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Sweety Sharma*, Amardeep Ankalgi, Chandra Shekhar Sharma, Hemendra Pratap Singh, Priyadarshani Kamble, Mahendra Singh Ranawat.
Deptt. Of Pharmaceutical Chemistry, B.N.College of Pharmacy,
Udaipur-313002, Rajasthan, India.

Impurity is defined as any substance coexisting with the original drug, such as starting material or intermediates or that is formed, due to any side reactions. According to the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) guideline on impurities in new drug substances, an impurity is defined as 'any component of the new drug substance that is not the chemical entity defined as the new drug substance’.Identification of impurities is done by variety of Chromatographic and Spectroscopic techniques, either alone or in combination with other techniques. There are different methods for detecting and characterizing impurities with TLC, HPLC, and HPTLC etc.  The most exploited techniques, for impurity profiling of drugs are LC-MS-MS, LC-NMR, LCNMR- MS, GC-MS, and LC-MS.


Group of analytical activity, the aim of which is the detection, identification, or structure elucidation & quantitative determination of organic & inorganic impurities, as well as residual solvents in bulk drug & formulation [1]. A description of the identified and unidentified impurities present in a new drug substance[2]. Drug impurity profiling, i.e. identification, structure elucidation and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations[3]. Pharmaceuticals impurities are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or are developed during formulation or upon aging of both API and formulated APIs to medicines [6]. According to the International Conference on Harmonization of Technical Requirements for  the Registration of Pharmaceuticals for Human Use (ICH) guideline on impurities in new drug substances,[1] an impurity is defined as 'any component of the new drug substance that is not the chemical entity defined as the new drug substance'.[4]

It provides useful information for drug low enforcement authorities. The practical value of this studies for routine analysis is low enforcement investigate work in four different areas as following-
1) Establishing specific links between two or more samples.
2) Establishing drug distribution patterns.
3) Identifying the source of drug sample.
4) Monitoring methods used for drug manufacturing.

Depending on the nature of the drug sample investigated, the information generated by this method may be used to identify from where, how & to what extent the drug has been distributed. Enables measurement of the relative concentration of major, minor & trace elements. By such an approach, a characteristic chemical signature can be assigned to every drug sample.

3. ACCEPTANCE CRITERIA [8,9, 10, 11]
The new drug substance specification should include, where applicable, the following list of impurities:
? Each specified identified impurity;
? each specified unidentified impurity;
? Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold;
? total impurities.

Maximum Daily Dose1

Reporting Threshold2,3

Identification Threshold3

Qualification Threshold3

≤ 2g/day


0.10% or 1.0 mg per day intake (whichever is lower)

0.15% or 1.0 mg per day intake (whichever is lower)

> 2g/day





4.1 ACCORDING TO USP [8, 14]
The United States Pharmacopoeia (USP) classifies impurities in various sections (A) Impurities in Official Articles (B) Ordinary Impurities. This found in bulk pharmaceutical chemicals that are innocuous by virtue of having no significance on biological activity of the drug substance. These impurities may arise out of the synthesis, preparation or degradation of chemical.And (C) Organic Volatile Impurities-Organic volatile chemicals are produced in the Manufacture of drug substances or excipients or the preparation of drug products; they are volatile in nature and by themselves get removed out at time of storage or processing.

The new drug substance specifications should include, limits for-
i) Organic Impurities
- 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

iii) Inorganic impurities


4.3.1 Organic impurities
They are the most common impurities found in every API unless proper care is taken throughout the multistep synthesis. Although the end products are always washed with solvents, there is always a chance that the residual unreacted starting material remain, unless the manufactures are very careful about the impurities.

It can be any of following.
a. Starting Material-Example: In PCM Bulk, there is a limit test for p-aminophenol, which could be starting material or intermediate for synthesis.
b. By product-Example: In the case of paracetamol bulk, diacetylated+ paracetamol may be formed as a by product.
c. Intermediates
d. reagents

The spectroscopic studies (NMR, IR, MS etc. ) conducted to characterize the structure of actual impurities present in the drug substance above an apparent level of 0.1% (e.g., calculated using the response factor of the drug substance) should be described. All recurring impurities above an apparent level of 0.1% in batches manufactured by the proposed commercial process should be identified of these studies.

4.3.2 Inorganic impurities
They may also derive from the manufacturing processes used for bulk drugs. They are normally known & identified & include the Reagents, Ligands, Catalysts, Heavy Metals, Filter aids, Charcoals etc. Inorganic impurities are normally detected and quantified using Pharmacopeial or other appropriate standards. Carryover of catalysts to the drug substance should be evaluated during development.

4.3.3 Residual solvents
Residual solvents are organic volatile chemicals used during the manufacturing processes or generated during the production. Some solvents that are known to cause toxicity should be avoided in the production of the drugs.

Depending on the possible risk to humans, residual solvents are divided into 3 classes,
Class 1: Human carcinogens.
Class 2: Non genotoxic.
Class 3: Lower risk to human health.

4.3.4 Genotoxic impurities
These are the impurities that damage DNA by mutation of genatic code. Example: Alkylation


5.1 Crystallization
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.

5.2  Stereochemistry
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 index with a more favorable adverse reaction profile.

5.3  Synthetic Intermediates & By Product
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 ecstasy tablets by GC-MS, and MDMA samples, produced impurities in intermediates via reductive amination route.

5.4  Residual Solvents
Residual solvents are organic volatile chemicals used during the manufacturing process or generated during the production as vehicle, dissolution media or for granulation. Some solvents that are known to cause toxicity should be avoided in the production of bulk drugs. 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.

5.5  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.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. 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.

5.6  Impurities 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.

5.7  Method Related Impurities
Due to deviation in pH and column temperature. Example: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.

5.8  Environmental
Effect of humidity, temperature, light.



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