Degradation and Depletion of Pharmaceuticals in ... - ACS Publications

Chapter 19

Degradation and Depletion of Pharmaceuticals in the Environment

Downloaded by PENNSYLVANIA STATE UNIV on July 28, 2012 | http://pubs.acs.org Publication Date: July 30, 2001 | doi: 10.1021/bk-2001-0791.ch019

Ranga Velagaleti and Michael Gill BASF Corporation, 8800 Line Avenue, Shreveport, LA 71106

Manufacture of pharmaceutical compounds is conducted under Good Manufacturing Practice Regulations (GMPs), which require contained manufacture, and process and product accountability for both the bulk drug substance and the drug product. Cleaning of equipment may contribute drug or related substances to the manufacturing process waste effluents. These effluents are processed on-site and discharged into domestic sewage and then into Publicly Owned Treatment Works (POTW) in compliance with prevailing regulations. The on-site processing facilities and the POTW are designed to facilitate extensive degradation and depletion of drug residues. According to the United States Food and Drug Administration's (FDA's) guidance on Environmental Assessments, regulated articles produced and disposed of in compliance with all applicable regulations are considered to have no effect on the environment. During use, human and animal health drugs are metabolized in the target species, sometimes extensively resulting in partial depletion of drugs. For human drugs, the remaining drug residues containing parent compound and metabolites are released through the excreta into the domestic sewage, which is processed in POTW, where further degradation and depletion

© 2001 American Chemical Society

In Pharmaceuticals and Care Products in the Environment; Daughton, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

333

334 of the residues are facilitated. When animal (as manure applied to soil) or human health drug residues (from POTW) are released into the environment, dilution in soil or water plays a major role in their decline, followed by degradation and depletion through chemical and biological processes. The degradation and depletion processes and a rationale for zero risk to the environment from drug manufacture and use are discussed in light of current regulations.


Introduction The manufacture, use, and disposal of pharmaceutical active ingredients and drug products are contained and their exposure to the environmental matrices is limited. This is in contrast to crop protection and other external use chemicals which by their very nature of intended use and application may be directly released into the environment (air, soil, and water) from the target or non-target crops and soil, or other domestic and industrial uses. This manuscript discusses how the release of drug active ingredients into the environment could occur under their contained manufacture, use and disposal scenarios. It subsequently describes the general degradation and depletion mechanisms in various environmental matrices that could lead to zero risk exposures for the majority of drugs. Finally, a discussion of the current regulatory perspective driving the Environmental Risk Assessments (ERA) is provided. Manufacture and disposal issues are well regulated and are largely common to human and animal health drugs, and, therefore, are discussed under one topic. The disposition of drug residues resulting from human and animal health use are unique to each use and, therefore, discussed separately. Drug Manufacture The manufacture of pharmaceuticals in general is contained, with minimal release of raw materials, intermediates or bulk drug substance during the manufacture of active pharmaceutical ingredient (API) and finished drug product (tablets, capsules, etc.). A P I and drug product manufacture is governed by Current Good Manufacturing Practice (CGMP) regulations (1,2). C G M P s require accountability of all raw materials that go into the production of drug substance or drug product. For example, the C G M P s for A P I manufacture state: "Raw materials used for manufacturing APIs and intermediates should be weighed and measured ... Weighing and measuring devices should be of suitable accuracy for the intended use." Further, in terms of the accountability of final yields from raw materials the CGMPs state: "Actual yields and


335


percentages of expected yields should be determined at the conclusion of each appropriate phase of manufacturing or processing of an A P I or intermediate" (/). Similar controls for the accountability of raw materials (API and excipients) are required under C G M P s for drug product manufacture, which state "Actual yields and percentages of expected yields should be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product" (2). These strict controls and accountability for A P I and drug product manufacture under C G M P s as described above preclude any significant release of pharmaceutical compounds into the environment. A P I Manufacture Intermediates used in A P I manufacture and/or APIs can become a part of the process waste effluent stream during the cleaning of the equipment used in manufacture. Most commercial A P I manufacturing plants have holding tanks for process waste effluents, where the effluents are processed to encourage biodégradation. Specifications are set and approved by regulatory authorities for the limits on carbon loading of these effluents. These waste streams must meet regulatory specifications on discharge limits upon release into municipal sewer collection systems. Extensive treatment and stringent discharge limits are applied to effluents when directly discharged from API manufacturing facilities to surface waters. Depending on the chemical nature of the A P I or intermediate, and the physical and chemical condition of the collection systems and treatment facilities, biological and chemical degradation processes could reduce or even deplete the concentrations of these components in the waste effluents. For example, aerobic biodégradation could result in reduction in concentration of these components through biotransformation (metabolism to transformed products mediated by microorganisms present in the holding tanks) or complete depletion of these components through mineralization (conversion to C 0 and H 0 ) . Biotransformation of an organic molecule can occur through one or more of the following mechanisms: oxidation, oxidative dealkylation, decarboxylation, epoxidation, aromatic hydroxylation, aromatic nonheterocyclic ring cleavage, aromatic heterocyclic ring cleavage, hydrolysis, dehalogenation, and nitroreduction (5). Also, chemical degradation processes such as hydrolysis and photolysis could reduce the concentration of these components in effluents. Hydrolysis is a key reaction of organic compounds with water. The chemical reaction is mediated by a direct displacement of a chemical group by the hydroxyl group (4). The components in the waste effluents can also be degraded i f they are exposed to natural sunlight, either by direct photodegradation or indirect photodegradation. Direct photodegradation by natural sunlight occurs in pharmaceutical compounds or their intermediates 2

2



336 that have absorbance in the range of 290 to 800 nm. Pharmaceutical compounds that do not have absorbance in 290 to 800 nm range can also be photodegraded through indirect photodegradation i f one or more of the chemical components (sensitizer) present in the waste effluent can absorb light in this region and transfer energy to and facilitate the degradation of those non-absorbing pharmaceutical residue components. Photodegradation of A P I or intermediates can occur through any of the following mechanisms: fragmentation into free radicals or neutral molecules, rearrangement and isomerization reactions, photoreduction, dimerization and other addition reactions, photoionization and electron transfer (4). Through the use of appropriately designed process waste treatment facilities that facilitate biological and/or chemical degradation, the concentration of the components present in the process waste effluents can be reduced to acceptable levels. Degradation processes such as hydrolysis and biodégradation could reduce components discharged into municipal domestic sewage before they reach the Publicly Owned Treatment Works (POTW). The POTWs are designed to facilitate degradation of organic molecules present in the domestic sewage. Extensive biodégradation is possible in the activated sludge aeration tanks where the microbial load is very high due to aerobic multiplication of microbes. Also, the open aeration tanks at the P O T W facilitate extensive hydrolysis and photodegradation of organic molecules. The wastewater and the sludge solids (containing predominantly microbial biomass) are separated during processing at POTW. Organic molecules that have a high octanol/water partition coefficient (Kow) tend to partition into sludge solids. The sludge solids at many POTWs are subjected to anaerobic digestion where anaerobic biodégradation of most organic molecules typically results in the production of methane, C 0 , and biotransformed products. These degradation processes at the P O T W will account for decline and depletion of any drug residues present. A combination of these processes should eliminate most drug residues before the effluents enter the aquatic or terrestrial environmental compartments. Wastewater effluent from POTW is discharged to rivers or streams where dilution will reduce residues further. Similarly, residues in sludge solids are diluted when applied to soil. 2

Drug Product Manufacture During drug product manufacture, the only source of release of drug residue will be through the cleaning of equipment used for coating, blending, tablet compressing and packing operations. These residues are minimal and they may be discharged into domestic municipal sewage systems, especially when water is used for the cleaning process. When organic solvents are used,


337


the washes are collected and disposed as hazardous wastes or the solvent is recycled. Most residues released through the cleaning operation will enter the domestic sewage where they are extensively diluted (possibly depleted) before entering the POTW. Residues entering the POTW undergo degradation and depletion through chemical (hydrolysis and photolysis) and biological (aerobic and anaerobic biodégradation) degradation processes. The minimal releases during drug product manufacture and their degradation, depletion, and dilution may lead to minimal or non-detectable residue components related to drug product manufacture in the wastewater effluents or sludge solids released from the POTW. D r u g Disposal The material accountability under C G M P s applies to the unused, expired, or returned APIs or drug products. C G M P s for APIs state; "Records of returned APIs and intermediates should be maintained and should include the name, batch or lot number, reason for the return, quantity returned, date of disposition, and ultimate disposition" (/). C G M P s for finished drug products state: "Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the drug product" (2). When the ultimate disposition status is to destroy, a majority of the pharmaceutical compounds are disposed of through incineration or landfilling in a certified incinerator or landfill, respectively. Both these methods of disposal are designed specifically to eliminate the exposure of subject articles to the environment. The end users for the drug products are hospitals, pharmacies, clinics, and domestic users (5). Empty or partially empty packages are disposed of according to hospital, pharmacy, or clinic procedures. Typically, such procedures will include collection in appropriate containers and ultimate disposition through certified landfill or incinerator. Domestic users will typically dispose of the empty or partially empty containers through a community solid waste management system, which may include certified landfills or incineration (5). No significant environmental releases are likely to occur from disposal by end users of drug products.

Regulatory Perspective on Environmental Issues Related to Manufacture and Disposal F D A guidance (5) states that the regulated articles produced and disposed of in compliance with all applicable emission requirements do not significantly


338


affect the environment. Therefore, F D A ' s Center for Drug Evaluation and Research (CDER) and Center for Biologies Evaluation and Research (CBER) will not routinely request submission of manufacturing and disposal information as a part of the Environmental Assessment (EA) requirement of drug applications (5). If there are unique emissions resulting from the manufacture or disposal of a particular drug that may harm the environment, F D A may request manufacturing and disposal information as well as the evaluation of the environmental impact of such emissions in an E A . The degradation and depletion mechanisms for such emissions should be provided to support a "no impact" scenario. Use of H u m a n Health Drugs Human health drugs or biologies are likely to be metabolized by the patient and excreted through urine and feces. The excreted compounds may include the substance and/or its structurally related substances (SRSs) such as the dissociated parent compound, metabolites, conjugates, or dégradâtes (drug residues), which will form part of the domestic sewage. The domestic sewage is carried through the municipal sewer system, which then enters the POTW. Sand and grit are removed from the domestic sewage at the P O T W by screen filtration after which it is subjected to primary and secondary treatments. After processing at the POTW, the domestic sewage is partitioned into wastewater effluent and sludge solids. The wastewater from the P O T W is released into nearby streams or rivers, thus exposing the surface water and underlying sediment. The sludge solids (biosolids) are landfilled, incinerated, or applied to agricultural soils as an organic supplement, the later practice being more common. Degradation, Depletion and Dilution Processes The A P I or biologic substance and their SRSs may undergo degradation and depletion at every step beginning with metabolism by the patient. Almost all drugs are metabolized to some extent prior to excretion. Extensive metabolism (and some depletion) in the human body is reported for many drugs. After they are excreted, the drug residue components could be diluted in the domestic sewage and undergo aerobic and/or anaerobic degradation and hydrolysis en route to the POTW. After the domestic sewage reaches the POTW, aerobic biodégradation, hydrolysis, and photolysis could result in degradation and depletion of these components in the activated sludge aeration tanks and in the settling tanks. The sludge solids are typically digested anaerobically after they are separated from the wastewater, where additional



339 depletion of the drug residues may occur via anaerobic biodégradation. Upon discharge of P O T W effluents to receiving waters, a typical dilution of an order of magnitude occurs resulting in additional decline in the concentration of drug residues (5). Further decline may occur through aerobic and anaerobic degradation in surface water and anaerobic degradation in sediment. Approximately 6.8 million tons of biosolids are generated per year with 54% of that quantity applied to the land as an organic supplement (5). Application of sludge solid to agricultural lands results in decline of drug residues due to dilution with soil. Photodegradation and hydrolysis could result in further degradation and depletion of drug residue components in the upper layers of soil to which the sludge is applied. The microorganisms present in the soil (i.e., bacteria, such as actinomycetes, and fungi) facilitate extensive degradation of organic molecules. In all these matrices, biodégradation may result in biotransformation to small molecules or complete mineralization of an organic molecule to C 0 and H 0 . Products formed as a result of hydrolysis and photodegradation could also be mineralized by a secondary degradation process of biodégradation. The biotransformed degradation products could also undergo mineralization by further microbial attack. When drug residue components are completely mineralized to C 0 and H 0 , they are considered completely depleted. The potential matrices and the chemical and biological degradation and depletion processes that could facilitate elimination of drug residues are presented in Table I. 2

2

2

2

Regulatory Limits on Estimated Concentrations of Human Drugs in the Environment and Their Relation to Degradation and Depletion Regulatory Limits for Estimated Introduction Concentrations The vast majority of new human drug applications qualify for any one of the five categorical exclusion criteria listed in E D A guidance (5). The most commonly applied categorical exclusion is based on the maximum annual use, which is derived from a five-year marketing projection. If F D A ' s approval of the application increases the use of active moiety but the estimated introduction concentration (EIC) of the substance at the point of entry into the aquatic environment is below 1 part per billion (ppb), the drug application will qualify for a categorical exclusion. If the EIC is >lppb, submission of a full ΕA is required. Estimation of the EIC is, therefore, very important prior to addressing the E A component of drug applications. The EIC at the point of entry into the aquatic environment is estimated using the formula provided in F D A guidance (5): EIC-Aquatic (ppb) = A x B x C x D , where A = kg/year produced for direct use as active moiety; Β = 1/liters per day entering POTW, an estimate of 1.214 χ 10 from the 1996 Needs Survey by the E P A ; C = year/365 days; and 11


340

Table I. Degradation and Depletion of Human Drugs


Human Body Metabolism - Transformation and Depletion (C02 or other expired gases) Adsorption and Assimilation — Depletion Exeretion - Parent Compound and its Metabolites/Degradates (contribution to domestic sewage) Domestic Sewage Hydrolysis - Chemical Transformation/Degradation Biodégradation - Microbial Mediated Biotransformation/Degradation Mineralization - Depletion Dilution - Residue Decline/Depletion POTW Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Photolysis - Degradation Aerobic Biodégradation — Degradation/Mineralization (Depletion) Anaerobic Biodégradation - Degradation/Mineralization/Methane Production (Depletion) Surface Water Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Photolysis - Degradation Aerobic Biodégradation - Degradation/Mineralization (Depletion) Sediment Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Anaerobic Biodégradation - Degradation/Mineralization/Methane Production (Depletion) Soil Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Photolysis - Degradation Aerobic Biodégradation — Degradation/Mineralization (Depletion) Anaerobic Biodégradation - Degradation/Mineralization/Methane Production (Depletion)


341


9

D = ΙΟ μg/kg (conversion factor). Using this equation, an EIC of one part per billion evaluates to 44,300 kg/year. Use of the active moiety below this EIC limit qualifies the application for a categorical exclusion. This calculation assumes: 1) that all drug product produced in a year enters the P O T W ; 2) drug product usage occurs throughout the United States in proportion to the population and the amount of waste generated; and 3) that there is no metabolism of the active moiety. The kg/year of active moiety (rather than the salt or the complex) should include: 1) the highest quantity of active moiety expected to be produced for direct use by humans (quantities for inventory build up are excluded) in any of the next five years, normally based on marketing projections; 2) the quantity used in all dosage forms and strengths included in the application; and 3) quantities in applicant's related applications. Very few human pharmaceutical compounds with annual production of >44,300 kg are produced in the United States. A vast majority of the drugs are, therefore, granted categorical exclusions by F D A .

EIC Based on Drug Metabolism, Degradation, Dilution and Depletion In a hypothetical situation, where human metabolism data suggests that 10% of the ingested drug has been metabolized to C 0 or other expired gases (known to occur with some drugs), then this 10%, representing a known depletion mechanism, can be used to adjust the EIC estimate downward by 10%. The extent, to which an administered dosage is converted to pharmacologically inactive metabolites, is, therefore, an important mechanism to consider when addressing the E A component of the drug application. The F D A guidance (5) considers the following half-life (t ) estimates (equal to or less than) as rapid depletion mechanisms that will warrant no further fate or effects tests: hydrolysis - 24 hours; aerobic biodégradation in water - 8 hours; soil biodégradation - 5 days. The guidance (5) also advises photodegradation to be considered as a depletion process. If rapid and complete depletion is not achieved, further evaluation is necessary including the conduct of toxicity tests. When the wastewater effluents from the POTW are released into surface waters, an order of magnitude of dilution factor is applied [dilution factor of 10 is suggested in the F D A guidance (5), but may vary with each POTW], and as a result of which, the concentration in surface water could be further reduced. Further degradation and dilution in surface waters and sediment (Table I) could possibly deplete the drug completely or reduce it to undetectable levels (using modern analytical methodology). Similarly dilution of residues in sludge solids when applied to soil and subsequent degradation and depletion could result in undetectable levels. A s stated in the F D A guidance (5), an estimated environmental concentration (EEC) should be evaluated taking into account the degradation, depletion, and dilution processes ( E E C = EIC - degradation, 2

1/2


342 depletion, dilution). The maximum expected environmental concentration ( M E E C = EIC or E E C , whichever is greater) is compared against the no observed effects (NOEC) from the toxicity tests, to evaluate the risk to environmental organisms. For example, i f M E E C is lower than N O E C , then no risk is anticipated.


Use of Animal Health Drugs Like human drugs, animal health drugs or biologies are likely to be metabolized, partially depleted and/or excreted through urine and feces. The excreted compounds may include the parent substance and/or its SRSs, such as the dissociated parent compound, metabolites, conjugates, or dégradâtes (drug residues). The urine and feces along with the bedding will constitute the manure, which is either stored in manure pits for subsequent application or is immediately applied to the agricultural field as an organic matter supplement and fertilizer. A significant number of animal health drugs are used to control various diseases of domestic animals such as dogs and cats. The urine, feces and bedding are disposed of as a part of domestic municipal solid waste, which is sent to either licensed incinerators or landfills. Exposure from these drug residues is, therefore, not an environmental concern. The use of animal health drugs in farm animals (cattle, poultry, swine, and sheep) may result in the unchanged parent molecule (if any) and the SRSs in the manure being exposed to soil when manure is applied to agricultural land. Degradation, Depletion and Dilution Processes When manure is applied to soil, there is significant dilution of any drug residues present. Aerobic soil biodégradation is the major pathway of degradation and depletion of animal health drugs in soil. Biotransformation (degradation to polar or non-polar dégradâtes) and mineralization (degradation to C 0 and H 0 ) are the main mechanisms of biodégradation. Complete mineralization leads to complete depletion of a chemical from soil. Other degradation and depletion mechanisms include soil photolysis, especially in the upper few centimeters of soil where the manure may be dispersed. The photodegradation products may also be subjected to aerobic biodégradation in upper soil layers. Soil hydrolysis could occur in moist soils at any given depth. The degradation products of hydrolysis could undergo aerobic biodégradation in upper soil layers or anaerobic degradation in deeper soil layers with sufficient moisture that facilitates both hydrolysis and anaerobic microbial growth and consequent biodégradation. The run-off from soil may carry the drug residues to surface water. Photolysis and aerobic biodégradation may be the major 2

2


343 degradation and depletion mechanisms in surface water while anaerobic biodégradation is the major mechanism of degradation and depletion in sediment. The major degradation and depletion mechanisms for animal health drugs are summarized in Table II.


Regulatory Limits on Estimated Concentrations of Animal Drugs in the Environment and Their Relation to Degradation and Depletion The Committee for Veterinary Medicinal Products ( C V M P ) under the direction of the European Agency for the Evaluation of Medicinal Products ( E M E A ) published a guidance document (EMEA/CVMP/055/96-FINAL, which came into operation on January 1, 1998), titled "Environmental Risk Assessment for Veterinary Medicinal Products Other than GMO-Containing and Immunological Products", which describes a phased (Phase I and Phase II) approach to E R A of animal drugs (6). This is the primary guidance document currently under review by the Veterinary International Conference on Harmonization (VICH) in conjunction with other guidances [U.S. F D A and Animal Health Institute (AHI)] and published literature, to arrive at a global harmonized guideline for performing E R A for animal health drugs. The following discussion pertains to the C V M P / E M E A guidance. Phase I E R A evaluations could exempt a drug from further testing under the following conditions: 1) the active substances consist of vitamins, electrolytes, natural amino acids or herbs; 2) the target animals for the active substance(s) are companion animals or i f only a small number of animals are treated; 3) the active substance(s) is applied externally (pour-ons, dips, fumigation, etc.,) and the substances are not expected to enter the environment; 4) the active substance(s) are present in manure or slurry, for spreading on land, in concentrations lower than 100 μg/kg; 5) the substance/s used for pasture animals are excreted in concentrations lower than 10 μg/kg; 6) the D T (degradation half life of active moiety) in manure is less than 30 days; 7) the predicted environmental concentration (PEC) in soil demonstrated by a worst case calculation is below 10 μg/kg; and 8) the predicted environmental concentration (PEC) in ground water is below 0.1 μg/kg. No degradation and depletion mechanisms need to be established under these criteria. Phase II assessment is required under the following conditions: 1) the active substance is used to treat a large number of animals; 2) there is a potential for direct entry into aquatic environment; 3) the drug substance is used for internal application, and the drug or its major metabolite is present on pasture in concentrations of >10 μg/kg (10 ppb); 4) the manure is spread on to the land and the drug or its major metabolite concentration exceeds 100 μg/kg (100 ppb); and 5) the P E C in soil and ground water exceeds 10 μg/kg (10 ppb) and 0.1 μg/L, respectively. The Phase II 5 0


344


Table II. Degradation and Depletion of Animal Health Drugs Animal Body Metabolism - Transformation and Depletion (C02 or other expired gases) Adsorption and Assimilation — Depletion Excretion - Parent Compound and its Metabolites/Degradates (Contribution to Manure and Soil) Manure Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Photolysis - Degradation Aerobic Biodégradation — Degradation/Mineralization (Depletion) Anaerobic Biodégradation — Degradation/Mineralization/Methane Production (Depletion)

Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Photolysis - Degradation Aerobic Biodégradation — Degradation/Mineralization (Depletion) Anaerobic Biodégradation — Degradation/Mineralization/Methane Production (Depletion) Surface Water Dilution — Residue Decline/Depletion Hydrolysis — Chemical Transformation/Degradation Photolysis — Degradation Aerobic Biodégradation — Degradation/Mineralization (Depletion) Sediment Dilution - Residue Decline/Depletion Hydrolysis - Chemical Transformation/Degradation Anaerobic Biodégradation - Degradation/Mineralization/Methane Production (Depletion)


345 evaluations should establish dilution, degradation, and depletion mechanisms in the manure, soil, and water to estimate the final P E C to compare with the predicted no effect concentrations (PNEC) for environmental species to provide an E R A .

References


1.

Current Good Manufacturing Practice for Active Pharmaceutical Ingredients: Guidance for Industry - Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients; U . S . Food

and Drug

Administration, 03/98.

2. Current Good Manufacturing Practice for Finished Pharmaceuticals. 21 CFR Part 211; U.S. Food and Drug Administration, Revised 02/95.

3.

Expert Systems Questionnaire. Survey Concerning Biodegradation. Prepared by Gregg, B . ; Gabel, N.W.; Campbell, S.E. (Versar, Inc). For Office of Toxic Substances, Exposure Evaluation Division, U . S . Environmental Protection Agency, Wahington,DC,1987.

4.

Handbook of Chemical Property Estimation Methods. Lymann J.W.; Rosenblatt, D . H . , Eds.; American Chemical Society: Washington, D C , 1990.

5.

Guidance for Industry - Environmental Assessment of Human Drugs and Biologics Applications; U.S. Food and Drug Administration, 1998.

6.

Environmental Risk Assessment for Veterinary Medicinal Products Other Than GMO-Containing and Immunological Products (EMEA/CVMP/055/96-FINAL, Operational Effective January 1, 1998),

Committee for Veterinary Medicinal Products; The European Agency for Evaluation of Medicinal Products, London, U . K . 1998.

Thanks are due to Dr. Joseph Robinson of Pharmacia Corporation for discussions on this topic, and M r . Phil Burns of B A S F Corporation for review and comment on the manuscript.


Degradation and Depletion of Pharmaceuticals in ... - ACS Publications

Recommend Documents