Enjoy the gin but spare a little thought for the tonic….

Gin is rapidly becoming the nations favourite tipple. Its undergone a modern renaissance with familiar trade names such as Gordon’s, Plymouth and London and multiple artisan distilleries appearing country-wide. It’s even drawn synthetic organic chemists out of the lab and into the refineries.

This week at our 5th Winter Process Chemistry Conference in Manchester UK our delegates, speakers and sponsors will be sampling gin, and hopefully learning a thing or two about the science behind its manufacture. But like many things in life it is better together- and the humble ‘tonic’ is very much the ‘Dr Jekyll’ to gin’s ‘Mr Hide’. The implied medical salutation is somewhat appropriate in this choice of metaphor since tonic water hides a secret ingredient-the alkaloid quinine.  Isolated from the bark of the Cinchona tree, quinine has been used medically to treat malaria for almost 400 years.


Malaria is a plasmodium parasitic infection speared through the bite of an infected female anopheles mosquito. It remains one of the most prolific diseases in human history, with over 200 million infections worldwide in 2016 and almost half a million deaths.1 It’s endemic in many tropical countries, particularly southern Asia and Africa.

 Historically quinine was added to carbonated water as a prophylactic against malaria. Its bitter taste was somewhat unpalatable leading colonial British officers stationed in India in the early 19th century to add flavours to mask the taste- sugar, fruit essences and gin.2 The pairing of gin and tonic has endured throughout history, as has the addition of quinine to tonic water. There has always been some doubt as to whether there is enough quinine present in the tonic to inhibit or kill the plasmodium falciparum parasite in vivo. The FDA limits the acceptable concentration of quinine in tonic to 83mg/l- however, what does this mean in terms of the volume consumed and efficacious dose?

In the spirit of scientific endeavour, a team of 6 healthy volunteers at the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany, each drank almost a litre of tonic water containing 58 mg/l of quinine within 15 minutes (no gin!). Peak plasma concentrations of 0.6 mg/l were obtained after a couple of hours- the low end of the minimum inhibitory concentration (0.68-0.89 mg/l), equating to an unbound plasma concentration of around 0.2 mg/l. To target multiple strains of the parasite, some of which are more resistant than others, this value needs to be higher-in the range 0.2-2 mg/l. This fact, coupled with the relatively short half-life of quinine (10-12 hrs, clearance is 1.2-4 ml/min/Kg) revealed it would be suboptimal for parasiticidal effects.2 Clinically- high loading doses are required to maintain efficacious concentrations and, of course, a low concentration in fizzy water is not the preferred route of administration to the patient.

 This study admittedly was a ‘school science project’ and somewhat light-hearted, however it does demonstrate that even consuming large volumes of tonic water cannot maintain the level of continuous exposure required for effective prophylaxis.

The malaria parasites feed on blood- digesting haemoglobin, spitting out the heme iron in the form of ferriprotoporphyrin IV (or a-haematin). This pro-oxidant catalyses the formation of reactive oxygen species (ROS) that are toxic to the organism. To protect itself the parasite detoxifies the hematin by biocrystallization- converting the a-form to an inert, insoluble b-form called hemozoin or hematin pigment. Crystals of hemozoin (Figure 1) form in the parasites food vacuole and can be seen clearly via microscopy. Quinine and related antimalarial compounds are believed to function as biocrystallization inhibitors, both of free heme and hemozoin, binding to the growing face of the crystal.3 Figure 1 shows the structure of the repeating unit with coordination of the oxygen atom in the b-hematin carboxylate side chain with the central heme iron atom.  Detoxification of the cytotoxic iron by-product produced is thus impeded and the parasite is killed.

Figure 1: Crystal Structure of hemozoin

The synthesis of quinine, though of great academic and intellectual significance, is not relevant to the material supply- Nature retains her monopoly. The position is eloquently summarised by Gilbert Stork “The value of a quinine synthesis has essentially nothing to do with quinine. It is like the solution to a long-standing proof of an ancient theorem in mathematics: it advances the field.”4

So the next time you enjoy a gin and tonic, spare a thought for the ‘Dr Jekyll tonic’ and raise a toast to quinine- the bitter sweet alkaloid.5


  1. WHO world malaria report 2017 (https://www.who.int/malaria/media/world-malaria-report-2017/en/).
  2. Tropical medicine and international health 2004, 9(12), 1239-1240.
  3. Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design Chem. Rev. 2008, 108, 4899-4914.
  4. For a review of the synthetic history see Angew. Chem. Int. Ed. 2018, 57(33), 10737-10741 and references therein.
  5. For a good review of the history of quinine see: The quest for quinine: those who won the battles and those who won the war Angew. Chem. Int. Ed. 2005, 44(6), 854-885.