Polysorbates and their alternatives

In the intricate world of pharmaceuticals, even the smallest components can play a significant role in the success of a drug. One such unassuming yet vital ingredient is polysorbates. While these compounds may not grab the headlines, their importance in the pharmaceutical industry cannot be overstated, and the reason why comes down to one word – stability.

Understanding how a mixture of chemicals becomes unstable can help with grasping the importance of polysorbates. We’ve all heard the phrase ‘oil and water don’t mix’ – it’s usually a way of expressing that two people can’t get along. But it’s also true on a molecular level because of the hydrophobic properties of oil and the hydrophilic – meaning readily mixes with water – properties of water. In this example, the mixture of oil and water is ‘unstable’ because there’s no uniform distribution of oil molecules. This inability to mix with uniform distribution of molecules is what makes oil and water immiscible liquids.

Bringing the balance

Polysorbate 20 and Polysorbate 80 (hereafter referred to as just polysorbates) are examples of a class of excipient known as a surfactant, and their unique molecular structure allows them to create stability within a mixture of hydrophobic and hydrophilic substances. “Polysorbates form micelles when dissolved in water in a sufficient concentration,” explains Lukas Bollenbach, a PhD student at the Institute of Pharmacy at Martin- Luther University Halle-Wittenberg. “Micelles are colloidal aggregates of several surfactant molecules, which form a more hydrophobic compartment in the centre of the micelle.”

These micelles are like tiny spheres, and within them the hydrophobic tails of the surfactant molecules cluster together on the inside, while the hydrophilic heads point outward and interact with the water. The result is that the hydrophobic molecules are ‘wrapped’ in surfactant molecules, and because of the latter’s hydrophilic head, the former are dispersed uniformly within the mixture.

To continue with the oil and water example, the surfactant has made the oil more ‘soluble’, and the same benefits apply in pharmaceutical formulations. In the case of biopharmaceutical APIs that contain certain hydrophobic peptides or proteins, there’s another bonus, as proteins with exposed hydrophobic regions are prone to degradation through aggregation – where individual protein molecules form larger structures or aggregates – and the shielding effect created by surfactants helps prevent this, preserving the function of the protein-based API. “Poorly soluble drugs can be solubilised in these micelles,” explains Bollenbach. “On the other hand, polysorbates decrease the surface tension of solutions, and with that can stabilise, for example, suspensions against caking or proteins from aggregation.”

Making the insoluble soluble

Bollenbach could have replaced the word polysorbates with surfactants and his explanation would have been just as accurate, but it’s no secret that the former has become almost synonymous with the latter due to widespread industry use. There’s a good reason for this, and it comes down to just how well polysorbates do their job. “The characteristics of polysorbates are used in many different formulation types,” says Bollenbach. “Solubilisation of poorly soluble drugs might be the main field of application, while polysorbates also play a key role in the formulation of proteinic drugs. In both application fields, polysorbates are not easy to replace.”

All of this begs the question – why would anybody want to replace polysorbates as the surfactant of choice for their (bio)pharmaceutical? Well polysorbates aren’t perfect, and in their effort to better understand the degradation pathways of common excipients, researchers have highlighted two main ways they can be destabilised. The first of these is the most common, and occurs in the presence of water molecules.

Polysorbates are synthetic compounds made from fatty acids and polyoxyethylene sorbitan, a surfactant made by reacting sorbitan (a sugar alcohol derived from glucose) with ethylene oxide (a chemical compound). Both ingredients are joined together by chemical linkages known as ester bonds, and water molecules can sever them in a process known as hydrolysis, leading to the formation of degradation products and jeopardising the stabilising properties of the compound.

The second degradation pathway is oxidation, a chemical reaction in which a substance loses electrons to another molecule, resulting in changes to its chemical structure and properties. Polysorbates have unsaturated carbon-carbon double bonds in their fatty acid chains that make them more susceptible to attack by reactive oxygen species (ROS) due to the presence of reactive sites in their molecular structure.

Mitigating risk

The natural occurrence of oxygen in the environment makes oxidation a risk, as does the use of products containing hydrogen peroxide (H2O2), a chemical compound (and oxidative agent) used to disinfect and decontaminate cleanrooms used in drug production. Whether the risk of one or the other degradation pathways is higher depends on the formulation, but hydrolysis tends to occur more frequently in biologics, oxidation more so in small molecule drugs. In both cases, formulation scientists add other excipients to the reduce degradation risk, and the standards of procedure followed for manufacturing and storage are designed to reduce exposure to any stimuli that could excite molecules towards an oxidative or hydrolytic reaction.

Bollenbach is eager to stress that this level of risk mitigation is par for the course for many excipients. “It’s not only polysorbates that can show instabilities that affect their shelf life and might impact the quality of the finished product,” he says. “These findings have led to the search for alternatives, but also to more research in the field of excipient stability.”

The bar a surfactant must reach to become a viable alternative to polysorbates is high. After all, more than 90% of EU approved monoclonal antibodies (mAbs) are formulated with either polysorbate 20 or polysorbate 80. This is significant when mAbs constitute the majority of biologic drug approvals each year.

But it hasn’t stopped researchers from evaluating alternative surfactants for potential advantages over polysorbates. “The choice of a sufficient surfactant for a biological is very complex,” explains Bollenbach. “Beside regulatory considerations, every biologic drug has its own specific characteristics, and finding the right surfactant candidate and concentration is something that must be evaluated.”

A promising candidate

One of the more promising candidates is poloxomers, a group of block copolymers composed of hydrophilic polyethylene oxide and hydrophobic polypropylene oxide blocks. These components give them the properties required in a surfactant, and much like polysorbates, the stability, safety and tolerability of several products have been demonstrated in oral and parenteral applications. “Poloxamer 188 has even shown advantages over polysorbates in some special formulation cases,” adds Bollenbach. “Beside that, poloxamers have a less complex structure and composition than polysorbates, which is thought to be more manageable.”

Poloxamers are particularly well suited for applications that require gel formation at lower temperatures and rapid dissolution at higher temperatures, meaning they’re often found in topical products. But the ability to transition from a liquid to a gel phase upon contact with physiological fluids or body heat also makes them ideal for slow-release formulations in both oral and parenteral drug delivery.

In the gel phase, poloxamers can effectively trap and hold the drug molecules within their structure, and when formulated with other excipients, they can be used to tune the kinetics of drug release to achieve a specific dosing regimen. On the other hand, polysorbates are not designed to create a gel or matrix that can control the release of drugs over an extended period. Instead, they are used to improve drug solubility and dispersion, which can lead to relatively rapid drug release upon administration.

It goes without saying that polysorbates and poloxomers aren’t the only surfactants about, and there are many other promising alternatives, like the highly biocompatible Lecithin found in egg yolk and soy beans, or cremophors – derivatives of castor oil shown to improve the solubility of drugs in lipids (fats) to a higher degree than polysorbates.

These contextual differences help to illustrate how the use of surfactants in pharmaceuticals has developed as a result of research, and when we consider that a large amount of that research is on polysorbates, it’s not hard to understand why they’re the most common choice in small molecule and biologic formulations. Formulation science is an evolving discipline however, and with a growing interest in the study of excipient stability in pharmacologically relevant environments, like the human body or storage rooms, research developments might lead to new applications for surfactants, or the discovery of a new surfactant altogether.

“As polysorbates have been used more often and for a longer time in protein formulations, there is more knowledge behind formulating with polysorbates,” says Bollenbach. “Poloxamers, as well as polysorbates, will be considered when new biologic drugs need suitable formulations. Meanwhile, the characteristics of both, as well as other surfactants will continue to be evaluated, especially regarding their stability and stabilising properties.”