Chemicals & raw materials
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
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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
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The hydrophilic head of a micelle allows it to interact with water molecules while the hydrophobic tail keeps them away from the centre, where an API can be safely carried.
Ph-HY/
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