Classification of Impurities

Classification of impurities

Definition:-The impurities in drug are unwanted chemicals that remains with the active pharmaceutical ingredients (API), develop during formulation and upon aging of API/drug products. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical products.

1. Classification of Impurities Impurity profile is the description of identified and unidentified impurities present in new drug substances. Various types of Impurities and its sources are enlisted in Table 1.

Impurity type

Impurity source

1.

Process-related drug Substance

- Organic- Starting material- Intermediate- By-product- Impurity in starting material

2. Process-related drug product -Organic or inorganic- Reagents, catalysts, etc.

3. Degradation drug substance or drug product

- Organic- Degradation products

4. Degradation drug product - Organic- Excipient interaction

Table 1. Description of impurity types and their sources

Impurities have been named differently or classified as per the as follows;

a) Classification on the basis of common names

1. By-products2. Degradation products3. Interaction products4. Intermediates5. Penultimate intermediates6. Related products7. Transformation products

1. By- products:- The compounds produced in the reaction other than the required intermediates.

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2. Degradation products:-These compounds are products due to decomposition of the active ingredient or the material of interest.

3. Interaction products:-Interaction products that could occur between various involved chemicals intentionally or unintentionally.

4. Intermediates:-The compounds produced during synthesis of the desired material or as part of the route of synthesis.

5. Penultimate intermediates:-It is the last compound in the synthesis chain prior to the production of the final desired compound.

6. Transformation Products:-They are very similar to by-products which relates to theorized and non-theorized products that may be produced in the reaction.

7. Related Products:-These products have similar chemical structure and potentially similar biological activity.

b) Classification of Impurities as per United State Pharmacopoeia

The United States Pharmacopoeia (USP) classifies the impurities in the following sections;- Impurities in Official Articles- Ordinary Impurities- Organic Volatile Impurities

c) Classification as per ICHAccording to ICH guidelines, impurities in the drug substance produced by chemical synthesis can broadly be classified into following three categories;

- Organic Impurities (Process and Drug related)- Inorganic Impurities- Residual Solvents

Organic impurities may arise during the manufacturing process and or storage of the drug substance may be identified or unidentified, volatile or non-volatile, and may include;

- Starting materials or intermediates- By-products- Degradation products

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Impurities are found in API’s unless; a proper care is taken in every step involved throughout the multi-step synthesis, for example; in paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for one manufacturer or be an intermediate for the others.In synthetic organic chemistry, getting a single end product with 100% yield is very rare; there is always a chance of having by-products. In the case of paracetamol bulk, diacetylated paracetamol may be formed as a by-product.Impurities can also be formed by degradation of the end product during manufacturing of the bulk drugs. The degradation of penicillin and cephalosporins are well-known examples of degradation products. The presence of a β-lactam ring as well as that of an a-amino group in the C6/C7 side chain plays a critical role in their degradation. Another example is, the degradation of ibuprofen (IBP) to 2-(4-formylphenyl) propionic acid (FPPA), 2-(4-isobutylphenyl) propionic acid (IBP), 2-(4-methylphenyl) propionic acid (MPPA), 2-(4- ethylphenyl) propionic acid (EPPA), 4- isobutylacetophenone (4-IBAP), 2-(4-n-propylphenyl) propionic acid (PPPA) and 2-(4-n-butylphenyl) propionic acid (BPPA), which are reported to be well known impurities in IBP .The degradation products of diclofenac sodium and clotrimazole, paclitaxel are also reported.

2. ICH limits for impurities

According to ICH guidelines on impurities in new drug products, identification of impurities below 0.1% level, is not considered to be necessary, unless potential impurities are expected to be unusually potent or toxic. The maximum daily dose qualification threshold as per ICH is tabulated in Table 2. [RP-4]

Maximum daily dose a Reporting threshold b

≤1 g>1 g

0.1%0.05%

Maximum daily dose a Identification threshold b,C

<1 mg1 mg–10 mg>10 mg–2 g>2 g

1.0% or 5 μg TDI, whichever is lower0.5% or 20 μg TDI, whichever is lower0.2% or 2 mg TDI, whichever is lower0.10%

Maximum daily dose a Qualification threshold b,C

<10 mg10 mg–100 mg>100 mg–2 g>2 g

1.0% or 50 μg TDI, whichever is lower0.5% or 200 μg TDI, whichever is lower0. 2% or 3 mg TDI, whichever is lower0.15%

Table 2: Thresholds for degradation products in drug products

a. The amount of drug substance administered per day.

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b. Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product.

Lower thresholds can be appropriate if the degradation product is unusually toxic.C. Higher thresholds should be scientifically justified.

i) Organic Impurities Each specific identified impurity - Each specific unidentified impurity at or above 0.1%- Any unspecific impurity, with limit of not more than 0.1%- Total impurities

ii) Residual solvents- [RP-5]Residual solvents are organic volatile chemicals used during the manufacturing process or generated during the production. Some solvents that are known to cause toxicity should be avoided in the production of bulk drugs. These are potentially undesirable substances. They either modify the properties of certain compounds or may be hazardous to human health. The residual solvents also affect physicochemical properties of the bulk drug substances such as crystallinity of bulk drug, which in turn may affect the dissolution properties, odor and color changes in finished products. As per the ICH guidelines, depending on the possible risk to human health, the solvents used in the manufacturing of drug substances classified into four types.a) Class I solvents: Solvents to be avoided These are known human carcinogens, strongly suspected human carcinogens, and environmental hazards. Class I solvents and their permissible concentration limits given in the Table 3. These solvents not employed in the manufacture of drug substances, excipients and formulations because of their unacceptable toxicity or their deleterious environmental effects. If use of these solvents is unavoidable, then their usage should be restricted.

Solvent Concentration Limit(ppm)

Concern

Benzene 2 Carcinogenic

Carbon tetrachloride 4 Toxic and environmental Hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Environmental hazard

Table 3. Class 1 solvent in pharmaceutical products.

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b) Class II solvents: Solvents to be limitedThese are non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities. PDEs (permitted daily exposure) are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm. Its usage should be limited in pharmaceutical products because of their inherent toxicity. Table 4 lists class II solvents with their daily permissible exposure.

Solvent PDE (mg/day) Concentration Limit(ppm)

Acetonitrile 4.1 410

Chloroform 3.6 360

Chlorobenzene 0.6 60

Cyclohexane 38.8 3880

1,2-dichloroethane 18.7 1870

Dichloromethane 6.0 600

1,2-Dimethooxyethane 1.0 100

N,N-Dimethylacetamide 10.9 1090

N,N-Dimethylformamide 8.8 880

1,4-Dioxane 3.8 380

2-Ethoxyethanol 1-6 160

Ethylene glycol 6.2 620

Formamide 2.2 220

Hexane 2.9 290

Methanol 30.0 3000

2-Methoxyethanol 0.5 50

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Methylbutylketone 0.5 50

Methylcyclohexane 11.8 1180

N-methylpyrrolidone 48.4 4840

Nitromethane 0.5 50

Pyridine 2.0 200

Sulfolane 1.6 160

Tetralin 1.0 100

Toluene 8.9 890

1,1,2-Trichloroethane 0.8 80

Xylene 21 2170

Table 4. Class 2 solvents in Pharmaceutical products

c) Class III Solvents: Solvents with low toxic potentialThese solvents in Class 3 may be regarded as less toxic and of lower risk to human health. It includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in this class. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5%) would be acceptable without justification. The use of class III solvents in pharmaceuticals does not have any serious health hazard. Class III solvents, viz. acetic acid, ethanol, acetone have permitted daily exposure of 50 mg or less per day, as per the ICH guidelines. A selective gas chromatography (GC) method has been developed to determine the purity of acetone, dichloromethane, methanol and toluene. Using this method, the main contaminants of each organic solvent can be quantified. Moreover, the developed method allows the simultaneous determination of ethanol, isopropanol, chloroform, benzene, acetone, dichloromethane, methanol and toluene with propionitrile as the internal standard.

Acetic acid Heptane

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Acetone Isobutyl acetate

Anisole Isopropyl acetate

1-Butanol Methyl acetate

2-Butanol 3-Methyl-1-butanol

Butyl acetate Methylethylnketone

Tert-Butylmethyl ether Methylisobutyl ketone

Cumene 2-Methyl-1propanol

Dimethylsulfoxide Pentane

Ethanol 1-Pentanol

Ethyl acetate 1-propanol

Ethyl ether 2-propanol

Ethyl formate Propyl acetate

Formic acid Tetrahydrofuran

Table 5. Class 3 solvents which should be limited by GMP or other quality based requirements.

d) Class IV Solvents: In case of Class IV solvents, adequate toxicological data is not available. The manufacturers should justify the residual levels for these solvents in pharmaceutical products. The solvents under class IV enlisted in table 6.

1,1-Diethoxypropane Methylisopropyl ketone

1,1-Dimethoxymethane Methyltetrahydrofuran

2,2-Dimethoxypropane Petroleum ether

Isooctane Trichloroacetis acid

Isopropyl ether Trifluroacetic acid

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Table 6. Class IV Solvents iii) Inorganic impurities-Inorganic impurities are derived from the manufacturing process and excipients. Generally, excipients contain high levels of heavy metals such as arsenic, bismuth, cadmium, chromium, copper, iron, lead, mercury, nickel and sodium. Sometimes they might present in the product during processing or they leached from packing material. For example, excipients such as hydrogenated oils and fats, which produced using metal catalysts, found to contain high concentrations of metals platinum and palladium). This may be due to leaching from process equipment or storage container.

3. Sources of Impurities

Impurities can originate from several sources; such as;

3.1. Starting Materials and Intermediates, 2. Impurities in the Starting Materials,

3. Reagents, Ligands and Catalysts related impurities 4. Crystallization-related impurities, 5. Stereochemistry-related impurities, 6. Synthetic intermediates and by-products, 7. Formulation-related impurities, 8. Impurities arising during storage, 9. Method related impurity, 10. Functional group-related typical degradation. 11. Impurities on Aging:-

-Mutual interaction amongst ingredients, -Hydrolysis -Oxidation -Photolysis -Decarboxylation -Packaging material

3.1. Starting Materials and Intermediates:-

Starting materials and intermediates are the chemical building blocks used to construct the final form of a drug substance molecule. Unreacted starting materials and intermediates can potentially survive the synthetic and purification process and appear in the final product as impurities. For example, in the synthesis of tipranavir drug substance, the “aniline” is the intermediate in the last step of the synthesis. Because the similarity between the structures of the “aniline” and the final product, it is difficult to totally eliminate it in the subsequent purification step. Consequently, it appears in the drug substance at around 0.1%.

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3.2. Impurities in the Starting Materials:-

Impurities present in the staring materials could follow the same reaction pathways as the starting material itself, and the reaction products could carry over to the final product as process impurities. Knowledge of the impurities in starting materials helps to identify related impurities in the final product, and to understand the formation mechanisms of these related process impurities. One such example is the presence of a 4-trifluoromethyl positional isomer in 3-trifluoromethyl-a-ethylbenzhydrol (flumecinol), due to the presence of 4-trifluoromethylbenzene impurity in the starting material, 3-trifluoromethylbenzene. An another example involves a 2-methyl analogue present as a trace impurity in tolperisone, due to the presence of 2-methylpropiophenone in the starting material, 4-methylpropiophenone.

3.3. Reagents, Ligands and Catalysts:-

These chemicals are less commonly found in APIs; however, in some cases they may pose a problem as impurities. Chemical reagents, ligands, and catalysts used in the synthesis of a drug substance can be carried over to the final products as trace level impurities. For example, carbonic acid chloromethyl tetrahydro-pyran-4-yl ester (CCMTHP), which is used as an alkylating agent in the synthesis of a ß- lactam drug substance, was observed in the final product as an impurity. Many chemical reactions are promoted by metal based catalysts. For instance, a Ziegler-Natta catalyst contains titanium, Grubb’s catalyst contains ruthenium, and Adam’s catalyst contains platinum. In some cases, reagents or catalysts may react with intermediates or final products to form by-products. Pyridine, a catalyst used in the course of synthesis of mazipredone, reacts with an intermediate to form a pyridinium impurity.

3.4. Crystallization-related impurities:-

Based on the realization that the nature of structure adopted by a given compound upon crystallization could exert a profound effect on the solid-state properties of that system, the pharmaceutical industry is required to take a strong interest in polymorphism and solvatomorphism as per the regulations laid down by the regulatory authorities.Polymorphism is the term used to indicate crystal system where substances can exist in different crystal packing arrangements, all of which have the same elemental composition. Whereas, when the substance exists in different crystal packing arrangements, with a different elemental composition; the phenomenon is known as Solvatomorphism.

3.5. Stereochemistry-related impurities:-

It is of paramount importance to look for stereochemistry related compounds; that is, those compounds that have similar chemical structure but different spatial orientation, these compounds can be considered as impurities in the API’s. Chiral molecules are frequently called enantiomers. The single enantiomeric form of chiral drug is now considered as an improved chemical entity that may offer a better pharmacological profile and an increased therapeutic

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index with a more favorable adverse reaction profile. However, the pharmacokinetic profile of levofloxacin (S-isomeric form) and ofloxacin (R-isomeric form) are comparable, suggesting the lack of advantages of single isomer in this regard. The prominent single isomer drugs, which are being marketed, include levofloxacin (S-ofloxacin), lavalbuterol (R-albuterol), and esomeprazole (S- omeprazole). 3.6. Synthetic intermediates and by-products:-

Impurities in pharmaceutical compounds or a new chemical entity (NCE) can originate during the synthetic process from raw materials, intermediates and/or by-products. For example, impurity profiling of tablets by GC-MS, and MDMA samples, produced impurities in intermediates via reductive amination route.

3.7. Formulation-related impurities:-

Many impurities in a drug product can originate from excipients used to formulate a drug substance. In addition, a drug substance is subjected to a variety of conditions in the process of formulation that can cause its degradation or have other undesirable reactions. If the source is from an excipient, variability from lot to lot may make a marginal product, unacceptable for reliability. Solutions and suspensions are inherently prone to degradation due to hydrolysis or solvolysis. Fluocinonide Topical Solution USP, 0.05%, in 60-mL bottles, was recalled in the United States because of degradation/impurities leading to sub- potency. In general, liquid dosage forms are susceptible to both degradation and microbiological contamination. In this regard, water content, pH of the solution/suspension, compatibility of anions and cations, mutual interactions of ingredients, and the primary container are critical factors.Microbiological growth resulting from the growth of bacteria, fungi, and yeast in a humid and warm environment may results in unsuitability of an oral liquid product for safe human consumption. Microbial contamination may occur during the shelf life and subsequent consumer-use of a multiple-dose product, either due to inappropriate use of certain preservatives in the preparations, or because of the semi-permeable nature of primary containers.

3.8. Impurities arising during storage:-

A number of impurities can originate during storage or shipment of drug products. It is essential to carry out stability studies to predict, evaluate, and ensure drug product safety.

3.9. Method related impurity:-

A known impurity, 1-(2, 6-dichlorophenyl) indolin-2-one is formed in the production of a parenteral dosage form of diclofenac sodium, when it is terminally sterilized by autoclave. The conditions of the autoclave method enforce the intramolecular cyclic reaction of diclofenac sodium forming an indolinone derivative and sodium hydroxide. The formation of this impurity has been found to depend on initial pH of the formulation.

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3.10. Functional group-related typical degradation

Ester hydrolysis can be explained with a few drugs viz. aspirin, benzocaine, cefotaxime, ethyl paraben, and cefpodoxime proxetil. Hydrolysis is the common phenomenon for ester type of drugs, especially in liquid dosage forms viz. benzylpenicillin, oxazepam and lincomycin. Oxidative degradation of drugs like hydrocortisone, methotrexate, hydroxyl group directly bonded to an aromatic ring (viz. phenol derivatives such as catecholamines and morphine), conjugated dienes (viz. vitamin A and unsaturated free fatty acids), heterocyclic aromatic rings, nitroso and nitrite derivatives, and aldehydes (especially flavorings) are all susceptible to oxidative degradation. In mazipredone, the hydrolytic and oxidative degredation pathway in 0.1 mol L-1 hydrochloric acid and sodium hydroxide at 800C were studied.Photolytic cleavage includes example of pharmaceutical products that are exposed to light while being manufactured as solid or solution, packaged, or when being stored in pharmacy shops or hospitals for use by consumers. Ergometrine, nifedipine, nitroprusside, riboflavin and phenothiazines are very liable to photo-oxidation. In susceptible compounds, photochemical energy creates free radical intermediates, which can perpetuate chain reactions. Most compounds will degrade as solutions when exposed to high-energy UV exposures. Fluroquinolone antibiotics are also found to be susceptible to photolytic cleavage.In ciprofloxacin eye drop preparation (0.3%), sunlight induces photocleavage reaction producing ethylene diamine analog of ciprofloxacin.Decarboxylation of some dissolved carboxylic acids, such as p-aminosalycylic acid; shows the loss of carbon dioxide from the carboxyl group when heated. An example of decarboxylation is the photoreaction of rufloxacin.As seen earlier, impurities in drug products can come from the drug or from excipients or can be brought into the system through an inprocess step by contact with the packaging material. For most drugs, the reactive species consist of;

• Small electrophiles- like aldehydes and carboxylic acid derivatives• Peroxides- that can oxidize some drugs• Metals- which can catalyze oxidation of drugs and the degradation pathway• Water- that can hydrolyze some drugs or affect the dosage form performance• Leachable or Extractable can come from glass, rubber stoppers, and plastic packaging materials. Metal oxides such as Nao2, Sio2, Cao, Mgo, are the major components leached/extracted from glass. Generally most synthetic materialscontain leachable oligomers/monomers, vulcanizing agents, accelerators, plasticizers, and antioxidants. Some examples of leachable/extractable from synthetic materials include styrene from polystyrene, diethylhexylphalate (DEHP, plasticizer in PVC), dioctyltin isooctyl mercapto acetate (stabilizer for PVC), zinc stearate (stabilizer in PVC and polypropylene), 2-mercaptobenzothiazole (accelerator in rubber stopper), and furfural from rayon.

3.11. Impurities on Aging:- a) Mutual interaction amongst ingredients:-Most vitamins are very labile and on aging they create a problem of instability in different dosage forms, especially in liquid dosage forms. Degradation of vitamins does not give toxic impurities; however, potency of active ingredients drops below Pharmacopoeial specifications.

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Because of mutual interaction, the presence of nicotinamide in a formulation containing four vitamins (nicotinamide, pyridoxine, riboflavin, and thiamine) can cause the degradation of thiamine to a sub-standard level within a one year shelf life of vitamin B-complex injections. The marketed samples of vitamin B-complex injections were found to have a pH range of 2.8 - 4.0. A custom-made formulation with simple distilled-water and a typical formulated vehicle including disodium edetate and benzyl alcohol were investigated, and similar mutual interactions causing degradation were observed.

b) Hydrolysis: - Well-known examples of such reactions in pharmaceutical compounds are esters and amides. Many drugs are derivatives of carboxylic acids or contain functional groups based on the moiety. For example, esters, amides, lactones, lactams, imides and carbamates, which are susceptible to acid base hydrolysis are aspirin, atropine, chloramphenicol, 12 barbiturates, chlordiazepoxide, oxazepam and lincomycin.

c) Oxidation: -Drugs which prone to oxidation are hydrocortisone, methotrexate, adinazolam, catecholamine, conjugated-dienes (Vitamin–A), heterocyclic aromatic rings, nitroso and nitrite derivatives. In pharmaceuticals, the most common form of oxidative decomposition is auto oxidation through a free radical chain process. For example, in auto-oxidation of ascorbic acid, cupric ion known to oxidize ascorbic acid rapidly to dehydroascorbic acid and potassium cyanide. As a result, there is a cleavage of chain due to the formation of copper complexes.In case of substituted 5-amino-ethyl-1, 3benzenediol sulfate (AEB) revealed that copper effectively catalyses AEB degradation down to 10 ppb level in presence of oxygen, leading to discoloration of product. The effectiveness of metals in terms of AEB degradation follows Cu2+ > Fe3+ > Ca2+.

d) Photolysis: - Photolytic cleavage on aging includes examples of pharmaceutical drugs or products that are prone to degradation on exposure to UV-light. During manufacturing process as solid or solution, packaging or on storage, drugs like ergometrine, nifedipine, nitropruside, riboflavin and phenothiazines are liable to 20-22 photo oxidations. This oxidation involves generation of free radical intermediate, which will degrade the products. For example, the formulation of ciprofloxacin eye drop 0.3% on exposure to UV light induces photolysis thereby resulting in the formation of ethylene 2,3 di-amine analogue of ciprofloxacin.

e) Decarboxylation: -Some of the carboxylic acids such as p-amino salicylic acid shown loss of carbon dioxide from carboxyl group when heated. For instance, photo reaction of rufloxacin tablet enteric coated with cellulose acetate phthalate (CAP) and sub-coating with calcium carbonate cause hydrolysis of CAP liberating acetic acid, which on reacting with calcium carbonate produced carbon dioxide, a side product that blew off the cap from the bottle after cap was loosened.

f) Packaging material: -Impurities result also from 25 packaging materials i.e., containers and closures. For most drugs the reactive species for impurities consists of; Water – hydrolysis of active ingredient.

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Small electrophiles – Aldehydes and carboxylic acid derivatives. Peroxides – oxidize some drugs.Metals – catalyze oxidation of drugs and their degradation pathway.Extractable or leachables – Emerge from glass, rubber stoppers and plastic materials, in which oxides like No2, Sio Cao, Mgo are major components leached, or extracted from glass.

Some examples of synthetic materials include styrene from polystyrene, diethylhexylpthalate (DEHP) plasticizer in PVC, dioctyltin iso octyl mercaptoacetate stabilizer for PVC, zinc stearate stabilizer in PVC and polypropylene.

REFERENCE:-

1. Basak, A.K., et al., 2007. Pharmaceutical impurities: regulatory perspective for Abbreviated New Drug Applications. Adv Drug Deliv Rev. 59(1), 64-72.

2. Roy, J., et al. 2002. Pharmaceutical impurities. AAPS PharmSciTech. 3(2),12-18.

3. Pan, C., Liu, F., Motto, M., 2010. Identification of pharmaceutical impurities in formulated dosage forms. J Pharm Sci. 20(1), 14-17.

4. Ahuja S., 1998. Impurities Evaluation of Pharmaceuticals. Marcel Dekker, New York, NY . 2-8.

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http://www.ncbi.nlm.nih.gov/pubmed?term=%22Motto%20M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Liu%20F%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pan%20C%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Basak%20AK%22%5BAuthor%5D

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Classification of Impurities