Detection of impurities in acetaminophen intravenous and oral formulations: Health-risk assessment

Introduction

Active pharmaceutical ingredients (API) are produced by chemical synthesis. Residual solvents and trace amounts of inorganic and organic compounds are typically present; they remain in the final product and are known as impurities. Impurities are defined by the International Conference of Harmonization (ICH) as “Any component of the drug product that is not the chemical entity defined as the drug substance or an excipient in the drug product” [1]. The ICH Q3A(R2) “Impurities in new Drug Substances” guidance classifies impurities into three main categories: organic impurities, inorganic impurities, and residual solvents. Regulatory authorities around the globe are emphasizing on the importance of identifying impurities and controlling their presence in APIs as well as in formulations.

Impurities have chemical structures that are, to some degree, like the API. They can have undesirable side effects that can, in some cases, outweigh the benefits of the drug [2]. The presence of pharmaceutical impurities in the final product can affect the safety and stability of the drug [3]. Thus, the development of analytical techniques for the detection of these impurities in pharmaceuticals is of great significance. Both qualitative and quantitative profiling of impurities has taken the attention of regulatory authorities around the world.

Acetaminophen, also known as paracetamol, is a commonly used drug for its analgesic and antipyretic properties. Acetaminophen was first made in 1877; it is the most used medication for pain and fever in both the United States and Europe. The use of acetaminophen became even more significant with corona virus pandemic, as it is the analgesic and antipyretic of choice in the treatment of infected patients.

A total of 14 impurities in acetaminophen products were identified by the European pharmacopeias. These impurities are labeled by letters, impurity A to N, however, not all of them have a well identified chemical structure and chemical name [4]. Organic impurities that may appear in acetaminophen preparations are process-related impurities. The characteristics are determined by the synthesis method, material and reagent quality, reaction conditions, work-up, purification, and equipment design [5].

Variability in the amount of trace impurities in acetaminophen products leads to batch-to-batch variability in product characteristics (including surface characteristics, crystallite size, aggregate size, surface roughness, wettability, dissolution, drug release, granulation …) which can significantly influence the processability and therefore the quality of the final product [6]. Organic impurities also have potential to influence the intrinsic physical properties (Keshavarz et al., 2019).

Several analytical techniques have been employed to detect acetaminophen impurities in acetaminophen active ingredient, acetaminophen formulation as well as when acetaminophen is present in combination with other APIs. Recent studies have also identified potential separation techniques between acetaminophen and its highly similar impurities. Typically, intravenous acetaminophen formulations are analyzed using LC-MS techniques for their impurity profiling. To the best of our knowledge, static headspace GC–MS has been seldom reported and limited to the analysis of paracetamol tablets.

This study was designed to detect organic volatile impurities in different acetaminophen formulations on the market. The study also aimed at developing and optimizing a headspace gas chromatography method for the detection of acetaminophen impurities that are organic and volatile.

Read more here

Yolande Saab, Rita Rahme, Zahi Nakad, Rony S. Khnayzer, Detection of impurities in acetaminophen intravenous and oral formulations: Health-risk assessment, Microchemical Journal, 2024, 112019, ISSN 0026-265X, https://doi.org/10.1016/j.microc.2024.112019.

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