In the Australian city of Brisbane, 55 years ago, there was a widespread overdose of anticonvulsant medication among people with epilepsy. It turned out that those affected were all taking the same brand of the drug phenytoin. Just a few months before the outbreak, the main excipient within its formulation, calcium sulphate dihydrate, had been replaced with lactose. In 87% of patients, the blood phenytoin levels were above the therapeutic range, and conclusions were drawn that the lactose changed the solubility of the drug so that more – too much in fact – of the active ingredient was absorbed by the blood. Luckily, a reduction of phenytoin dosage relieved the intoxication in all patients, but the event serves as a good example of the importance of formulating using the right excipients.
Excipients are substances added to a drug alongside the active pharmaceutical ingredient (API) that establish the functional properties it 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 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 can give rise to API deterioration, and it just so happens that the atoms in oxygen, the most abundant element on earth, are some of the most highly reactive.
To avoid oxidation, you could use antioxidants, says Amal Eli Elkordy, professor of pharmaceutics at the University of Sunderland. Antioxidants can delay or inhibit the oxidation process by supplying electrons to free radicals, which interrupts their effects. “This is actually protection from oxidation for APIs,” Elkordy explains. One antioxidant that’s commonly used is ascorbic acid, more commonly known as vitamin C.
“Some excipients can, based on the chemical structure of the drug and the chemical structure of the excipient, actually have some adverse effects.”
Amal Eli Elkordy, professor at the University of Sunderland
Excipients also must be able to withstand stability testing, a required step in the drug development process that ensures the product will remain intact across its shelf life. The API must be maintained throughout testing and no impurities should form. For solid-dose products like pills, this typically means putting the product in its package within a chamber that’s warmer and has higher environmental moisture than room temperature for three or six months, Muzzio explains. “You can then test the product and see if the API has degraded. If it has degraded, what has been produced as a result of the degradation? And, are those acceptable levels of both the API remaining in the product and whatever impurities the API degradation led to?”
Preventing undesirable effects
While the aim is always for excipients to interact with APIs via desired mechanisms, unexpected – and unwanted – reactions can also happen. “Some excipients can, based on the chemical structure of the drug and the chemical structure of the excipient, actually have some adverse effects,” says Elkordy. They may create impurities or interact with the API in ways that cause degradation, as seen via oxidation or the effects of moisture. Another of these scenarios would be if a precipitate formed. Elkordy gives the example of excipients with molecules which are negatively charged, but then some moisture gets into the formulation that is positively charged. The substances could interact and cause the formation of precipitate, which changes how much of the API is available to be dissolved. “Once the drug is precipitated, this means that the patient will not take the right dose,” she says.
A process called adsorption can have a similar effect. This happens when there’s an imbalance in attractive forces between particles, causing API molecules to adhere to the surface of excipient particles. While adsorption can be used to good effect when brought on deliberately, it can also alter an API’s solubility accidentally. “Drug release [can] be longer than expected, and this means the patient will not get the therapeutic dose of the API,” says Elkordy.
Choosing the right excipient is the best defence against unwanted reactions. Here, knowing its properties is only half the battle: you also need to predict how it will fare in various manufacturing conditions. Will your formulation stay intact if you’re going to expose it to heat or moisture, for example?
Making better formulations
An excipient might also have processing requirements that could introduce problems. “If I’m using a binder that requires a larger amount of water, or a longer drying time, that particular excipient is promoting the use of conditions that could lead to undesired outcomes,” Muzzio explains. “We know enough about how excipients work that we can choose them deliberately to achieve the purpose we want.” But with the help of new technologies, he believes we’re only going to get better at predicting undesirable reactions.
“[With] artificial intelligence…we will be able to run through all the possible reactions with these excipients. But that’s a few years into the future, we’re not there yet,” Muzzio explains.
Looking at drug development from a different angle, Luxenhofer hopes to see more investigation into how a formulation’s efficacy may vary between different types of people. For example, could the makeup of someone’s gut microbiome affect how well a certain drug dissolves? “We know very little about this,” he says. “It’s one of the puzzle pieces that we’re working on.”
