High-Purity Auxiliary Materials

High-Purity Excipients: A Simple Solution to a Complex Problem Introduction It is hardly surprising that there are many varieties of active pharmaceutical ingredients (APIs). Small molecule, large molecule, peptide, monoclonal antibody; the list goes on. These molecules have the ability to alleviate or improve compelling conditions that could permanently change a person's life. Therefore, it is an undisputed fact that these components have primary importance in a formulation, and appropriate measures must be taken to preserve their stability and efficacy. As these active pharmaceutical ingredients become more complex, they may become increasingly vulnerable over time to a number of different degradation pathways. Changes in pH environments can cause acidification and lead to degradation. Exposure to moisture can also initiate hydrolysis and subsequently lead to the formation of secondary byproducts. Residual catalyst not removed from an excipient can trigger side reactions and cause degradation not only of the active pharmaceutical ingredients but of everything else in the formulation. Ensuring that the components used in a formulation are of the highest quality and purity is a practical solution. This prevents drug degradation; it ensures the preservation of efficacy and longevity.  

Polysorbates for Biopharmaceuticals

It is well documented that biopharmaceutical active ingredients such as proteins and nucleic acids are easily degraded when exposed to various external stresses including heat, pressure, purification procedures and mixing. These factors cause adverse effects either within the protein structure or in interactions with an external surface, ultimately leading to reduced biological efficacy. Additionally, these adverse interactions and product breakdown can begin through exposure to degrading agents within the formulation. In this scenario, the culprit is the excipient that is co-formulated with the therapeutic agent. Although in small amounts, one of the main components these agents are formulated with is polysorbates, particularly Polysorbate 20 and Polysorbate 80. Polysorbates are used in a wide variety of applications as a stabilizing agent for proteins and a substance that prevents surface adsorption. Their natural biocompatibility and strong ability to preserve internal protein structure make polysorbates a more advantageous choice compared to other stabilizers such as human serum albumin and disaccharides1. However, polysorbates are also known to undergo autoxidation. Although the exact degradation mechanism of these components remains unclear, there is a theory that the primary pathways are acid or base-catalyzed hydrolysis or stress-initiated degradation to aldehyde and acid subunits2. These subunits not only advance polysorbate degradation but also interfere with the stability of the active ingredient. Therefore, the use of the highest purity content in such sensitive applications is very important and even mandatory. Croda's Super Refined™ Polysorbate 20 and Super Refined™ Polysorbate 80 products have the low impurity and high stability profile required for these applications. Super Refined Polysorbates dissolve and stabilize the most sensitive active pharmaceutical ingredients in dosage forms, including injectable or oral uses. Super Refinement removes polar impurities (including primary and secondary oxidation products) from an excipient without changing its chemical composition, helping to reduce negative active pharmaceutical ingredient interactions and degradation.

The Real Benefits of Purity

The fundamental problem with oxidative impurities in excipients is not solely related to the stability of the active ingredient. Component instability is associated with a number of issues related to formulation and drug delivery. It is known that certain impurities are cellular irritants that prevent adequate drug delivery and may even cause pain at the application site. Small molecular weight impurities such as formaldehyde can interfere with additional delivery containers such as gelatin capsules, altering and even preventing formulation release. As can be seen below, Super Refined Polysorbate 20 contains approximately 46% less formaldehyde compared to standard grade Polysorbate 20 (Figure 1). Similarly, when a comparison was made for Super Refined Polysorbate 80, it was observed that Super Refined Polysorbate 80 contains approximately 81% less formaldehyde compared to standard grade Polysorbate 80 (Figure 2). [caption id="attachment_153226" align="aligncenter"] Figure 1: A graph showing the difference in formaldehyde content between Super Refined Polysorbate 20 and standard grade Polysorbate 20.[/caption] [caption id="attachment_153227" align="aligncenter"] Figure 2: A graph showing the difference in formaldehyde content between Super Refined Polysorbate 80 and standard grade Polysorbate 80.[/caption] A product must not only be synthesized in accordance with its purity but also be used in accordance with its purity. This applies not only to polysorbates but to all components used in the manufacture of pharmaceuticals. Critical measures such as controlling cleaning protocols of production equipment, appropriate inert packaging and filling environments are very important for excipient stability and final product performance.

Conclusion

As conditions evolve, so do active pharmaceutical ingredients. Complexity in design and structure leads to specialized and effective delivery for those who need it most. In many cases, drug degradation can have toxicological effects, and this mechanism should be minimized as much as possible. The best solution for this is to ensure the selection of appropriate components with both high quality and purity, and their use throughout the entire pharmaceutical product life cycle. Croda's Super Refined™ excipients are a definition of the term purity. With expertise in numerous formulation and drug delivery areas as well as a broad range of materials available worldwide, Croda offers complete solutions that help bring innovative and groundbreaking treatments to market. Super Refined™ excipients are comprehensively purified to remove residual catalyst from the synthetic process as well as primary and secondary oxidation products, including aldehydes, hydroperoxides and ketones. This results in a cleaner and clearer product with longer stability and shelf life, as well as allowing any active ingredient dissolved within it to have better stability.  

References

1. Arsiccio, Andrea, and Roberto Pisano. "Surfactants as Stabilizers for Biopharmaceuticals: An Insight into the Molecular Mechanisms for Inhibition of Protein Aggregation." European Journal of Pharmaceutics and Biopharmaceutics, vol. 128, 9 Apr. 2018, pp. 98–106., doi:10.1016/j.ejpb.2018.04.005. 2. Kerwin, Bruce A. "Polysorbates 20 and 80 Used in the Formulation of Protein Biotherapeutics: Structure and Degradation Pathways." Journal of Pharmaceutical Sciences, vol. 97, no. 8, 29 Jan. 2016, pp. 2924–2935., doi:10.1002/jps.21190.

  Gizem Uzun Sales Representative - Pharmaceuticals Croda Türkiye