Journal of Xenobiotics 2016; volume 6:5774

Pharmaceutical compounds about 1 lakh ton/year. This data reveals the worldwide average consumption of 15 gm/capi- Correspondence: Bhavtosh Sharma, Uttarakhand in drinking water ta/annum.1,2 The large diversity of the human Science Education and Research Centre pharmaceuticals may be noticed by 12,000 (USERC), Dehradun, Uttarakhand, India. Vikas Chander,1 Bhavtosh Sharma,2 approved (authorized) human pharmaceuti- E-mail: [email protected] Vipul Negi,3 Ravinder Singh Aswal,4 cals. From environmental consideration, there Prashant Singh,1 Rakesh Singh,3 Key words: Pharmaceutical effluent; pharmaceu- are 850 active compounds in human pharma- tical global market; fate and water . Rajendra Dobhal5 ceuticals.3 India has now emerged as one of the top five pharmaceutical markets of the 1Department of Chemistry, DAV (PG) Received for publication: 22 January 2016. world. As pharmaceutical industry is the lead- Revision received: 21 April 2016. College, Dehradun, Uttarakhand; ing science based industry in India, thus it Accepted for publication: 25 April 2016. 2 Uttarakhand Science Education and contributes 1% of the country’s total gross Research Centre (USERC), Dehradun, domestic product.4 Due to regularly increasing This work is licensed under a Creative Commons Uttarakhand; 3Department of Chemistry, international demand, pharmaceutical indus- Attribution NonCommercial 4.0 License (CC BY- NC 4.0). DBS (PG) College, Dehradun, tries are rapidly growing. This development of 4 Uttarakhand; Department of the pharmaceutical industries supplies over 65 ©Copyright V. Chander et al., 2016 Environmental Sciences, Gurukula Kangri countries and earns more than 50% revenue Licensee PAGEPress, Italy Vishwavidyalaya, Haridwar, Uttarakhand; through exports.5 United States of America is Journal of Xenobiotics 2016; 6:5774 5Uttarakhand Council for Science and the largest customer of Indian made drugs, doi:10.4081/xeno.2016.5774 Technology (UCOST), Dehradun, which procured drugs worth Rs. 1.4 billion US 6 Uttarakhand, India dollar during the year 2007. The pharmaceuti- cal industries consist of approximately 300 large scale and 8000 small scale organizations, ceutical units are running in India and China, 15 producing thousands of formulations contain- respectively. However, the production of phar- ing 350 different bulks of drug.4 Many pharma- maceuticals at global level as per continent Abstract ceutical manufacturing units are rapidly wiseonly is shown in Figure 1. India has progres- increasing in India,7 which dispose-off their sively producing and consuming the pharma- ceutical drugs.16 According to a recent Indian Pharmaceutical products and their wastes effluents into the stream either directly or report, the Indian pharmaceutical market is play a major role in the degradation of environ- after partial treatment. Therefore, proper man- expected to be US $ 55 billion by the year 2020 ment. These drugs have positive as well as agement along with complete and use effective 17 negative consequences on different environ- treatment of pharmaceutical industrial wastes among all third world countries. The mental components including biota in differ- as well as of expired drugs is required to be European Federation of Pharmaceutical 18 ent ways. Many types of pharmaceutical sub- undertaken with latest tools and techniques. Industries and Associations (EFPIA) shows stances have been detected with significant The pharmaceutical drugs get excreted with that Switzerland is the largest producer of concentrations through various advanced urine and feaces as parental compound and as pharmaceutical drugs in European continent. instrumental techniques in surface water, sub- a number of its metabolites. The waste water It produces pharmaceutical drugs worth 32,380 surface water, ground water, domestic waste of toilet is subsequently flushed with clean million €. Whereas, Latvia has the lowest pro- water, municipal waste water and industrial water, which is known as black water. This duction of these drugs worth only 108 million effluents. The central as well as state govern- black water enters to the municipal sewer and €. The Cyprus has market value and export of ments in India are providing supports by creat- ultimately enters the adjoining water bodies only 203 million € and 223 million €, respec- ing excise duty free zones to promote the phar- and may affect the water quality and aquatic tively. While, Germany has highest market maceutical manufacturers for their produc- commerciallife.8 The due to pharmaceuti- value and export of 26,122 million € and tion. As a result, pharmaceutical companies cal wastes in Andhra Pradesh (India) has been 50,818 million €, respectively. Similarly, the are producing different types of pharmaceuti- reported to be about 150 times more than the Belgium has imported pharmaceutical drugs of cal products at large scale and also producing highest level of pharmaceutical pollution in 26,757 million €. While, Cyprus has imported complex non-biodegradable toxic wastes by- USA.5,9-14 However, very few studies on pharma- drugs of 237 million €. The statistical graph as products and releasing untreatedNon or partially ceutical based water pollution have been car- depicted in Figure 2 represents country wise treated wastes in the environment in absence ried out in India. The present paper highlights position in terms of production, market value, 18 of strong regulations. These waste pollutants and reviews the impact of pharmaceutical pol- import and export respectively. In 1947, the are contaminating all types of drinking water lutants on quality of water sources. turnover of registered Indian pharmaceutical sources. The present paper focuses on water industries was Rs. 10 Crore. Now, it has quality pollution by pharmaceutical pollutants, increased up to US $ 5.5 billion in 2004 with 19 their occurrences, nature, metabolites and 17% annual growth rate. their fate in the environment. Global pharmaceuticals market status Route of entry of pharmaceuti- Globally, the developed countries are main Introduction producers of pharmaceutical drugs. The five cal compounds into water system major countries in the world namely USA, The utilization of pharmaceutical drugs Japan, Germany, United Kingdom and France Pharmaceutical substances are widely used keeps rising due to improvement in health are collectively two-third global pharmaceuti- for human and veterinary related health prob- care system and expectations of people for cals manufacturers, while China and India are lems. More than hundreds of tonnes of phar- longer life. The global utilization of different main global low cost producers of pharmaceu- maceutical compounds are used in Austria, pharmaceutical drugs by human beings is ticals. Approximately 20,000 and 7500 pharma- England and Germany collectively.20 According

[Journal of Xenobiotics 2016; 6:5774] [page 1] Review to an investigation, the consumption of phar- efficiently removed from aqueous phase of maceuticals i.e., 836 ton of acetylsacylic acid Fate and occurrence of phar- waste water in a water treatment plant [non-steroidal anti-inflammatory drugs maceuticals in environment through several processes namely bio-degrada- (NSAIDs)], 622 ton of paracetamol (NSAIDs), tion, sorption, stripping to air and abiotic 517 ton of metformin (antidiabetic), 345 ton of transformation (photolytic degradation). ibuprofen (NSAIDs), 88 ton of carbamazepine The distribution of pharmaceutical products Complete biodegradation, which results into

(antiepileptic) was found in Germany, where in the environment is mainly by aquatic medi- carbon dioxide (CO2) and water (H2O) is called as 35 ton of naproxen (NSAIDs) was observed um followed by food-chain dispersal due to mineralization. Incomplete or partial biodegra- in England in year 2001.21 But due to incom- their low volatility.20 Although pharmaceuticals dation includes the conjugation of the pharma- plete metabolism these drugs excrete through persist low in environment, they are ubiqui- ceutical and the degradation of a compound to defecation and urinary systems as unchanged tous in environment due to their higher rate of a metabolite (also occurs in the human body). form and still remain in sufficient concentra- release as compared to the rate of transforma- Conjugations of pharmaceuticals occur usually tion level. The discharge of treated, partially tion.30 Composition of sewage, weather condi- before excretion from human body. Due to treated and untreated effluents of pharmaceu- tions, design and operation of treatment plants this, compound becomes more polar and might tical industries in open areas as well as into determine the transformation of various active excrete more easily from body.8 Ibuprofen, the streams22 and unacceptable dispose of pharmaceutical products.31 The pharmaceuti- reached in the aquatic environment through unused (i.e., expired drugs) ultimately con- cal products contaminated sludge, when used metabolic process, has been studied by many taminate various compartments of environ- as an agricultural fertilizer can reach to the researchers. The metabolism of ibuprofen ment.23,24 These pharmaceutical residues may terrestrial environment and through chain it leads to the formation of hydroxyl-ibuprofen enter: i) in water supplies and soil through the may enter into surface as well as ground (OH-Ibuprofen), carboxy ibuprofen (CA- 32 excretion of animals and human beings: ii) in water. Pharmaceutical compounds can be Ibuprofen) and carboxy-hydratropic acid (CA- surface water through plants and agricultural runoff; and iii) in ground water through soil.25 In the world, United States of America and Europe have the most advanced and comprehensive waste only treatment directives.26 In India, pharmaceuti- cal industries discharge their treated and untreated effluents in open area and into streams.22 Due to change in the pharmaceuti- use cal production and effluents input characteris- tics, the treatment techniques are either inap- propriate or inefficient.27 Pharmaceutical com- pounds have been found to enter the environ- ment by different sources such as discharge of treated or untreated or partial treated industri- al wastewater and improper disposal of expired or unused drugs etc.23,24 Figure 1. Status of global pharmaceuticals production continent wise.

Regulations for monitoring commercial the presence of drugs in environment

The regulating authorities of pharmaceuti-Non cal industries must require regular monitoring and enforcement of laws for proper disposal of pharmaceutical wastes for preventing environ- mental degradation. Central Pollution Control Board (CPCB) and State Pollution Control Boards (SPCBs) established by Water Act, 1974 and Water Cess Act, 1977 provided the option to tax water users violating regulations.28 The CPCB has issued Minimum National Acceptable Standards (MINAS), according to which, SPCBs are required to enforce the laws for pharmaceutical industries. If the industry fails to comply with the Water Act, the SPCBs have authority to cut power supply, water sup- ply, close the firm or even pursue public inter- est litigation before the Supreme Court.29 Figure 2. Statistical representation of pharmaceutical’s market situation.

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AH) as 3 degraded products of ibuprofen.33 identified different types of pharmaceutical cetrizine, terbinafine and citalopram in more These metabolites are also formed during compounds in various types of water samples than 1 mg/L concentration whereas higher con- metabolism of ibuprofen in human body. The with specific extraction methods using high- centration of ciprofloxacin (6.5 mg/L), nor- degradation process of ibuprofen34,35 is given in performance liquid chromatography (HPLC), floxacin (0.52 mg/L), enoxacin (0.16 mg/L) and Figure 3. high-performance liquid chromatography cou- cetirizine (1.2 mg/L) drugs were investigated The adsorption and complexation of phar- pled with mass spectrometry (HPLC-MS), in two of the area using C 18 column in maceutical drugs in water or soil are still large- high-performance liquid chromatography cou- HPLC instrument. ly unidentified. Among studied anti-inflamma- pled with tandem mass spectrometry (HPLC- tories and anti-blockers, most of them were MS/MS) etc. from mg/L to ng/L concentration removed less than 5%, while some ranges.42-45 can be even removed upto 90% by sorption Impact of pharmaceutical pol- technique onto sludge.36 Pharmaceutical com- lutants on water quality pounds, particularly tetracyclines, have the Pharmaceuticals in Indian propensity to sorb the soil particles or to form The effluents released from pharmaceutical complexes with ions, which are present in the drinking water industries consist of different chemical and 37 terrestrial ecosystem. Numerous pharmaceu- Larsson and his group46 have reported the biological compounds. Due to such nature, tical substances might have great impact on concentration (90-31,000 mg/L) of various these effluents may lead changes in water their behaviour in spite of being weak acids, drugs like metoprolol, enoxacin, enrofloxacin, quality. Out of all drinking water quality weak bases, or zwitterions and site-specific citalppram, norfloxacin, lomefloxacin parameters, some characteristics viz. pH, tem- water, soil, or sediment conditions viz. pH, ciprofloxacin, losartan, cetirizine, ofloxacin perature, total solids, total dissolved solid cation exchange capacity, etc.38 The sixty nine and ranitidine in the effluent of sewage treat- (TDS), total suspended solid, chloride, oil and pharmaceutical drugs belonging to fifteen dif- ment plant in Patancheru Enviro Tech Ltd. grease, biochemical oxygen demand (BOD) ferent therapeutic classes have been detected (PETL) of Patancheru, in Hyderabad. and chemical oxygen demand (COD) indicated in more than effective concentration (>0.1 The pharmaceutical compounds with detect- higher pollution level in effluents of Taloja mg/L) in urban wastewater 0.10 mg/L-38.00 ed concentrations in ground and surface water industrialonly area, Mumbai, India.48,49 In mg/L corresponding to salbutamol and aceta- have been summarized in Table 2.42-44 In anoth- Patancheru industrial area, Medak (India), the minophen, respectively.39 er study, the average total concentration of concentrations of TDS, BOD, COD, copper, detected pharmaceutical compounds was arsenic, selenium, fluoride and iron were found 24 ng/L in each studied sample. While, recorded 5 to 10 times higher than maximum antipyrine (analgesic) and sulfamethizoleuse permissible limit50,51 in waste water of inlet Characteristics of pharmaceuti- () were detected for first time in and outlet of a septic tank in pharmaceutical cal drugs drinking water sources of USA.47 Fick et al. industrial area of Bangalore in India. However, have reported the presence of drugs in the several researches have focused on physico- Many endocrine disrupting chemicals samples of wells, lakes and rivers of nearby chemical characteristics and heavy metals 41 (EDCs) as synthetic organic chemicals like areas of Hyderabad in India (Table 3). The analysis of pharmaceutical effluents in various surfactants, pesticides, poly aromatic hydro- authors found that all the wells were contami- parts of India and are summarized in Tables 48,52-54 49,52,55,56 carbons, pharmaceuticals, brominated flame nated with drugs like Ciprofloxacin, enoxacin, 4 and 5. retardants, polychlorinated biphenyls and phthalates are being released in the environ- ment through human induced activities.20 Generally, some pharmaceutical compounds commercial have hydrophilic nature, whereas some have hydrophobic nature. But, the nature of some pharmaceuticals even varies as per environ- mental conditions. Besides, the nature of a pharmaceutical compound dependsNon upon its chemical composition. Some of the pharma- ceutical compounds with their nature have been provided in Table 1.8 Figure 3. Oxidative metabolism of ibuprofen.

Table 1. Different classes and nature of pharmaceutical drugs. Detection of pharmaceutical compounds in fresh water and Pharmaceutical classes Pharmaceutical drugs Nature of pharmaceutical drug wastewater samples Anti-inflammatory Aspirin Hydrophilic Diclofenac Varies Ibuprofen Moderate hydrophobic In the past decade, the numbers of papers Lipid regulators Clofibric acid Moderate hydrophobic on the analysis of pharmaceuticals in drinking Bezafibrate Hydrophobic water samples have increased consider- Fenofibric acid Hydrophobic ably.23,24,40 After 8 years period, a follow-up Antiepileptics Carbamazepine Moderate hydrophobic study has reconfirmed that pharmaceutical residues were still present in the water of b-blockers Metoprolol Hydrophilic adjoined areas.41 Several researchers have Antibiotics Ciprofloxacin Hydrophilic

[Journal of Xenobiotics 2016; 6:5774] [page 3] Review

compounds are used as steroid estrogen ana- Health impacts due to pharma- logue in the feminine pill and subsequently Conclusions ceutical drugs present in fresh released in the environment through waste water and waste water water treatment plant in the form of effluent. The pharmaceutical drugs and their The predicted no-effect concentrations of the metabolites are being found with increasing natural feminine hormones i.e., estrone, 17 - concentrations in aquatic as well as in terres- Pharmaceutical compounds present in estradiol, estriol were determined upto 6 ng/L, trial ecosystems. Due to continuous release of water bodies directly affect the user’s health 2 ng/L and 60 ng/L respectively, which is 20 to pharmaceutical compounds through different through respiratory disorders, cancers, repro- 600 times greater than the prescribed limit. anthropogenic ways in significant amount, the ductive problems, chronic depression and con- The antineoplastics and immune modulating impacts of drugs are increasing and affecting genital problems including mental retardation agents are responsible for genotoxic effects the environment. In recent years, the develop- and physical abnormalities, whereas indirectly i.e., damage of DNA, cause cancer, etc.61,62 by lowering productivity of agricultural land, ment of advanced and sophisticated analytical altering agricultural infrastructure and leads Pharmaceutical substances i.e., tamoxifen instruments has enabled scientists to detect to massive death of livestocks and fishes.57-59 and used against breast the concentrations of these drugs upto ppm Trace amount of pharmaceuticals in drinking cancer and ifosfamide, used for a large variety and ppb levels and even lower. Present study water may cause considerable adverse effects of cancer have already been detected in sur- focuses on global production, occurrences, 31,61 to human health after long term exposure. The face water. It was also observed that all fate, properties, toxicity, chemical composi- concentrations of pharmaceuticals detected in eukaryotic organisms are found to be suscepti- tions, behaviour patterns and health hazards drinking water samples have numerous disor- ble to the pharmaceutical drug namely cytosta- of these drugs on environmental components ders.60 The release of EDCs into the environ- tic.62 Caffeine works as metabolic stimulant and other living beings. The study highlights ment may lead endocrine related diseases in and increase its effectiveness, when combined the need of development of new techniques to the health of users, which are increasing in with medicines.20 However, Chiral pharmaceu- safeguard the society from adverse health the wildlife and also changing the reproductive tical compounds can be a better option to related acute and chronic effects of drugs. health of human beings includes declining reduce the load of pharmaceutical dosages to Pharmaceutical based environmental pollution male fertility, birth defects, breast and testicu- the patients and to protect the drinking water has only become an international issue, which lar cancer.20 EDCs also affect different hor- resources from unnecessary impact of phar- requires due attention and changes in policies mones of the organisms. 17 -ethinylestradiol maceutical drugs.63,64 and regulations. Thus, detailed studies and use Table 2. Pharmaceutical compounds with detected concentrations in different water bodies with their extraction methods. Pharmaceutical Concentration Extraction Instrument Country References compound method used Ground water Acetaminophen 1.89 mg/L Solid phase extraction HPLC-MS USA 42 Caffeine 0.29 mg/L Carbamazepine 0.42 mg/L Codeine 0.214 mg/L P-xanthine 0.12 mg/L Sulfamethoxazole 0.17 mg/L Trimethoprim 0.018 mg/L commercial Surface water Ibuprofen 414 ng/L Solid phase extraction using high HPLC with tandem MS South Korea 43 performance extraction disks (SBD-XD) Carbamazepine 595 ng/L Non Atenolol 690 ng/L Clarithromycin 443 ng/L Mefenamic acid 326 ng/L Erythromycin 137 ng/L Fluconazole 111 ng/L Levofloxacin 87.4 ng/L Indomethacin 33.5 ng/L Propranolol 40.1 ng/L Ifenprodil 35.4 ng/L Finofibric acid 3.20 mg/L Oasis HLB solid phase Reverse Phase HPLC through Douro River 44 extraction diode array detector Estuary with C18 column Carbamazepine 0.60 mg/L Diazepam 1.60 mg/L Fluoxetine 32.00 mg/L Propranolol 0.80 mg/L Sulfamethoxazole 1.40 mg/L Trimethoprim 8.00 mg/L HPLC-MS, high-performance liquid chromatography coupled with mass spectrometry; SBD-XD, ….

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Table 3. Detection of pharmaceuticals in fresh water samples in Hyderabad area, India. Drug Lakes( 03 sampling sites of 02 lakes) River (06 sampling points) Wells (06 wells)

Norfloxacin 60,000-520,000 ND-4700 ND-31 Ciprofloxacin ND-6,500,000 10,000-2,500,000 44-14,000 Ofloxacin ND-11,000 180-10,000 ND-480 Enoxacin 14,000-160,000 ND-66,000 ND-1900 Enrofloxacin ND-25,000 ND-30,000 ND-67 Metoprolol 7000-ND ND-240 ND-90 Cetirizine 5000-1,200,000 5,400-530,000 550-28,000 Citalopram 2000-8000 ND-76,000 ND-1400 ND, not detected.

Table 4. Physico-chemical characteristics in pharmaceutical industrial effluents. S. No. Characteristics Unit Ref. 48 Ref. 52 Ref. 53 Ref. 54 1. pH - 5.1 12.54 10.34 8.00 2. Temperature ºC 29.8 - 36.34 28.87 3. Conductivity mS/cm - 27,400 1534.21 1733.13 4. TSS mg/L 654 2980 2673.22 348.75 5. TDS mg/L 3412.5 8741 2655.43 873.81 6. DO mg/L - 3.50-4.70 8.43 5.78 7. BOD mg/L 1083.5 546 only 341.11 52.13 8. COD mg/L 2797.3 1271 698.11 218.42 TSS, total suspended solid; TDS, total dissolved solid; DO, dissolved oxygen; BOD, biochemical oxygen demand; COD, chemical oxygen demand.

Table 5. Concentrations of heavy metals in pharmaceutical industrial effluents. use S. No. Characteristics Unit Ref. 49 Ref. 52 Ref. 55 Ref. 56 1. Chromium mg/L 30.6 0.57 2.34 0.31 2. Cadmium mg/L 35.8 - ND 0.55 3. Nickel mg/L 33.6 0.43 - 0.12 4. Zinc mg/L 26.8 3.31 - 1.3 5. Copper mg/L 17.6 14.06 2.30 0.38 6. Lead mg/L 21.7 0.42 ND 0.263 7. Iron mg/L 10.4 18.93 19.38 19.38 ND, not detected. commercial investigations are required to develop the sus- maceutical products. Wat Sci Technol May 11, 2016. tainable and long term effective solutions in 2004;49:213-21. 7. Kumar A, Bisht BS, Joshi VD, Singh AK, order to save the health of mankind,Non other liv- 4. Vijay G. Systemic failure of regulation: the Talwar A. Physical, chemical and bacterio- ing organisms and environment from any type political economy of pharmaceutical and logical study of water from rivers of of pharmaceutical related pollution. bulk drug manufacturing. In: Lofgren H, Uttarakhand. J Hum Ecol 2010;32:169-73. ed. The politics of the pharmaceutical 8. SWITCH, Biodegradability and fate of phar- industry and access to medicines: world maceutical impact compounds in different pharmacy and India. Hyderabad: Social treatment processes. Katarzyna Kujawa- References Science Press; 2012. Roeleveld, Els Schuman WU, Environmental 5. KPMG International. The Indian pharma- Technology, Wageningen, The Netherlands. 1. Ternes TA, Joss A. Human pharmaceuti- ceutical industry: collaboration for growth; Sustainable water management in the city cals, hormones and fragrances - The chal- 2006. Available from: of the future 2014. Available from: lenge of micropollutants in urban water http://www.in.kpmg.com/pdf/Indian%20ph http://www.switchurbanwater.eu/outputs/pd management. London: IWA Publishing; arma%20outlook.pdf Accessed: June 10, fs/W41_GEN_RPT_D4.1.3_Biodegradability 2006. 2014. _and_fate_of_phamarceutical_com- 2. Kummerer K. Pharmaceuticals in the envi- 6. Mason M. World’s highest drug pollution pounds.pdf Accessed: May 11, 2016. ronment: sources, fate, effects and risks. levels found in Indian stream; 2009. 9. Reddy AGS, Boraa S, Ganji S. Berlin, Heidelberg: Springer; 2004. Available from: http://usatoday30.usato- Hydrogeochemical characterization of 3. Derksen JGM, Rijs GBJ, Jongbloed RH. day.com/tech/science/environment/2009- contaminated in Patancheru Diffuse pollution of surface water by phar- 01-26-drug-india-stream_n.htm Accessed: industrial area, Southern India. Environ.

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