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*Ramchandra Gupta2, Prabhakar Sharma2, Prakash Pandey2, Pratik Jain1, Ajay Shukla3
1Department of Pharmacognosy,
2Department of Pharmaceutics,
3Department of Pharmaceutical Chemistry

1,2,3Guru Ramdas Khalsa Institute of Science and Technology (Pharmacy) Jabalpur, 483001, M.P.

In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s. Pharmaceuticals impurities are the unwanted chemicals that remain or are generated during the formulation of medicines. The presence and quantity of impurities in pharmaceutical drugs can have a significant impact on their quality and safety, with the continuous pressure for increased industry productivity, there is urgent need for a systematic and comprehensive drug impurity profiling strategy. The impurities present in the drug are adversely affecting the quality of the drug product. There are various types of impurities like starting materials, intermediates, penultimate impurity, by product and degradation product. Impurity profiling helps in detection, identification and quantification of various types of impurities as well as residual solvents in bulk drugs and in pharmaceutical formulations. It is a best way to characterize quality and stability of bulk drugs and pharmaceutical formulations. This review paper deals with the impurity profile of pharmaceuticals.



Impurity is something that impure or makes something else impure. An impure substance may be defined as a substance of interest mixed or impregnated with an extraneous or usually inferior substance[1-3]. During the production of active pharmaceutical ingredients (API), many opportunities for the generation of impurities may arise[4]. Dictionary meaning of impurity is something that is impure or makes another thing impure. So, impurity in short way can be defined as, any material that affects the purity of the material of interest, i.e. an active pharmaceutical ingredient (API) or drug substance, it can also be defined as ‘any substance coexisting with the original drug substance, such as starting material or intermediates from reaction or that is formed, due to any chemical interaction or by products from side reaction’[5]. The safety of the drug depends not only on the toxicological properties of the API itself, but on the impurities it contains. For this reason, accurate assessment of impurity profiles of API is one of the most important fields of activity in pharmaceutical analysis. In the meanwhile, any changes in the synthetic process, such as synthetic routes, reaction conditions, purification processes, etc. which are common as a drug candidate goes through various development stages and process scale up, may lead to changes in the impurity profile and in questions about safety. Hence, the impurity profiling becomes a frequent task, which often time-consuming and labor-intensive[6].

Impurity profiling is a group of analytical activities, with the aim of detection, identification/structure elucidation and quantitative determination of organic and inorganic impurities, as well as residual solvents in bulk drugs and pharmaceutical formulations. Various regulatory authorities like ICH, USFDA, Canadian Drug and Health Agency are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredient’s (API’s)[7]. The description, characterization and quantization of the identified and unidentified impurities present in new drug substances are known as impurity profile[8]. It gives an account of impurities present in the bulk and finished drug. It helps in identifying and quantifying the impurities present in drug substance (API) or pharmaceutical formulation. It gives maximum possible types of impurities present in drug substance (API) and in pharmaceutical formulations[9].


Pharmaceuticals can be divided in to two major areas active pharmaceutical ingredients (APIs) which is also referred as drug substance (DS) and drug product (DP) which is also called as finished pharmaceutical product (FPP). The Impurities of pharmaceuticals are classified on the basis of pharmacopeia and ICH guidelines[10].

A. Common names

  • By-products
  • Degradation products
  • Interaction products
  • Intermediates
  • Penultimate intermediates
  • Related products
  • Transformation products

B. United State Pharmacopeia
The United States Pharmacopoeia (USP) classifies impurities in various sections;

  • Impurities in Official Articles
  • Ordinary Impurities
  • Organic Volatile Impurities

C. ICH Terminology
According 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

There are various sources of impurities in any pharmaceutical drug and dosage form from the beginning of product to its finishing. There are 2 types of impurities in medicines: (1) Impurities associated in with active pharmaceutical ingredients and (2) Impurities that form are created during formulation and or with aging or that are related to the formulated forms[11]. In general, the various types of impurities that may be present in pharmaceutical substances can come from the following sources:
1. The raw materials used.
2. The method of manufacture adopted.
3. Due to the instability of product and
4. from the atmospheric contaminants[12].



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It is very important to authenticate sample for estimations, when it is available. If the estimations indicate that a given impurity content is greater than 0.1% then it must be characterized as per the FDA requirements. Hyphenated methods such as gas chromatography, mass spectroscopy, or liquid chromatography, mass spectrometry or the number of other chromatographic-spectroscopic configuration are perfectly suitable for initial characterization of the impurities.
A. Spectroscopic Techniques.
B. Chromatographic Techniques.
C. Hyphenated techniques

Highly sophisticated instrumentation, such as MS attached to a GC (Gas Chromatography) or HPLC (High Performance Liquid Chromatography), are inevitable tools in the identification of minor components (drugs, impurities, degradation products, metabolites) in various matrices. Identification  and characterization of drug metabolites in biological fluids (biological analysis) by various hyphenated techniques like LC-MS,GC-MS etc which are as follows;

(1) N.M.R. The ability of NMR (Nuclear Magnetic Resonance) to provide information regarding the specific bonding structure and stereochemistry of molecules of pharmaceutical interest has made it a powerful analytical instrument for structural elucidation. The ability of NMR- based diffusion coefficient determination to distinguish between nonnumeric and dimeric substances was validated using a standard mixture of authentic materials containing both monomers and dimmers. Unfortunately, NMR has traditionally been used as a less sensitive method compared to other analytical techniques. Conventional sample requirements for NMR are on the order of 10 mg, as compared with MS, which requires less than 1 mg.

(2) M.S.(Mass spectroscopy) has an increasingly significant impact on the pharmaceutical development process over the past several decades. Advances in the design and efficiency of the interfaces, that directly connect separation techniques with Mass Spectrometers have afforded new opportunities for monitoring, characterizing, and quantification of drug related substances in active pharmaceutical ingredients and pharmaceutical formulations. If single method fails to provide the necessary selectivity, orthogonal coupling of chromatographic techniques such as HPLC-TLC and HPLC-CE (High Performance Liquid chromatography coupled with Capillary Electrophoresis), or coupling of chromatographic separations with information rich spectroscopic

Methods such as HPLC-MS or HPLC-NMR may need to be contemplated, but hopefully only as a developmenttool rather than a tool for routine QC (Quality control) use[13-25].

Various applications have been sought in the areas of drug designing and in monitoring quality, stability, and safety of pharmaceutical compounds, where they have produced synthetically, extracted from natural products or produced by recombinant methods. The applications of alkaloids, amines, amino acids, analgesics, antibacterial, anticonvulsants, antidepressant, include tranquilizers, antineoplastic agents, local anesthetics, macromolecules, steroids, miscellaneous[26].In development of Bioanalytical method ,which is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them.

Qualificationof impurities is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing impurity acceptance criteria that includes safety considerations [20].

The studies considered appropriate to qualify the impurity will depend on a number of factors, Including the patient population, daily dose, route, and duration of drug administration. The following are descriptions of methods for qualifying impurities

An impurity of drug substance covered by an ANDA (Abbreviated New Drug Application) can be qualified by comparing the analytical profiles of the drug substance with those in an approved human drug product using the same validated, stability-indicating analytical procedure (e.g. comparative HPLC studies). This approved human drug product is generally the reference-listed drug (RLD). However, the impurity profile of a different drug product, having the same drug substance, with the same route of administration and similar characteristics (e.g., tablet versus capsule) may also be used if samples of the reference listed drug are unavailable, or in the case of an ANDA submitted pursuant to a suitability petition.

The level of the identified specified impurity is adequately justified by the survey of scientific literature, no further qualification is considered necessary. An impurity which is also a significant Metabolite of the drug substance is generally considered qualified.

Toxicity studies are the least preferred method to qualify impurities. The study is used only when impurities cannot be qualified by either of the above procedures. The toxicity tests are designed to detect compounds that induce general toxic or genotoxic effects in experimental systems. If performed, such studies should be conducted on the drug product or drug substance containing the impurities to be controlled, although in toxicity studies using isolated impurities may also be used [23]

In this article, we reviewed various articles which based on several areas including sample preparation, impurity separation and detection, Impurity profiling is very important during the synthesis of drug substances and manufacture of dosage forms, as it can provide several data regarding the toxicity, safety, various limits of detection, and limits of quantitation, of various organic and inorganic impurities, usually accompany with bulk drugs and finished products. An accurate method development and validation of the procedures make the impurity profiling task easy. In this we also propose pathway for determination of impurities and acceptance criteria based on general principles of ICH guidelines. Impurity Guideline for new drug substance is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. These are types of drug substances .Which are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived from, herbal products, and crude products of animal or plant origin.

The authors are very thankful to analytical department of Guru Ramdas Khalsa Institute of Science and Technology Pharmacy Jabalpur, for providing necessary facilities and help to make this review article.

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