Impurities defined as a foreign particle that affects the purity of a substance. Usually, impurities occurring in many pharmaceutical or medicinal preparations may be of the different types.
A Foreign particle that brings about adverse or toxic reactions when present in excess beyond their limits. Example: lead, heavy metals, arsenic, etc.
Impurities which may not cause toxic effects but bring about deterioration of the activity of chemical. Example: hard soap containing an excess of water.
Impurities that cause incompatibility of the active ingredient with other substances or which reduce the properties of the active ingredient.
Types of Impurities in pharmaceutical drug substances:
According to the ICH, guideline impurities are classified as organic impurities, inorganic impurities, and residual solvents.
Organic impurities – The impurities due to Starting materials, By-products, Intermediates, Degradation products, Reagents, ligands, and catalysts.
Inorganic impurities – Inorganic impurities may be derived from the manufacturing process and are normally known and identified as reagents, ligands, inorganic salts, heavy metals, catalysts, filter aids, and charcoal, etc.
Residual solvents – Residual solvents are the impurities introduced with solvents i.e. Class 1- Solvents To Be Avoided, Class 2 – Solvents To Be Limited, Class 3 – Solvents with Low Toxic Potential.
Basically Veeprho laboratories Pvt Ltd involves in synthesis of organic impurities i.e. The impurities due to Starting materials, By-products, Intermediates, Degradation products, Reagents, ligands, and catalysts.
Impurity sources in pharmaceutical substances.
The origin of impurities in drugs is from various sources and phases of the synthetic process and preparation of pharmaceutical dosage forms. The majority of the impurities are characteristics of the synthetic route of the manufacturing process. There are several possibilities of synthesizing a drug; it is possible that the same product of different sources may give rise to different impurities.
The above three types, the number of inorganic impurities and residual solvents are limited. These are easily identified and their physiological effects and toxicity are well known. For this reason, the limits set by the pharmacopeias and the ICH guidelines can guarantee that the harmful effects of these impurities do not contribute to the toxicity or the side effects of the drug substances. The situation is different with the organic impurities. Drugs prepared by multi-step synthesis results in various impurities, their number and the variety of their structures are almost unlimited and highly dependent on the route and reaction conditions of the synthesis and several other factors such as the purity of the starting material, method of isolation, purification, conditions of storage, etc. In addition, toxicity is unknown or not easily predictable. For this reason, the ICH guidelines set a threshold limit above which the identification of the impurity is obligatory
Impurities in Starting materials and intermediates: Starting materials and intermediates are the chemical building blocks used to construct the final form of a drug substance. Unreacted starting materials and intermediates, particularly those involved in the last steps of the synthesis, can potentially survive the synthetic and purification process and appear in the final product as impurities. For example, in the synthesis of the tipranavir drug substance, aniline is the intermediate in the last step of the synthesis. Due to the similarity between the structures of 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%.
By-products of the synthesis: All chemical reactions are not 100% selective; the side-reactions are common during the synthesis of drug substances. 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, isomerization, dimerization, rearrangement, or unwanted reactions of starting materials or intermediates with chemical reagents or catalysts.
Products of over-reaction: In many cases, the previous steps of the syntheses are not selective enough and the reagents attack the intermediate not only at the desired site. For e.g. in the synthesis of nandrolone decanoate, the last step of the synthesis is the decannulation of the 17-OH group. In the course of overreaction the reagents also attack the 4-ene- 3 oxo group leading to an enol ester-type impurity (3, 17β- dihydroxyestra-3, 5- diene disdecanoate).
Products of side reactions: Some of the frequently occurring side reactions (which are unavoidable in drug synthesis) are well- known to the synthetic chemist; others which lead to trace level impurities have to be detected and elucidated during impurity profiling. The formation of diketopiperazine derivative is a typical side reaction in peptide synthesis.
Impurities originating from degradation of the drug substance: Impurities can also be formed by degradation of the end product during the manufacturing of bulk drugs. Degradation products resulting from storage or formulation of different dosage forms or aging are common impurities in the medicines. The definition of degradation product in the ICH guidelines is a molecule resulting from a chemical change in the substance brought about by overtime or due to the action of light, temperature, pH, or water or by reaction with excipient and/or the intermediate container closure system.
Enantiomeric impurities: The majority of therapeutic chiral drugs used as pure enantiomers are natural products. The high level of enantioselectivity of their biosynthesis excludes the possibility of the presence of enantiomeric impurities. In the case of synthetic chiral drugs, the racemates which are usually marketed, if the pure enantiomer is administered, the antipode is considered to be an impurity. The reason for its presence can be either the incomplete enantioselectivity of the syntheses or incomplete resolution of the enantiomers of the racemate. Although the ICH guidelines exclude enantiomeric impurities, pharmacopeias consider them as ordinary impurities. A single enantiomeric form of the 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 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), levalbuterol (R-albuterol), and esomeprazole (Esomeprazole).
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.