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*Abhijit Chanda1, N.Ramalakshmi2, C.N Nalini2, S. Mahabubi1
1Department of Quality Assurance, Baxter (India) Pvt. Ltd
2Dept. of Pharmaceutical Analysis, C. L. Baid Metha College of Pharmacy
Chennai-600097, Tamilnadu, India

Impurity profiling brings tremendous efforts in the group of analytical activities, the aim of which is the detection, identification/structure elucidation and quantitative determination of organic and inorganic impurities, as well as residual solvents in bulk drugs and pharmaceutical formulations. The control of impurities is currently a critical issue to the healthcare manufacturing. Various regulatory authorities like ICH, USFDA, UK-MHRA, CDSCO are emphasizing on the requirements and the identification of impurities in Active Pharmaceutical Ingredient’s (API’s) and as well as finished products. International Conference on Harmonization (ICH) formulated guidelines concerning the control and limit of impurities. To isolate and characterize impurities in pharmaceuticals diverse methods are used such as, capillary electrophoresis, gas–liquid chromatography, high performance liquid chromatography, solid-phase extraction methods, Ultraviolet Spectrometry, infrared spectroscopy, supercritical fluid extraction chromatography, mass spectroscopy, Nuclear magnetic resonance (NMR) spectroscopy etc. On the beginning of hyphenated techniques, the most browbeaten techniques for impurity profiling are Liquid Chromatography (LC)-Mass Spectroscopy (MS), LCNMR, LC-NMR-MS, GC-MS and fully automated Comprehensive Orthogonal Method Evaluation Technology (COMET). That is why it has plentiful claim in the field of drug design, monitoring quality, stability and as well as safety of the product.


PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 3, Issue 11

Received On: 22/07/2015; Accepted On: 02/08/2015; Published On: 01/11/2015

How to cite this article: A Chanda, N Ramalakshmi, CN Nalini, S Mahabubi; Impurity profiling an emerging trend in Pharmaceuticals: A Review; PharmaTutor; 2015; 3(11); 29-35

Over the last few decades there was much interest was compensated towards the quality of pharmaceuticals that enter into the market. The source of active pharmaceutical ingredient (APIs) of specific quality of the bulk drug industry which forms the base of all formulation based pharmaceuticals. So it is obligatory to carry outdynamic quality control checks in order to uphold the quality and purity of output from each industry. Impurity of pharmaceuticals may produce at any stage; it may occurduring synthesis, storage, due to side reaction, degradation, changes of any physiochemical property upon storage. So stability study of pharmaceutical also play key role in the field of impurity profiling.Impurities present more than 0.1% should be identified and quantified by selective methods.

Hence it is essential to know the structure of these impurities in the bulk drug in order to modify the reaction condition and to bring the quantity of impurity to an standard level[1,2] . Isolation, identification and quantification of impurities help us in various ways, to obtain a pure substance with less toxicity and, safety in drug therapy. Quantitative determination of these impurities could be used as a method for the quality control and validation of drug substances. Regulatory authorities and board such asICH (International Conference on Harmonization), USFDA (United sates Foods and Drug Administration), UK-MHRA (UK Medicines and Healthcare Products), Indian CDSCO (Central Drugs Standard Control Organization) Australian TGA (Therapeutic Goods Administration) firm on the impurity profiling of drugs. So it is very important to do qualification of impurities present in pharmaceuticals. Impurities in new drug substances are addressed from two perspectives:

Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and

Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies

Terminology for Impurity
Impurities have been named differently by a choice of scientists who deals with them. Terms that are used by official bodies such as compendia or that have been found acceptable by ICH and various regulatory bodies.

Impurity is defined by ICH as any component of the new drug substance which is not the chemical entity defined as the new drug substance or any component of the drug product which is not the chemical entity defined as the drug substance or an excipient in the drug product.”

Impurity Profiling is a group of analyticalactivities for detection, isolation identification/structure elucidation, Quantitative determination of organic and inorganic impurities and residual solvents in bulk drugs &pharmaceutical formulations.

Impurities can be classified into the following categories:[2]
- Organic Impurities (process and drug related).
- Inorganic impurities.
- Residual solvents.

Organic impurities
It can arise during the manufacturing process and/or storage of the new drug substance. This organic impurities can be identified or unidentified, volatile or nonvolatile and also include -
- Starting materials
- By-products
- Intermediates
- Degradation products
- Reagents, ligands and catalysts

Inorganic Impurities
Inorganic impurities are usually detected and quantified using Pharmacopeial or other appropriate principles. Carryover of catalysts to the drug substance should be evaluated throughout development. Thesekinds of impurities can result from the manufacturing progression. Theseare normally known and identified and include -
- Reagents, ligands and catalysts
- Heavy metals or other residual metals
- Inorganic salts.
- Other materials (e.g., filter aids, charcoal)

Residual Solvents
Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. The control of residual solvents used in the manufacturing process for the drug substance should be discussed. Acceptance criteria must be based onPharmacopeial standards, or ICH (Q3C) guidelines or known safety data, depends on the dose, duration of treatment, and route of administration.[3] Depending on the possible risk to human health, residual solvents are divided into three classes.

Table No. 1: Classification of residual solvents


Risk assessment


Class I

Solvents to be avoided

Benzene (2ppm), Carbon tetrachloride (4ppm), Methylene chloride (600ppm), Methanol (3000ppm), Pyridine (200ppm), Toluene(890ppm)

Class II

Solvents to be limited

N, N- dimethyl formamide (880ppm), acetonitrile (410ppm)

Class III

solvents with low toxic potential

Acetic acid, Ethanol, Acetone has permitted daily exposure of ≤50mg/day.

Limits for impurities:
According to the ICH guidelines on impurities in new drug products, identification of impurities below 0.1% level is not measured to be necessary, unless otherwise potential impurities are expected to be unusually potent ortoxic.[3] According to the ICH, the maximum daily dose qualification threshold to be considered is as follows;

Table No. 2: Drug substance impurities thresholds

Maximum Daily Dosea



Identification Thresholdc

Qualification Threshold

≤2 gm/day


0.1% or 1.0mg /day intake(whichever is lower )

0.15% or1.0mg/day intake whichever is lower

>2 gm/day




a. The amount of drug substance administered per day.
b. Higher reporting thresholds shall be scientifically justified.
c. Lower thresholds can be appropriate if the impurity is unusually toxic.

From the earlier discussion, it is clear that impurities can originate from several sources; such as;
· Crystallization-related impurities
· Stereochemistry-related impurities
· Impurities arising during storag
· Method related impurity
· Residual solvents
· Synthetic intermediates and by-products
· Functional group-related typical degradation
· Mutual interaction amongst ingredients

Crystallization-related impurities
As per the regulations laid down by the regulatory authorities, a pharmaceutical industry has to take strong enough interest on crystallization related impurities. The nature of structure adopted by a given compound upon crystallization can exert a profound effect on the solid - state properties of that system. Polymorphism of a substance exist in more than one crystalline form whereas, when the substance different crystal packing arrangements with a different elemental composition; the phenomenon is known as Solvatomorphism.

Stereochemistry-related impurities
It is of supreme importance to look for stereochemistry related compounds, that is those compound have similar chemical structure but different spatial orientation; these compound can be considered as impurities. Chiral molecules are frequently called as impurities. The single enantiomeric form of chiral drug may have better pharmacological action and broad therapeutic index.Single isomeric form of drug that are marketed include esomeprazole (S - omeprazole), levabuterol (R- albuterol) etc. The undesired chiral forms of drug are considered as impurity.

Impurities arising during storage
Upon storage or shipment number of impurities can generate in drug products. So it is must and soul to carry out stability studies to predict, evaluate, isolate and ensure the drug product safety. The degradation of penicillin and cephalosporin is well known example of degradation of drug products.

Method related impurity
Sometime a drug produce impurity based upon the formulation of the particular drug product, a well known example is formation of 1-(2, 6-dichlorophenyl) indolin-2-one in the diclofenac sodium ampoules when autoclave under 123±2ºC, that enforce the intramolecular cyclic reaction of diclofenac sodium forming indolinone derivative and sodium hydroxide. Here the formation of this impurity has been found to depend on initial pH of the formulation.

Residual solvents
Residual solvents are organic volatile chemicals used during the manufacturing process or may generate during production. Residual solvents are potentially detrimental substances. They may also affect physicochemical properties of the bulk drug substances such as crystalline of bulk drug, which in turn may affect the dissolution properties, odour and colour changes in finished products. The details of residual solvents as per ICH guideline mentioned above.

Synthetic intermediates and by-products
Impurities in pharmaceuticals or a new chemical entity (NCE) can originate during the synthetic process from raw materials, intermediates and/or by –products. Sometime solvents used for synthesis also contain impurities than traces level. Solvents used in synthesis may produce unwanted impurity and can react with number of chemicals used in the synthesis to produce impurities. By-products from the side reactions are among the most common process impurities in drugs. By-products can be formed through a variety of side reactions, such as incomplete reaction, overreaction, isomerisation, dimerization, and rearrangement, unwanted reactions between starting materials or intermediates with chemical reagents or catalysts.



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