Chemicals & raw materials
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.
The highly reactive nature of oxygen atoms means they can degrade APIs through oxidation.
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
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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.” ●
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