High purity Glycerin for sensitive drug formulations

Introduction

Excipients are essential components in pharmaceutical formulations, supporting drug manufacturing, administration and delivery, absorption, and stability. However, they can chemically or physically interact with active pharmaceutical ingredients (APIs), potentially compromising the drug’s efficacy, quality, and safety. Chemical interactions may lead to API degradation, reducing therapeutic effects and potentially producing harmful by-products. The physical interactions can affect dissolution rates, dosage uniformity, and ease of administration.

Reactive impurities in excipients – such as peroxides, aldehydes, organic acids, reducing sugars, elemental impurities, and more – even in trace amounts, can trigger degradation or contribute to form drug-excipient adduct, thereby affecting drug stability and quality. These reactions are influenced by several factors including the excipient chemical structure, the drug-to-excipient ratio, moisture content, pH, temperature, and exposure to light.

To ensure robust formulations, it is essential to understand the properties of excipients, their impurity profiles, and their compatibility with APIs. A well-designed formulation accounts for , excipients, processes and stability conditions.

Although excipients are often considered inert, their selection must be guided by both their functionality and chemical compatibility with the APIs to optimize drug performance, manufacturability, and patient compliance.

Glycerin

Glycerin, also referred to as glycerol, is one of these excipients. It is a liquid polyol, widely utilized in the pharmaceutical industry for various applications. It serves in oral and intravenous formulation drugs. Glycerin can be chemically synthesized or purified from plants. It serves as an excipient for injectable drugs like insulin, thymopentin, and freeze-dried biological products. Although glycerol oxidation, independently from the source of production, has been extensively reported, impurities arising during excipient production, purification and storage can also be present. These impurities can be effectively removed or diminished by optimizing the production processes, implementing specific purification techniques, and controlling the storage conditions. Some of these impurities which have been the focus of glycerin quality are glycerin-derived aldehydes.

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Glycerin-Derived Aldehydes: Formation and Sources

Glycerin, particularly from plant origin, contains variable levels of aldehydes, naturally found in plant extracts. Common aldehydes such as glyceraldehyde, formaldehyde, acetaldehyde may compromise drug

Glyceraldehyde is primarily formed as an intermediate in glycolysis and through the oxidative degradation of glycerol. Secondary byproducts such as acetaldehyde and formaldehyde are generated as oxidation progresses. The low-molecular weight aldehydes (C1–C8) may also be present in excipients as trace impurities in degraded glycerin.  These aldehydes can form due to exposure to heat or atmospheric oxygen during reception, storage, and most likely during handling and manufacturing.

Under conditions of oxidative stress, aldehyde accumulation increases, heightening their ability to interact with cellular proteins. This can lead to the formation of harmful entities such as AGEs (advanced glycation end products) particularly adverse in the case of T2D and insulin infection as they can contribute to the disease worsening. Therefore, the presence of aldehydes in glycerin poses a significant challenge, especially in pharmaceutical formulations containing proteins, such as insulin.

To mitigate this risk, it is essential to produce high quality glycerin with a minimal aldehyde content and ensure its stability throughout storage, avoiding the formation of aldehydes over time.

Pharmacopeias established quality requirements for impurities content, such as aldehydes, in pharmaceutical application. Aldehydes have to be 10 ppm or lower in the glycerin to full-fill these requirements.

Plant-derived glycerin

Due to lower cost of plant-derived glycerin compared to the synthetically made, companies start producing plant-derived glycerin. However, controlling aldehyde content remains a key challenge. ADM has successfully developed a plant-derived glycerin that combines lower cost with high quality and low aldehyde levels. ADM’s specifications limit aldehyde content to below 5 ppm, enabling the formulation of highly sensitive active pharmaceutical ingredients (APIs) with minimal risk of degradation or interaction.

Purified Glycerin LA

Purified Glycerin LA is manufactured under full GMP requirements for Injectable grade. It is ideally suited to replace synthetic glycerin in sensitive applications and formulations, particularly injectable insulin. The production process is optimized to obtain a low-aldehydes content glycerin, making it suitable for use in   injectable grade drug formulations.

Packaging and storage conditions are critical components of a product’s control strategy, especially when impurities are a concern. Purified Glycerin LA is produced and stored under conditions avoiding exposure to light, oxygen, humidity and elevated temperatures. The product is available in various packaging formats including single-use containers and 2,5-liter glass bottles, catering to small-scale production needs.

Conclusion

Reactive impurities in pharmaceutical excipients can compromise the safety and efficacy of drug formulations. By optimizing production processes and rigorously monitoring reactive impurities, ADM has developed a high-quality plant-based glycerin—Purified Glycerin LA—that offers both safety and cost advantages. Therefore, Purified Glycerin LA may help our customers in developing robust drug formulations, particularly protein-based drugs, like insulin. Using glycerol with minimal aldehyde content, such as Purified Glycerin LA, is the optimal choice to reduce the risk of protein modification and ensure drug stability and efficacy.

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Sources

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See also our CPhI Frankfurt overview article: