Active Pharmaceutical Ingredients (APIs), the aim of IMPACTIVE

An API is the essential component responsible for the therapeutic effect of a medicine. This crucial element can be sourced from various methods. In this article we explore what APIs are, why are they important, and the strict regulations they face to ensure their quality and safety in pharmaceutical production worldwide.

If you have a fever, you will take paracetamol; if you have allergies, an antihistamine; and if you have sprained your ankle, a pain killer. Thanks to the existence of pharmaceutical drugs, we can relieve and cure ourselves. However, of all the ingredients that make up a pill or a tablet, the credit goes to a very specific part of the medicine: the Active Pharmaceutical Ingredient, or API.

An API is therefore the component that produces the therapeutic effects within the pills and tablets we take. In other words, the functional compound. For instance, in the brand Nurofen, the API is the molecule ibuprofen. Likewise, in the famous antidepressant medicine Prozac, the API is fluoxetine, a molecule that inhibits the uptake of serotonin. There may also be medicines that include even more than one API. This is the case for Nurofen Plus, which includes ibuprofen and codeine, a mild opioid analgesic.

Creativity with blue pills and their ingredients, including APIs
A pill contains excipients, like a protective shell, together with the APIs.

And why not just take the APIs, if they are responsible for the healing effects of medicines? APIs need a little help from their friends, the excipients. These excipients are other ingredients that need to be present in the pharmaceutical formulations, so they can serve a variety of purposes. For example, to create a shield that protects active ingredient until it reaches the stomach, or a liquid vehicle to convey this precious ingredient or even colourants to enhance the aesthetic appearance of medicines.

How do APIs work?

APIs work by interacting with specific targets in the body—usually proteins like enzymes or receptors—to produce a desired physiological effect. The active ingredients can either block or support their activity, which results in their therapeutic effects.

For example, ibuprofen binds to certain enzymes – proteins that catalyse chemical reactions– pausing their activity for a while. The enzymes in question are involved in the production of hormones that cause pain and swelling in the body. So, while ibuprofen is acting, the “pain hormones” are not produced. And that’s why our headache disappears.

On the other hand, APIs can bind to receptors. These are proteins on a cell’s surface that trigger a variety of responses inside the cell when activated. Like a lock. In the case of the above-mentioned fluoxetine, it binds with some neuronal receptors blocking their activity. The result is that our brains have more serotonin available, leading to an uplift in mood!

Illustration of the synaptic space between two neurons
Two neurons communicating. Fluoxetine binds to some neuronal receptors, causing these cells to have more serotonin available (in purple)

How are APIs produced?

APIs can be produced through various methods: chemical synthesis, fermentation, biotechnological processes, or extraction from natural sources. Humanity’s earliest methods of obtaining healing substances relied on the latter, mainly plants. This remains true today, as many medicines on the market contain APIs extracted from plants and other living creatures.

The Spanish company PharmaMar, for example, dives into the sea to search for its active ingredients. They develop anti-tumour drugs based on marine invertebrates, such as sponges, because these organisms lack an immune system and cannot flee. The result: they have developed defence mechanisms to survive that might as well help us. At IMPACTIVE, we aim to produce APIs chemically, but in a unique way, without the use of solvents. That’s why we turn to mechanochemistry.

APIs and mechanochemistry

As mentioned before, APIs can be chemically manufactured and at IMPACTIVE we have chosen mechanochemistry. This means that we mash molecules together to synthesise the compounds. And why? Utilising mechanochemistry in pharmaceutical manufacturing has proven to significantly diminish waste generation, concurrently enhancing the quality and purity of APIs.

The interest in using mechanochemistry for the discovery and synthesis of API solid forms has been notably growing over the past 20 years. There is already an extensive list of exciting examples. Mechanochemical methods, such as liquid-assisted grinding (LAG), have demonstrated remarkable success in screening for new polymorphs, salts, or cocrystals of both real and model APIs. Particularly noteworthy is their capacity to scale up production of these compounds using batch or continuous processing methods.

Most excitingly, mechanochemical techniques have ventured into the synthesis of actual APIs! It is true that the number of reported mechanochemical API syntheses remains limited, but there is also a growing repository of procedures for generating pharmaceutically relevant fragments and functionalities through mechanochemistry.

At IMPACTIVE, we have proudly helped to enlarge that list. Our team has looked into the manufacturing of imatinib, an anticancer drug. Thanks to mechanochemistry, we discovered a synthetic route to do it in a way that is safer, greener and more efficient than the commercial method used nowadays. We have also produced paracetamol by using bead-milling technology. This is the first use of such method to perform a reaction in the absence of solvent.

Mechanochemical method vs commercial method of imatinib synthesis.

What regulations do APIs need?

Whether they come from the sea, from the land or from a chemical process carried out in a laboratory, the production of APIs follows strict standards of manufacturing and quality control. APIs are regulated by health authorities worldwide. The European Medicines Agency (EMA) oversees that in Europe. It follows the standards of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The good manufacturing practices covers several aspects of API manufacturing, including quality management, personnel, equipment, documentation, production, or distribution. Adhering to these guidelines helps to minimize risks associated with the production of APIs and ensures the safety and efficacy of pharmaceutical products. You can take a look at the EMA document here.

2 pharmaceutical factory workers
APIs manufacturing follows strict standars of quality control.

At a global level, problems with the quality of medicines and their supply led to the creation of World Health Organisation (WHO) medicines prequalification in 2001. This initiative aims to ensure that active ingredients and finished pharmaceuticals are safe, appropriate and meet high-quality standards. WHO works closely with national regulatory agencies and partner organisations to make quality priority medicines available to those who urgently need them.

The primary beneficiaries from this initiative are populations requiring treatment for priority diseases –medicines designed specifically to meet low-income country needs–, and women and girls in need of medicines to ensure their reproductive health. Examples from the WHO List of Prequalified Active Pharmaceutical Ingredients include APIs to treat Tuberculosis, HIV/AIDS, Malaria, Diarrhoea, Reproductive health, Influenza, and Covid-19.

The future for APIs is incredibly bright thanks to mechanochemistry. In addition to improving their quality and doing so in a greener way, mechanochemistry represents an opportunity to diversify drug portfolios, democratise the development of life-saving medicines and reduce reliance on unstable supply chains.