than 95% efficiency was obtained by biologically activated sludge reactor,
films reactor, and trickling filter reactor. Biological treatment is best suited for
such waste.
El-Gohary et al.
51
12 anaerobic biological treatment using activated
sludge reactor
solvent containing wastewater from an API producing industry having propanol,
methanol, and acetone in water
A good COD removal efficiency with production of biogas was observed. Enright et al.
68
13 hybrid treatment technology (aerobic biological
pretreatment + ozonation + MBR), the
biological treatment for reducing the ozone
demands. Ozonation reduces almost all of the
organic compounds.
API formulation waste comprised of estrogens, many small steroids, and oral
contraceptives; no specific physiochemical characteristics
Aerobic biological treatment reduces most of the organics, and then ozonation
eliminated the bulk organic load and APIs. More than 90% COD and TSS
removal was obtained, and the MBR led to complete treatment of wastewater.
Helmig et al.
50
14 anaerobic granulation batch/column reactor COD, 40005000 mg/L; ammonical N, 20300 mg/L; TSS, 150300 mg/L; pH,
47
Nitrate and phosphate removal by precipitation was observed, as well as 95%
removal of COD.
Inizan et al.
67
15 catalytic wet air oxidation coupled with anaero-
bic biological oxidation
wastewater from a vitamins manufacturing company: COD, 70000120000 mg/L;
BOD, 50007000 mg/L; TSS, 5080 mg/L; pH, 35; NNH4,8150 mg/L
CWAO removed COD and BOD to the maximum and enhanced the
biodegradability of the wastewater; 94.66% removal of COD was obtained.
Kang et al.
71
16 aerobic biological treatment with variable tem-
perature study
effluent: soluble COD, 81507170 mg/L; soluble BOD, 38007900 mg/L; total
ammonia, 220750 mg/L
Soluble COD removal in a given batch reactor declined as temperature
increased by an average of 60 (mg/L)/°C.
La Para et al.
122
17 biological treatment by activated sludge: in seven
stages, a pilot plant study
effluent: high COD, more than 500 mg/L; BOD, more than 50 mg/L; total
ammonia, more than 5 mg/L
This is a table microbial reactor for a long time operation. LaPara et al.
48
18 suspended growth photo-bioreactor: nonsulfur
photosynthetic bacterium isolated from the
soil and fluorescent light reactor
wastewater: COD, 9450 mg/L; BOD, 197 mg/L; pH, 6.6 COD was reduced 80%, and there is the potential to improve the treatment
process without any considerable increase in cost. The biomass produced
could be economical.
Madukasi et al.
123
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Table 6. continued
no. technology and its features matrix comments ref
19 membrane bioreactor (GE ZeeWeed membrane
bioreactor technology)
pharmaceutical wastewater (typical ranges): COD, 200040000 mg/L; MLSS,
1000020000 mg/L; total Kjeldahl nitrogen (TKN), up to 1000 mg/L
The following results were achieved: COD and BOD, >90% (>98% for BOD)
removal; with permeate of , typically BOD < 5 mg/L, TSS > 99% removal;
with permeate typically TSS < 5 mg/L, TKN > 90% removal; with permeate
typically ammonia < 1 mg/L, phosphorus > 90% removal, using appropriate
chemical dosing
Noble
124
20 semiconductor photocatalysis Ti/TiO2: RuO2
IrO2as anode, graphite as cathode, and
chloride as electrolyte
phenolic compounds: COD, 8880 mg/L from a bulk manufacturing process This allowed 95% COD removal with first-order kinetics and was energy
efficient with consumption of 17 kWh/(kg of COD).
Rajkumar and Pala-
nivelu
100
21 pervaporation through water-selective mem-
branes
wastewater (having solvents such as ethanol, ethyl acetate, acetic acid, and
methanol along with sodium chloride and other organic impurities): TOC,
145000 mg/L; COD, 70000 mg/L
This allowed 4580% removal of COD, and TOC was observed in two
different compositions of waste. But, pervaporation cannot be applied to
dilute aqueous waste.
Shah et al.
125
22 sequencing batch reactor: an activated sludge
reactor
simulated wastewater with high COD and BOD levels: TDS, 10001500 mg/L;
COD, 15007000 mg/L; BOD, 10003000 mg/L; pH, 7.08.5
The removal efficiencies of COD and BOD are 93.34% and 98.98%,
respectively. The biosludge generated is nontoxic and can be used as a manure
for horticulture.
Shivaprasad et al.
126
23 solar photo-Fenton and biological treatment main effluent in water is 45 mg/L nalidixic acid with 775 mg of dissolved organic
carbon/L: COD, 3420 mg/L; pH, 3.98
COD elimination was 95%, of which 33% was accomplished by the solar photo-
Fenton treatment and 62% by the biological treatment. Wastewater can be
successfully treated by photo-Fenton treatment with peroxide usage and low
toxicity removal efficiency.
Sirtori et al.
98
24 anaerobic multichamber bed reactor (AMCBR)
+ AMCBR with continuous stirred tank
reactor (CSTR)
simulated antibiotic wastewater having oxytetracycline (155.56 and 177.78
(g of OTC/m3)/day with the organic loading rate (OLR) being 2.65 and 2.22
(g of COD/m3)/day, respectively
The combination anaerobic AMCBR and aerobic CSTR treatment system was
effective in removing OTC from synthetic wastewater with high yields
(>95%).
Sponza and Çele-
bi
63
25 ANAMMOX (anaerobic ammonium oxidation)
process with sequential biocatalyst (ANAM-
MOX granules) addition (SBA-ANAMMOX
process)
colistin sulfate and kitasamycin manufacturing wastewater: pH, 6.87.8; NH4N,
123257 mg/L; NO2N, 133264 mg/L; NO2N/NH4N, 1.01.4 mg/L;
COD, 415843 mg/L; BOD, 051mg/L
This method was unsuccessful in removing the toxic organic content but
efficient in removal of COD and BOD and ammonical nitrogen.
Tang et al.
64
26 Fenton oxidation (pretreatment) by oxidation
and coagulation stage followed by aerobic
biological degradation in sequencing batch
reactor
from the manufacturing process and wash waters: traces of organic compounds,
iodine, and metal salts; COD, 9006800 mg/L; BOD, 853600 mg/L
Fenton treatment removed 4550% of COD, and the biological treatment
reduced the COD by 98%.
Tekin et al.
52
27 catalytic wet air oxidation (CWAO) mixtures of
waste streams used in autoclave to form
polyoxometalates (POMs) as a cocatalyst
system
wash waters from the antibiotic industry: traces of fosfomycine (COD, 188108
mg/L; TOC, 46000 mg/L; phosphate, 3000 mg/L; pH, 11); berberine ( COD,
3201 mg/L; TOC, 1470 mg/L; Cu2+, 12790 mg/L; pH, 1); other toxic
intermediates
40% of COD and TOC removal can be easily realized in 1 h of WAO oxidation
at 523 K, 1.4 MPa; CWAO by Cu2+ and [PxWmOy]qcocatalysis was found to
be an effective method for treating the real pharmaceutical wastewater.
Wang et al.
127
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from these the presence of organic matter, COD, BOD, pH,
presence of non-biodegradable matter are other factors which
aect the eciency of AS method. Peng
46
achieved 99%
nitrogen removal eciency at 23 °C. The nitrite reduction
eciency was suitable for high ammonia content wastewater and
in a reduced cost. Tekin
52
obtained 98% COD removal for a
Fenton pretreated manufacturing process wastewater using an
aerobic sequential batch reactor. Ibuprofen, naproxen, bezabrate,
ethynilestradiol and several other estrogens show a high degree of
removal eciency but sulfa drugs like sulfomethaxazole,
carbamezapine and diclofenac showed limited removal.
43,53
Membrane Bioreactors. In the past decade, use of
membrane bioreactors (MBRs) for pharmaceutical wastewater
treatment has gained much attention as it is a technically and
economically feasible alternative for water and wastewater
treatment, especially because of high sludge retention time
(SRT) achieved within compact reactor volumes. In the MBR
the concentration of microorganisms can be increased to up to
20 mg/L.
54
This high concentration of biomass increases the
degradation capacity of larger organic molecules. Another
advantage of membrane treatment is separation of suspended
solids by membranes, so they are not limited by the settling
characteristics of the sludge.
55
Removal eciencies of 98.7% for
TSS and 90.4% for total COD were achieved for a MBR
coupled with conventional activated sludge reactor in a study
carried out
54
for wastewaters comprised of analgesics and anti-
inammatory drugs (ibuprofen, diclofenac, indomethacin, and
acetaminophen), antibiotics (ooxacin, sulfamethoxazole, and
erythromycin), and β-blockers (atenolol and metoprolol).
54
Noble
56
used a hollow ber submerged MBR, for fermentation
process wastewater having a very high COD of around
40000 mg/L. More than 90% COD and 98% BOD removal was
achieved. Apart from that 90% phosphorus removal was also
obtained by proper treatment measures. Comparative studies of
MBR AS
54
and CAS
57
showed that the elimination of this drug
is enhanced in the MBR treatment, probably due to better
adaptation of microorganisms. The poor removal of eryth-
romycin has been reported for CAS,
54,58
whereas laboratory-
scale MBR was capable of 67% elimination.
54
However,
complete removal of all pharmaceuticals by MBR or any single
operation is very rare.
50
MBR removed more than 10 estrogens
such as 17-α-estradiol, 17-β-estradiol (E2), 17-α-dihydroequi-
lin, trimegestone, estriol (E3), medrogestone, norgestrel, and
estradiol valerate and several others, to near and below
analytical detection levels in a study that was carried out,
50
but the system was resistant to a specic serotonin re-uptake
inhibitor venlafaxine. Thus, it becomes inevitable to use a
combination of various pre- and posttreatment methods for
complete removal of diverse pharmaceutical euents.
Tambosi
59
investigated that compounds acetaminophen and
ketoprofen had the highest removal eciencies, while
roxithromycin and sulfamethoxazole exhibited persistence to
microbial attack and were removed to a lesser extent in two
MBRs studied. However, in general terms, membrane retention
using micro- or ultraltration membranes can be neglected,
whereas biodegradation plays an important role, since higher
removal eciency was obtained for higher SRTs. Nevertheless,
the elimination by MBR treatment using ultraltration was only
partially successful, and therefore, persistent pharmaceuticals in
small concentrations and their transformation products were
discharged with the wastewater into the environment. This
discharge could be reduced with the application of additional
treatment steps using advanced treatment techniques, e.g.,
activated carbon adsorption, ozone oxidation, advanced
oxidation processes (AOP), NF, or reverse osmosis (RO).
The molecularly imprinting technology (MIP) possesses
several advantages over the conventional immunosorbent (IS)
and shows high selectivity and anity, high stability, and the
ease of preparation. The MIPs can be used repeatedly without
loss of activity with high mechanical strength and are durable
against harsh chemical media, heat, and pressure compared to
biological receptors. MIP targeting tetracycline (TC) and oxy-
tetracycline (OTC) was developed by Caro et al.
60
to selectively
remove the antibiotics and several tetracycline analogues from pig-
kidney tissue. Use of molecularly imprinted polymers from a
mixture of tetracycline and its degradation products to produce
anity membranes for the removal of tetracycline from water has
been reported by Suedee et al. (Scheme 1).
61
Many of the
Scheme 1. Use of Molecularly Imprinted Polymers from a Mixture of Tetracycline and Its Degradation Products To Produce
Anity Membranes for the Removal of Tetracycline from Water
64
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successful applications in various elds, especially in solid-phase
extraction (SPE) for sample cleanup, have proved the potential of
MIP. There are MIP-based SPE cartridges that have been
commercialized by companies, for examples, clenbuterol-selective,
triazine-selective and chloramphenicol-selective MISPE.
62
In the case of membrane processes, a general approach to
produce clean water from dirty or polluted water in the
pharmaceutical industry will be based on the size of the
pollutants in the following order: bacteria particles (micro-
ltration), macromolecules and viruses (ultraltration), divalent
ions (nanoltration), and monovalent ions (reverse osmosis).
4.2.1.2. Anaerobic Treatment. Anaerobic treatment has
been done by using continuous stirred tank reactors (anaerobic
digestion), uidized bed reactors, and up-ow anaerobic sludge
reactors, etc.
6368
Anaerobic hybrid reactors, which are a
combination of suspended growth and attached growth
systems, have recently gained much attention. The signicance
of anaerobic treatment over aerobic processes is the ability to
deal with high concentration wastewater, with lesser energy
inputs, low sludge yield, low operation cost, and economical
byproduct recovery of biomethane as a valuable energy
source.
43
Up-ow anaerobic batch reactor (USAR) has been
shown to be very ecient in removal of high concentrations of
PhPs from pharmaceutical wastewater.
65,69
A USAR operating
at higher temperatures of about 55 °C showed a high COD
(6575%) and BOD (8094%) removal even at a very high
concentration of organic content of 9 kg of COD/(m3·day).
70
It is shown that 75% COD removal and more than 95% tylosin
removal from an antibiotic euent wastewater is possible
thereby making USAR a suitable application for such
wastewaters. In a study by Kang et al.,
71
catalytic wet air
oxidation was employed with anaerobic biological oxidation to
high COD (70000120000 mg/L) containing vitamin process
wastewater. With the combination, more than 94.66% COD
removal was obtained with total biodegradability of the organic
content. More than 6065% removal was achieved for chemical
synthesis wastewater having a COD of about 4000060000
mg/L by using a hybrid up-ow anaerobic sludge blank reactor.
Specic methanogenic analysis showed no inhibitory action,
and the biomass obtained was highly economical.
66
Recently, Sponza and Çelebi
63
used an anaerobic multi-
chamber bed reactor (AMCBR) coupled with a continuous
stirred tank reactor (CSTR) to an oxytetracycline spiked
antibiotic wastewater. The combination of anaerobic AMCBR
and aerobic CSTR treatment system was eective in removing
OTC from synthetic wastewater with high yields (>95%) at
OTC loadings < 177.78 g of OTC/(m3/day), respectively.
However, Tang et al.
64
were unsuccessful in removal of colistin
sulfate and kitasamycin containing anitibiotic wastewater.
4.2.2. Advanced Treatment Process. Advanced treatment of
pharmaceutical wastewater can be considered as the primary
treatment or pretreatment processes to accelerate the removal
eciency of pollutants by the secondary treatment. These
include membrane technology, membrane distillation, and
activated carbon adsorption.
4.2.2.1. Membrane Technology. Implementation of mem-
branes in water treatment is greatly increasing. It is well-known
that low-pressure membranes are capable of removing micro-
bial constituents without increasing disinfection byproducts,
thereby allowing compliance with the rules promulgated in
response to the 1986 Surface Water Treatment Rule Amend-
ments.
72
Whether the purpose is desalination or water reuse,
low-pressure membrane systems play an important role as
reverse osmosis pretreatment processes. In one of the studies
95% rejection of diclofenac was obtained by RO membranes.
57
Microltration/ultraltration (MF/UF) systems are strongly
recommended when there are space limitations and/or variable
feedwater quality.
73
Nanoltration and ultraltration processes
have been used in wastewater reclamation and drinking water
to remove micropollutants and natural organic matter (NOM).
The NF membrane retained EDC/PPCPs greater than the UF
membrane, implying that retention is aected by membrane
pore size. In addition, the retention of EDC/PCPs appears to
be aected by source water chemistry conditions.
74
Therefore,
it can be concluded that both RO and NF show better removal
of eciency of certain organic pharmaceuticals but the problem
of retentate/concentrate disposal remains the same. Thereby
further treatment of the concentrate generated is required.
4.2.2.2. Activated Carbon. Adsorption using activated
carbon (AC) is well-suited to remove OCs due to its high
surface area (over 1000 m2/g) and the combination of a well-
developed pore structure and surface chemistry properties.
Recently Mestre et al.
75
have demonstrated the removal of
ibuprofen by using waste derived activated carbon. The AC
process thus has an advantage of easy raw material input for the
production of carbon. The AC process makes use of powdered
activated carbon (PAC) or granular activated carbon (GAC).
PAC has an advantage over GAC as it is usually fresh as
compared to GAC which is usually recycled in xed bed
columns.
76,77
Although PAC gives higher eciency, it is not
cost eective and regeneration/disposal of saturated GAC
columns are also an issue.
72
Cyr et al.
78
found that a series of
GAC columns removed 99% of the total mercury (organic +
inorganic) and around 90% copper removal from a chemical
synthesis based pharmaceutical wastewater. The column was
also eective in turbidity as well as 96% phenol removal.
Another study on the adsorption of 62 EDCs and PPCPs by
PAC in dierent source waters showed that PAC was capable of
partially removing all target compounds, depending on the
physicochemical properties of each compound.
79
The major
diculty faced by using PAC is the separation of the adsorbent
from the treated water, and thus, it has to be integrated with a
ltration unit. Recently many studies have been carried out on
using AC along with other treatment technologies where
activated carbon can be used as a pretreatment.
80
4.2.2.3. Membrane Distillation. Membrane distillation is a
very important separation technology with interesting proper-
ties. Presently membrane distillation is used for the production
of demineralized water.
81,82
The membrane distillation process
operates at atmospheric conditions, and the heat requirement is
also very low.
83
The technology has been used to recover
process waters by using the heat generated during the industrial
processes and thus making the technology very promising for
application.
84
Membrane distillation provides very clean water,
but membrane fouling is a major disadvantage of this technique.
Membrane distillation has been very successfully applied for
recovery of the acids from fermentation broths.
85
4.3. Advanced Treatment Processes (Advanced
Oxidation Processes). Owing to the low biodegradability of
many pharmaceuticals, the commonly employed treatment
processes are not eective enough for complete removal of
such species and the discharge of treated euents into receiving
waters can lead to contamination with these micropollutants.
86
These compounds thus released into the environment have
proven to be high enough to cause toxic eects to
environmental organisms.
87,88
Advanced oxidation processes
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can be broadly dened as aqueous-phase oxidation methods
based on the intermediacy of highly reactive species such as
(primarily but not exclusively) hydroxyl radicals in the
mechanisms leading to the destruction of the target pollutant.
17
The main AOPs are heterogeneous and homogeneous
photocatalysis and ultraviolet (UV) or solar irradiation:
electrooxidation, Fenton and photo-Fenton process, wet air
oxidation, and, recent ones in this category, ultrasound
irradiation and microwave treatment, which typically operate
around 2450 MHz in either a monomode or multimode type of
vessel. Depending upon the nature of the pharmaceutical
euent and the treatment objective of destruction or
transformation, AOPs can be employed either alone or coupled
with other physiochemical and biological processes.
4.3.1. Ozone/Hydrogen Peroxide Treatment. Ozone is a
very strong oxidizing agent that either decomposes in water to
form hydroxyl radicals which are stronger oxidizing agents than
ozone itself, thus inducing the so-called indirect oxidation, or
attacks selectively certain functional groups of organic
molecules through an electrophilic mechanism.
17,89
Pharma-
ceutical wastewater contains various kinds of recalcitrant
organics such as toluene, phenols, nitrophenols, nitroaniline,
trichloromethylpropanol (TCMP), and other pollutants that
exhibit resistance against biodegradation. Since these pollutants
cannot be easily removed by biological treatment, biologically
treated euent exhibits a considerable BOD and COD, in the
euent. It has also been reported that activated carbon
adsorption may not always be successful in removing such
recalcitrant organics.
72
Economic constraints may also prohibit
the treatment of pharmaceutical wastewater by activated carbon
adsorption. In such cases, ozone/hydrogen peroxide treatment
may appear to be a proven technology for treating such
pollutants from pharmaceutical wastewater. The removal of
high concentrations of penicillin and the enhancement of
biodegradability of the fermentation process wastewater have
been studied.
90
However, as stated earlier, the best approach
should be removing penicillin by ultraltration and subjecting
the ltrate to oxidation. Ozonation has been largely employed
in removal of antibiotics.
50,89,91
But ozonation cannot be
employed in all circumstances as compounds with amide
linkages are resistant to ozone.
92
Thus, in such cases a combination of ozone with hydrogen
peroxide has been successfully utilized for the degradation of
penicillin formulation wastewater.
91,93,94
It was shown that the
conjugate base of H2O2at millimolar concentrations could
initiate the decomposition of ozone much more rapidly into
hydroxyl radicals than with the hydroxide ion and that the
COD removal eciency was greatly enhanced by 76%.
91
Combination of hydrogen peroxide with photocatalysis has also
been successfully studied.
95
4.3.2. Fentons Oxidation Treatment. Fentons reagent
involves the reaction of hydrogen peroxide with ferrous or ferric
ions via a free radical chain reaction which produces hydroxyl
radicals. It is a heterogeneous catalytic reaction in which iron
acts as a catalyst.
52,93
Since iron is an abundant element, this
process is the most viable for wastewater treatment. Recent
research has shown the use of Fenton oxidation capable of
reducing a load of refractory euents to being less toxic and
more readily amenable to biological posttreatment.
52,96
More
than 95% COD removal was observed in a pharmaceutical
euent containing chloramphenicol, paracetamol, and COD of
12000 mg/L.
97
Penicillin was completely eliminated after 40
min of advanced oxidation with Fenton/UV treatment.
90
However, Fenton processes suer a major drawback of pH
dependency and a lot of iron sludge which is generated. The
Fenton process can be best applied as a pretreatment
technology to convert the non-biodegradable pharmaceutical
euent into biodegradable and thus make treament of the
euent by biological process more ecient.
93,98
Enzymatic Water Purication: Fenton Chemistry in Situ. A
very interesting case of enzymatic catalysis and Fenton
chemistry in situ has been advocated and has a potential for
treatment of a variety of wastewaters coming from dierent
industries as has been demonstrated through the integration of
nanostructured materials, enzymatic catalysis, and iron-
catalyzed free radical reactions within pore-functionalized
synthetic membrane platforms without use of toxic oxidants,
by Lewis et al.
99
They employed two independently controlled,
nanostructured membranes in a stacked conguration for in
situ synthesis of the oxidizing species. The upper bioactive
membrane contains an electrostatically immobilized enzyme to
generate hydrogen peroxide (H2O2) from glucose. The bottom
membrane contains either immobilized iron ions or ferrihy-
drite/iron oxide nanoparticles for the decomposition of
hydrogen peroxide to form powerful free radical oxidants. By
permeating (at low pressure) a solution containing organic
contaminant with glucose in oxygen-saturated water through
the membrane stack, signicant contaminant degradation was
realized.
4.3.3. Photocatalysis. Photocatalysis is the acceleration of a
photochemical transformation by the action of catalyst such as
TiO2or Fentons reagent.
43
The catalyst which is most
commonly employed for all pharmaceutical photocatalytic
studies is rutile TiO2. Photocatalysis is the best suited process
for euents having a high COD and for complete trans-
formation of highly refractory organic contaminants to reach
biological treatment level. In the context of pharmaceutical
treatment, it has also been reported that for the degradation of
sulfamethazine and chloramphenicol respectively ZnO2showed
higher catalytic activity than TiO2. Photocatalytic reactions
usually obey the LangmuirHinshelwood kinetic model which
is reduced to pseudo-rst- or zero-order kinetics depending on
the operating conditions.
17
The use of UV/TiO2along with H2O2has shown enhanced
removal eciency of phenols and COD from fermentation
euent.
95
Also, a combination of photocatalysis with ozonation
has also shown improvement of COD removal in penicillin
formulation euent.
93
A novel semiconductor photocatalysis
by using a combination of TiO2with RuO2IrO2as anode and
chloride as an electrolyte has also shown 95% COD removal
with rst-order kinetics.
100
From an economic point of view, photocatalysis can be
carried out by the usage of solar irradiation and much research
has been done in this regard for the treatment of
pharmaceutical euents.
101103
Photocatalytic process is also
found to be highly energy ecient with consumption of 17
kWh/(kg of COD removed).
100
4.3.4. Electrochemical Oxidation/Degradation. Electro-
chemical method is based on in situ production of hydroxyl
radical (OH) as the main oxidant, which is the second
strongest oxidizing agent known after uorine, having such a
high standard reduction potential (E°(OH/H2O) = 2.8 V vs
SHE) that it is able to nonselectively react with most organic
contaminants via hydroxylation or dehydrogenation until their
total mineralization.
104
The treatment of ethinylestradiol in
urine by electrodialysis has led to a 99% removal of toxicity.
105
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Simulated waste having pharmaceutical residues such as
diclofenac, carbamezapine, propranolol, ibuprofen, and ethiny-
lestradiol, treated with electrochemical method, has shown
complete degradation. Dominguez et al.
106
showed a
satisfactory removal of total organic carbon (TOC) by the
usage of boron doped diamond (BDD) anode which showed
higher corrosion stability. With the adequate combination of
current density and ow rate almost 100% TOC removal was
observed.
More than 97% TOC removal has been observed in
paracetamol and diclofenac spiked wastewater by BDD
electrochemical treatment.
107,108
The degradation rate of the
antibiotic was also enhanced with an increasing concentration
of doping boron and decreasing electrode thickness. Electro-
coagulation coupled with photocatalysis has shown 86% COD
removal eciency in chemical synthesis based wastewater. The
use of photocatalysis enhances the degradation capability.
109
The eciency of electrooxidation may be enhanced by the
synergetic action of dissolved iron, i.e., the electro-Fenton
process which catalyzes the degradation of H2O2to hydroxyl
radicals. It has been very well reported that EF with use of
doped BDD electrode reduces the toxicity of the byproduct
water which is formed in electrooxidation alone.
109,110
4.3.5. Ultrasound Irradiation. Ultrasound irradiation is a
relatively very recent technique which has been applied for
wastewater treatment. Not much literature is available on
sonochemical degradation of pharmaceutical compounds.
Sonochemical reactions are induced upon high-intensity
acoustic irradiation of liquids at frequencies that produce
cavitation (25 kHz). Thus, cavitation serves as a means of
concentrating the diused energy of ultrasound into micro-
reactors with the simultaneous release of radicals. Many estrogenic
compounds have been removed by ultrasonic irradiation from
contaminated waters, with a reduction of 8090% COD within
4060 min of treatment.
111
The technique can be best used for
treatment of two-phase wastewater having organics of low
solubility. Recently a combination of biological treatment and
hydrodynamic cavitation was used for the removal of
pharmaceutical compounds from wastewaters. Coupling the
attached-growth biomass biological treatment, hydrodynamic
cavitation/hydrogen peroxide process, and UV treatment resulted
in removal eciencies of >90% for clobric acid and >98% for
carbamazepine and diclofenac, while the remaining compounds
were reduced to levels below the level of detection (LOD). For
ibuprofen, naproxen, ketoprofen, and diclofenac the highest
contribution to overall removal was attributed to biological
treatment; for clobric acid UV treatment was the most ecient,
while for carbamazepine hydrodynamic cavitation/hydrogen
peroxide process and UV treatment were equally ecient.
112
4.3.6. Wet Air Oxidation. Wet air oxidation is a
thermochemical process where hydroxyl radicals and other
active oxygen species are formed at elevated temperatures
(200320 °C) and pressures (220 MPa).
113
Recent research
has shown the applicability of this process to remove COD to a
great extent. Catalytic wet air oxidation of a chemical synthesis
wastewater having a COD of 712 g/L showed removal of
total organic matter and the process enhanced with enhanced
loading of heterogeneous copper catalyst and high temper-
atures.
114
A study conducted by the usage of heterogeneous
nanocatalyst Fe2O3/SBA15 exhibited high TOC removal and
COD degradation capability.
115
This technique can also be
applied as a pretreatment process thereby making the
wastewater suitable for biological treatment.
4.4. Hybrid Technologies. Hybrid technologies are the
combinations of one or more conventional/advanced treatment
technologies for the complete eradication of pharmaceutical
contaminants. The need for hybrid technologies arises from the
fact that none of the single-treatment technologies can remove
all compounds.
76
There are a number of hybrid technologies
which have been used for the treatment of refractory pollutants
as well as to reduce the cost of the treatment process. The
technology basically uses the conventional ltration step to
remove any solid matrix and the sludge is removed for
incineration. The clear wastewater is then treated by the
dierent combination of processes.
4.4.1. Hybrid Technologies for Chemical Synthesis Process
Wastewater. Chemical synthesis process wastewater usually
contains high concentrations of organic contaminants ranging
from the reagents to the intermediates and the nal products.
Many researchers have used the combination of advanced
treatment method along with biological treatment methods to
deal with such a matrix. Chen et al.
116
have used a two-phase
anaerobic digestion (TPAD) system and a subsequential MBR,
TPAD system comprised of an up-ow anaerobic sludge
blanket-anaerobic lter (UASBAF) and continuous stirred tank
reactor (CSTR), working as the acidogenic and methanogenic
phases. The combined pilot plant removed 99% COD; and the
MBR reduced the pH in the neutral range. The combination of
TPAD-MBR can be successfully applied to chemical synthesis
based wastewater.
Boroski at al.
115
employed electrocoagulation (EC) followed
by heterogeneous photocatalysis (TiO2) and obtained removal
eciency of 86% COD and 90% turbidity; initial removal with
EC is 70% which is enhanced to 76% by the use of UV/H2O2.
Combination works best for wastewater with high concen-
trations of refractory/nonbiodegradable chemicals. Sreekanth et
al.
70
investigated a hybrid up-ow anaerobic sludge blanket
reactor for wastewater having the following: TDS, 85009000
mg/L; TSS, 28003000 mg/L; COD, 1300015000 mg/L;
BOD, 70007500 mg/L with a BOD:COD ratio of 0.450.6.
Such wastewater is highly pliable to biological oxidation.
Removal eciencies were as follows: COD, 6575%; BOD,
8090%. The process has a high biomass production rate thus
making the process economically feasible.
4.4.2. Hybrid Technologies for Fermentation Process
Wastewater. Fermentation process wastewaters mainly consist
of fermentation broth, mycelia, and the nutrients which are
added for the cell cultivation. Also, there are some organic
solvents which are added for recovery of the API of interest.
Helmig et al.
50
treated API formulation waste comprised of
estrogens with a hybrid treatment technology comprised of
pretreatment ozonation and the aerobic treatment, i.e.,
membrane bioreactor technology. More than 90% COD and
TSS removal was obtained. And the MBR led to complete
treatment of the wastewater.
Cokgor et al.
94
studied the penicillin formulation waste
comprised of wash water. They used ozonation (pretreatment)
coupled with biological activated sludge treatment by synthetic
biomass with 30% COD. Ozonation removed 34% COD and
24% TOC, and then the water showed ecient COD removal
with enhanced biodegradability using activated sludge.
Penicillin formulation euents sometimes have pollutants
such as tylosin which have refractory action on biological
processes and thus use of a hybrid process leads to complete
removal. Tylosin and avilamycin containing wastewater were
treated by a hybrid up-ow anaerobic stage reactor by
Industrial & Engineering Chemistry Research Review
dx.doi.org/10.1021/ie501210j |Ind. Eng. Chem. Res. 2014, 53, 115711159211587
Chelliapan and Sallis.
65
For avilamycin macrolide and tylosin
antibiotic waste stream, UASR can be used commendably as an
option for pretreatment with a COD reduction of 7075%;
thus in anaerobic conditions tylosin can be degraded eectively.
Tekin et al.
52
studied the manufacturing process and wash
waters containing traces of organic compounds, iodine, and
metal salts with 9006800 mg/L COD and 853600 mg/L
BOD. They coupled an AOP with biological treatment to tackle
this type of wastewater. The Fenton oxidation (pretreatment)
coagulation stage followed by aerobic biological degradation in
sequencing batch reactor gave 4550% COD removal and the
biological treatment reduced the COD to 98%.
5. RECOMMENDATIONS AND FUTURE
TECHNOLOGIES
The accelerating progress of novel pharmaceutical products is
being added exponentially to the already existing vast number
of chemical compounds that are introduced to the environ-
ment. As mentioned previously, the pharmaceutical waste
stream is of a diverse nature and thus treatment of the
wastewater is to be achieved for benign disposal of it into the
environment. Reduction of the waste stream at the source along
with recycling of the water or reclamation of some part of this
waste is among the desirable options. Nanoltration is a very
important operation to recover more than 80% of the complex
waste stream or single products, and it can impart quality better
than the quality of feedwater with high operational eciency
and product safety. It can be used to recover valuable single
products from mother liquors which could be reused or further
processed. This is a process intensication strategy which
permits increased production capacity without exceeding water
discharge limits, drastically reducing raw water requirements
and waste disposal costs. The waste stream can be further used
by other waste-treatment technologies. Membrane processes
will be eective to produce clean water in the pharmaceutical
industry based on the molecular size of the contaminant such as
bacteria particles (microltration), macromolecules and viruses
(ultraltration), divalent ions (nanoltration), and monovalent
ions (reverse osmosis). In some cases, in situ Fenton chemistry
as given by the group of Bhattacharyya
99,120
will be of immense
potential and needs further work.
On-site reduction can be achieved by deeply understanding
the process and analysis of the stages in the process and
identifying the pollutants to be released. By deep understanding
of this a recovery technology such as membranes can be applied
at the source of pollutant generation, the recovered material can
be utilized, and the concentrate can be treated with other
treatment technologies for safe disposal. In this way a
considerable value addition can be provided to the waste
generated, thus making the process economical.
Recovering and recycling in pharmaceutical wastewater
implies removal of impurities from the waste stream and
obtaining relatively pure substances for reuse or secondary
purposes. The strict quality control requirements of the
pharmaceutical industry often restrict reuse opportunities.
Recycling can either be done on-site or o-site. An alternative
to recycling of recovered products is waste exchange, which
involves the transfer of a waste to another company for use as is
or for reuse after treatment.
6. CONCLUSION
Pharmaceutical manufacturers must operate under strict
regulations by food and drug agencies in dierent countries
and ought to maintain acceptable water quality standards for
use, discharge, or reuse elsewhere in the plant. Huge quantities
of ultrapure water are required with regulatory requirements on
the limit or even presence of specic waste contaminants.
There can also be volume limits on water discharged into
municipalities or other waste streams.
Pharmaceuticals reach the environment primarily through
usage and inappropriate disposal from the manufacturing units.
Various production facilities are found to be the source of
pharmaceuticals in the environment out of which chemical
synthesis process and fermentation process wastewaters
constitute the bulk of it. These plants generate a large amount
of waste during manufacturing, purication, cleaning, washing,
and maintenance.
Several reports have been produced on the treatment of
pharmaceutical compounds and endocrine disrupting chemicals
in recent decades. Most of the treatment technologies deal with
the treatment of wastewaters from chemical and fermentation
processes. Use of hybrid technologies has been made for the
treatment of certain compounds which are not completely
eradicated by the single-stage treatment. The use of hybrid
technologies mainly removes the pollutant almost completely
or within safe discharge limits. The most common treatment
technology applied to both the wastewater streams is a
pretreatment stage comprising of the advanced oxidation
processes which is mainly to remove recalcitrant/refractory
compounds which are sometimes nonbiodegradable. Then the
waste having enhanced biodegradability thus can be treated
eectively by the biological treatment methods. Out of the two
biological treatment methods of aerobic and anaerobic, a
membrane bioreactor provides a promising solution. Also,
anaerobic reactors are employed on a wide scale as the
byproduct, i.e., biogas from the process, can be economically
used, along with the treated sludge, by the agriculture industry.
As it can be seen, most of the technologies mentioned are
removaltechnologies; emphasis has been laid on recovery
technology. Many researchers have been trying to implement
recovery options to recover important and valuable reagents,
byproducts, and solvents which can be reused thereon.
Extensive analysis on the characteristics of the system to
understand its benets or limitations from an individual and
global perspective, and thus leading to overall economic
consideration, should be taken into account rather than just
publications on the problem. More emphasis should be made
on recovery and reuse of the pharmaceutical wastewaters.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +91-22-3361-1001. Fax: +91-22-3361-1020. E-mail: gd.
yadav@ictmumbai.edu.in.
Notes
The authors declare no competing nancial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge nancial support under the Indo-
EU NEW INDIGO program Indigo-DST1-017 by DST, GoI
(G.D.Y., I.O., and Riitta Keiski (University of Oulu, Finland)).
We could interact and exchange ideas, arrange visits to
concerned laboratories, share laboratory facilities, and enable
Industrial & Engineering Chemistry Research Review
dx.doi.org/10.1021/ie501210j |Ind. Eng. Chem. Res. 2014, 53, 115711159211588
participation by a host of individuals. G.D.Y. acknowledges
support from the R. T. Mody Distinguished Professor
Endowment and J. C. Bose National Fellowship of DST.
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