Chemicals & raw materials
needs to be safe and effective. This could be extending shelf life or adding volume so that the drug can be taken as a pill, or as evinced by the phenytoin incident, controlling the release of the API. Often, excipients make up the bulk of a drug, sometimes accounting for 90% of its total mass or volume. And while they’re considered inert substances, they do interact with APIs in a variety of physical and chemical ways.
The outcomes of these reactions can be beneficial, such as improving a drug’s stability, but they can also be undesirable. For example, there may be chemical changes that cause the API to degrade. Excipients can be the difference between a drug failing and succeeding, and choosing the right ones can be complicated. To produce a drug with the required properties – and to prevent against unwanted effects – scientists must pick excipients that will behave in ways they want, both within a formulation and in various conditions.
Making drugs soluble If a drug won’t dissolve, it can’t be absorbed by the body once it’s administered. And since most drugs are hydrophobic – they don’t dissolve in water – one of the most important functions of excipients is to make drugs soluble. Water is a polar substance: one end of each molecule has a slight positive charge, while the other is slightly negative. To dissolve in it, other molecules also need to be polar, or have an electric charge. But many drug molecules are polar and insoluble. This is mainly because of their chemical structure, says Robert Luxenhofer, professor of Soft Matter Chemistry at the University of Helsinki. “They become more and more aromatic…[with] a lot of hydrogen bond acceptors and donors. What these molecules tend to do is crystallise.” If an acceptor meets a donor, then a hydrogen bond can form, a strong type of interaction that can help stabilise a drug but hinder its ability to dissolve. Plus, if chain-shaped, flat compounds called aromatic rings are present (giving the property of being aromatic), they can stack on top of each other – which also contributes to insolubility. To make a drug soluble, an excipient needs to work against these factors, says Luxenhofer. One that works quite well is a polymer called polyvinylpyrrolidone, or PvP, he adds. Or, following research Luxenhofer has been working on for the past 15 years, you could use polymers that contain tertiary amides – bonds between amino acids that are responsible for the 3D (tertiary) shape of proteins. These compounds act as hydrogen bond acceptors and don’t have any donors. “If we add an
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excipient that only has an acceptor, but no donor, it kind of pushes into the hydrogen bond [within drug molecules]. It overwhelms the donor-acceptor interaction between the molecules because you add so much acceptor,” he explains.
But, as well as ensuring a drug can dissolve, excipients can also control how fast it does so. This can determine the rate at which an API is released, and is key to producing the desired therapeutic effect. “Either you want to accelerate drug release – so you could use wetting agents, for example – or you want to slow down drug release, so you could use controlled release agents,” says distinguished professor of chemical and biochemical engineering at Rutgers University, Fernando Muzzio. A wetting agent aids solubility by reducing the force between drug and water molecules; controlled release excipients cause gradual release of the API via various mechanisms. For example, some use polymer matrices that “trap” the API, allowing it to trickle out over time.
Improving stability
For a drug to be safe and effective, it also needs to be stable, meaning the integrity of the API and other key properties must be maintained throughout its shelf life. Excipients can establish and improve a drug’s stability by preventing reactions that cause the API to degrade, for example by protecting it from moisture. If water gets into the product, this can trigger reactions that cause it to break down. “This is one of the reasons we coat the product. And we use coatings that provide a good moisture barrier,” says Muzzio. “For example, if the coating contains a polymer that could absorb the moisture or prevent the diffusion of moisture into that product.”
“Either you want to accelerate drug release – so you could use wetting agents, for example – or you want to slow down drug release, so you could use controlled release agents.”
Fernando Muzzio, professor at Rutgers University
Oxidation is another type of degradation that excipients can fend off. The atoms that make up all matter contain electrons, which like to exist in pairs, but certain processes that generate energy within atoms, like heat or light, can cause electrons to separate. An atom with an unpaired electron, known as a “free radical”, then becomes highly reactive and will seek to stabilise itself by taking an electron from another atom, which begins a cascade of degradation as each atom short of an electron does the same. In the chemistry of drug formulation, these highly reactive molecules
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