Impurity quantification in pharmaceutical dosage forms

Identification and quantification of impurities in drug compounds is a crucial task in pharmaceutical process development for quality and safety. Related components are the impurities in pharmaceuticals which are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during stability testing, or develop during formulation or upon aging of both API and formulated APIs in medicines.

The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products. Various analytical methodologies are employed for the determination of related components in pharmaceuticals.

An impurity as defined by the ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines is “any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient in the product”. Analytical methods for impurities estimation should be stability indicating to monitor the stability of pharmaceutical dosage forms during the investigational phase of drug development, and once the drug is marketed, the ongoing stability studies must be conducted/ performed. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, enables to establish a retest period/shelf life for a drug substance and a recommended storage condition. Methods can be developed which measure the amount of drug remaining, the amount of drug lost (or the appearance of degradation products), or both.

Sources of impurities 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. 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. According to the ICH impurities are classified as organic impurities, inorganic impurities and residual solvents.

Organic impurities may arise from starting materials, by products, synthetic intermediates and degradation products. 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 are the impurities introduced with solvents. Of 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 pharmacopoeias 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 threshold limit above which the identification of the impurity is obligatory

Sources of organic impurities

Organic impurities may arise during the manufacturing process and/or storage of the drug substance. These impurities are derived from drug substance synthetic processes and degradation reactions in drug substances and drug products. The process (synthetic process) related impurities can be derived from starting materials, intermediates, reagents, ligands, and catalysts used in the chemical synthesis, as well as by-products from the side-reactions or over reactions of the chemical synthesis. Degradation products are derived from the chemical degradation of drug substances and drug products under storage or stress conditions. They may be identified or unidentified, volatile or non-volatile.

Sources of Impurities:

A] Common names
 By-products
 Degradation products
 Interaction products
 Intermediates
 Penultimate intermediates
 Related products
 Transformation products
B] United State Pharmacopeia (USP)
 Impurities in Official Articles
 Ordinary Impurities
 Organic Volatile Impurities
C] ICH Terminology
Organic Impurities (Process and Drug related)

  • Starting materials
  • Intermediates
  • By-products
  • Degradation products
  •  Oxidative degradation
     Decarboxylation
     Hydrolysis
     Photolytic cleavage
     Inorganic Impurities

  • Enantiomeric impurities
  • Reagents, ligands and catalysts
  • Heavy metals or other residual metals
  • Inorganic salts
  • Other materials (e.g., filter aids, charcoal)
  •  Residual Solvents

  • Class I solvents
  • Class II solvents
  • Class III Solvents
  •  Formulation-related Impurities

  • Method related (In-process production)
  •  Crystallization related
     Stereochemistry related
     Leachables / Extractables

  • Environmental related
  •  Exposures to adverse temperatures
     Light-especially UV light
     Humidity
     Handling & Storage

  • Dosage form related
  •  Mutual interaction amongst ingredients
     Functional group- related typical degradation

  • Ester hydrolysis
  • Hydrolysis
  • Oxidative degradation
  • Photolytic cleavage
  • Decarboxylation
  •  Metabolite Impurities