Resins as Scavengers to Control the Metal Impurities in Active Pharmaceutical Ingredients (APIs)

Metals, such as transition metals and heavy metals, can be present as impurities in APIs due to various reasons, including raw material contamination, catalyst residues from synthesis processes, or interaction with equipment during manufacturing. These metal impurities can be harmful and have potential toxicological effects on human health. The use of resins for the reduction of metals in active pharmaceutical ingredients (APIs) is an important aspect of pharmaceutical manufacturing to ensure the purity, quality, and safety of pharmaceutical products. By effectively removing metal impurities, resins play a crucial role in meeting regulatory requirements and ensuring patient well-being. Further research and development in resin technology and process optimization are necessary to advance metal reduction methods in pharmaceutical manufacturing. Number of cost-effective and scalable methods have been developed to remove the metal impurities [4-11]. Merck group and Astra Zeneca developed carbon or silica gel adsorbents to remove these metal impurities [12,13]. Astra Zeneca successfully demonstrated this application on polit scale [13]. Resins functionalized with chelating ligands, such as iminodiacetic acid (IDA) or iminodiacetate (IDA) resin, are commonly employed for metal reduction [14]. These resins possess high affinity for metal ions due to their specific coordination chemistry. Metal ions bind to the resin’s chelating groups, allowing for their selective removal from the API solution. The resin’s capacity, selectivity, and compatibility with the API solution are critical considerations during resin selection (Figure 1). Some of the examples of resins were provided in the below Table 1.

Figure 1:General mechanism for chelation of metal to scavenger.

Table 1:Some examples of metal scavengers/ resins used in production of APIs.

The process involves passing the API solution through a resinpacked column, where metal impurities interact with the resin while the desired API and other impurities pass through. The bound metal ions can be subsequently eluted from the resin using appropriate elution solutions. Resins for metal reduction are also often used in combination with other purification techniques, such as filtration, chromatography, or precipitation, to achieve the desired purity level for APIs. These multiple purification steps help ensure that the final product meets regulatory requirements and quality standards. The choice of resin and operating conditions (e.g., pH, flow rate) depends on the specific metal impurities and the API being processed. Optimization of resin selection and process conditions (equivalents of scavenger/resin, reaction temperature and pH of the aqueous reaction mixtures (Figure 2) [18,19] is essential to ensure efficient metal reduction. Factors such as resin capacity, selectivity and stability under process conditions should be evaluated. Additionally, the compatibility of the resin with the API and the specific metal impurities must be considered [18].

Figure 2:Factors involved in effective metal scavenging.

Manufacturers are responsible for conducting appropriate analytical testing to ensure compliance with the established metal impurity limits. These tests typically involve validated analytical methods, such as atomic absorption spectroscopy (AAS), [20] inductively coupled plasma (ICP) techniques, [21] or other suitable analytical techniques capable of accurately detecting and quantifying metal impurities in APIs.

In conclusion, the use of resins for metal reduction in active pharmaceutical ingredients is an essential purification step in pharmaceutical manufacturing. These resins provide an effective means to remove metal impurities, thereby ensuring the safety and quality of pharmaceutical products. The choice of resin and process conditions should be optimized based on the specific requirements of the API and the target metal impurities.

The authors thank management of R&D, Neuland laboratories Private Limited for encouraging this review article.

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