From Pharmacy to the Pub — A Bark Conquers the World: Part 1
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From Pharmacy to the Pub — A Bark Conquers the World: Part 1

Author: Klaus Roth, Sabine Streller

 

Cinchona, or quina, refers to a genus of about 38 species in the family Rubiaceae, first found in forests of the tropical Andes. Known to natives in Peru as “quinaquina” (bark of the barks), it is perhaps the greatest gift from the New World to the Old World. In particular, its bark yielded the first effective remedy for malaria, one of the most dangerous of infectious diseases. The chief component of cinchona bark, quinine, is still used as a medication – but also for preparing tonic water and Bitter Lemon. There is thus good reason for having a closer look from a chemical point of view at this bitter tree bark.

 

1. A Good Medicine Needs to be Bitter!

Upon their discovery of cinchona bark, the Spanish conquistadors—acting on a premise firmly grounded in the healing arts since antiquity—assumed from the very outset that there had to be a connection between the fever-reducing activity of this curative agent and the material’s bitter taste. It would therefore not have been surprising if the Spanish had themselves attempted to treat the fevers of malaria—first encountered in the context of the slave trade [1]—with the bitter bark of the cinchona tree.

Jesuit missionaries active in South America in the 17th century were familiar with, and also documented, the antifebrile activity of cinchona bark, bringing large quantities of the unusual material back to Europe as a medicinal agent. Ground-up cinchona bark thus came to be known as “Jesuit powder”, and its curative powers soon aroused the interest of European apothecaries and botanists.

Scientific excursions were organized to the New World for the specific purpose of locating and describing the source plant. Its German name, “Chinarindenbaum”, represents a combination of the German (Rinde) and old Peruvian (kina or quina) words for bark, together with the German for “tree” (Baum). Also in old Peruvian, by the way, kina-kina means “highly cherished bark” [2].

A legend (since refuted) long held that the Spanish Countess of Chinchón, wife of a viceroy of Peru, was cured of malaria thanks to a brew of cinchona bark. The news of this cure so impressed the Swedish botanist Carl von Linné (1707–1778) that he conferred upon the genus to which the cinchona tree belongs, the name of the Countess. One “h” was lost supposedly through a typographic error, so the corresponding genus was officially designated Cinchona at the London International Botanic Congress of 1866, a name that still applies today [1].

 

2. Cinchona Trees

Cinchona trees can grow to a height of 30 m (nearly 100 ft). They are evergreens, distinguished by a rounded crown surmounting a slender trunk. The leaves may be up to 20 cm (ca. 8 In) long, although the blossoms (pink or red) are small, and occur as terminal panicles.

As already indicated, the bark of these trees is an important source of quinine and other alkaloids. A first harvesting can be undertaken when a tree is 6–7 years old. Maximal quinine concentrations are reached after about 10–12 years. For harvesting purposes, the bark is cut perpendicularly to the trunk, and in a circular fashion. The resulting strip is then removed from the trunk and dried in the sun (see Fig. 1).

 

Bark of the cinchona tree

Figure 1. Bark of the cinchona tree.

 

Cinchona trees, members (as noted above) of the family Rubiaceae, are native to the mountainous regions of Central and South America. Their genus (i.e., Cinchona) encompasses ca. 23 different species, although it is difficult to specify a precise number, both because various synonyms have been incorporated into the classification scheme, and there exist also many hybrids. “False” cinchona barks are any that fail to show antifebrile activity. In general, this is a straightforward consequence of a relatively low quinine content. On the other hand, the bark from many cinchona species presents a very high level of alkaloids, above all, the alkaloid quinine. This level varies among the individual species, which are otherwise very similar, causing the ruination of some plantation developers who suffered the misfortune of having tended the wrong plants. Trees of the species Cinchona ledgeriana or C. calisaya are noted for their especially high alkaloid content. These species have in the meantime been cultivated also in Africa and Asia, for the express purpose of quinine extraction.

 

3. Isolation of the Active Substance Quinine

As with any natural remedy, pulverized cinchona bark is difficult to dispense satisfactorily due to inevitable variation in the content of the active component. The first person to try to find this “active principle” of cinchona bark appears to have been the Portuguese physician Bernardino Antonio Gomes (1769–1812), who in 1811 succeeded for the first time in isolating a crystalline substance from a cinchona bark extract, one that he called “cinchonin” [3]. In 1819 the apothecary, chemist, and physician Friedlieb Ferdinand Runge (1794–1842) believed that he, too, had isolated the active principle from cinchona bark. Both had very probably recovered quinine, but as samples that were still highly impure.

It was left to the French apothecaries Pierre Joseph Pelletier (1788–1842) and Joseph Bienaimé Caventou (1795–1877) to further develop the isolation procedure of Gomes and thereby achieve the first preparation of pure quinine.

In their publication in 1820 the latter two scientists called upon colleagues to test, in practice, the therapeutic properties of this pure quinine [3]. Since Pelletier and Caventou described very precisely their isolation procedure, physicians and apothecaries everywhere found themselves in a position to isolate for themselves a supply of quinine, starting with cinchona bark. This pure and precisely dispensable substance was indeed found to be highly effective, and it quickly displaced pulverized bark as a remedial agent. Because of the high demand for pure quinine, the first quinine factories were soon established, representing in effect the advent of the modern pharmaceutical industry.

 

4. Theft of Seeds: A Crime Leading Directly to a Knighthood

Cinchona bark was such a profitable export for the Andean states Bolivia, Columbia, Ecuador, and Peru that, in the mid-19th century, total bans were declared with respect to the export of any vegetable matter related to the cinchona tree, this as a means of preserving absolute monopoly positions. Violations of the export ban were subject to the death penalty. The inevitable result of such export controls was a sharp increase in the world price for cinchona bark.

Europe had become heavily dependent on the bitter medicine against malaria, especially the major colonial powers after their annexation of extensive tropical regions infested with the disease. This led in turn to ever-increasing demand. The Dutch were especially conscious of the importance of having cinchona plantations on land under their own control, so that in 1851 the Dutch minister of colonial affairs commissioned a botanical excursion with an especially adventurous goal [1]: despite threats of the death penalty, this team was sent off to collect (better: steal) seeds and seedlings of the cinchona tree for the purpose of planting them in the Dutch colonies in Indonesia, thereby breaking the monopoly of the South Americans. As formal justification for this criminal act, a marvelously altruistic excuse was developed: the honorable purpose underlying the endeavor was “rescue of the cinchona tree from its otherwise potential extinction”, to be accomplished through targeted cultivation elsewhere.

The German botanist Justus Karl Hasskarl (1811–1894) was entrusted with this delicate Dutch assignment. He had already spent ten years in the Dutch Indies as director of the Buitenzorg Botanical Garden on Java, where he studied the flora and ecology of that island. In 1852 Hasskarl traveled to Peru, learned the local language, procured letters of recommendation and appropriate official passes, and set off on a long hike through the Andes. He wandered, incognito, for a total of two years through the forests and jungles of the mountainous region. By June, 1853, Hasskarl was able to send a small box of the delicate seeds back to Holland (Fig. 2). In May, 1854, he even managed to transport 200 fresh seedlings to Java, where he successfully planted them. For this thievery, or to put it more diplomatically “in recognition of his meritorious feat”, the Dutch king conferred upon Hasskarl a knighthood in the Order of the Lion, at the same time placing him in charge of establishing a Javan source of cinchona bark [4].

Figure 2. Seeds of the tree.

Hasskarl’s Java legacy proved, however, to be significantly less valuable to the Dutch crown than originally promised: only about 10 % of the cultivated trees were ultimately found to provide a sufficiently high level of quinine. The rest were disappointingly useless.

Apart from expeditions organized by governments, there were also independent adventurers who set out to track down and steal the valuable plant material. The Englishman Charles Ledger (1818–1905) read in a newspaper that the English government was planning an expedition for 1856 in search of cinchona seeds and plants. Ledger was himself interested in botany, and thus, accompanied exclusively by natives, he embarked on his own quest for seeds of the cinchona tree. In his case, however, the goal was seeds exclusively from trees whose bark was already known to have a high quinine content. The seeds he recovered were first offered to the English government, without success, so he also later turned to the Dutch, who rewarded him with 100 gulden [1, 5].

C. ledgeriana (C. calisaya). Incidentally, Ledger had financed his expedition himself, but in the end he earned very little from it. Once the promised spectacularly high quinine yield was confirmed, the Dutch reportedly paid Ledger an additional 500 gulden. Ledger himself, in a letter to his brother, acknowledged receiving a first payment, albeit of only £50, with a second installment of £100. He complained in a letter to his brother: “Investors are always losers”. Nevertheless, he went on also to write that he was proud that one of his dreams had been fulfilled: “Europe is no longer dependent on Peru or Bolivia for its supply of life-giving quinia.” [6]

 

5. Cinchona Conquers the World

Although the planting of cinchona trees for harvesting their bark was initially treated as a state monopoly, by the end of the 19th century private investors and farmers increasingly sought their fortunes here. In 1876 the first cinchona bark from a private source was marketed. Cultivation, harvest, and processing of the bark were further optimized: grafting of quinine-rich plants on to varieties that were seemingly quite robust made it possible to develop especially resistant yet highly productive strains. Indeed, the quinine content of bark in individual cases reached values as high as 20 % [1].

Various alternative harvesting techniques were also examined and introduced. In the 1930s, the cultivation of cinchona trees on Java was perfected to such a degree that 97 % of the quinine utilized worldwide originated in the ca. 10 million kilograms of bark from this one source.

Starting around 1870, the extremely lucrative cultivation of cinchona was promoted in other new regions as well: huge plantations appeared in Ceylon, India, Africa, and even the United States. As ever more cinchona bark was thrust upon the world market, the price inevitably crashed. Where in 1880 a kilogram of quinine sulfate sold for 385 RM, the price fell by 1896 to 32 RM. Many plantation owners were forced into bankruptcy, as a result of which the area under cultivation worldwide was drastically reduced; in Ceylon, for example, it went from 26,000 ha in 1883 to a mere 500 ha in 1898 [7].

 

6. Quinine, the Rhine, and Germany

From our vantage point today, malaria is seen exclusively as a tropical disease. This interpretation is contradicted by the facts, however, since not all that long ago malaria was a serious problem in Central Europe and in parts of the United States. Thus, in the swampy Rhine lowlands, for example, there was a heavy demand for quinine as an antifebrile medication, and it is little wonder that, among others, an Oppenheimer pharmacist, Friedrich Koch (1786–1865), would follow with considerable interest the quinine isolation techniques of Pelletier and Caventou, and then himself try to find a simple and economical way to obtain pure quinine from cinchona bark. Koch is said to have himself succumbed to an insidious case of malaria, and thus he had a vested interest in a practical isolation process.

Koch’s industrial extraction procedure of 1823/24 led not only to good yields, but was in fact so effective and economical that, in principle, it is still practiced today (Fig. 3). His success from an economic standpoint was truly overwhelming, so in 1850 Koch sold his pharmacy and opened a pharmaceutical factory in Oppenheim, a city on the upper Rhine between Mainz and Worms [10]. Production here reached as much as 60 tons of quinine a year, giving Koch’s firm a market share in Germany of 80 %, and thus clear frontrunner status. Subsequent worldwide developments in the quinine market nevertheless had serious consequences with respect to the Oppenheim quinine factory, and Koch’s son Carl was actually forced to shutter the company in 1888.

 

Industrial processes for isolating quinine

Figure 3. Industrial processes for isolating quinine – 1823 [8] and 2010 [9].

 

However, another German firm, Buchler & Co., founded in 1859 with quinine production in Braunschweig, is still today isolating quinine and other components from cinchona. Indeed, the authors of this contribution spoke at some length with the current chief executive officer of the company, Thomas W. Buchler, who represents the fourth generation of the Buchler family to occupy this position (the interview itself will be published as next month’s ChemistryViews installment).

 

References

[1] J. Hermann, Pharm. Z. online 2001, 18. Link; Fünf Pflanzen verändern die Welt, H. Hobhouse, dtv, Munich, Germany, 1992. ISBN: 978-3423300520
[2] U. Sellerberg, pta-forum online 2011. Link
[3] W. Sneader, Drug Discovery – A History, John Wiley & Sons, Chichester, UK, 2005.
[4] W. Hahn, Chemiker-Zeitung 1938, 62, 659.
[5] C. Ledger, Am. J. Pharm. 1881. Link (pdf)
[6] C. Ledger, Am. J. Pharm. 1881, 3, 53.
[7] W. Dethloff, Chinin, Chemie Verlag, Berlin, Germany, 1944.
[8] E. Schwenk, Die Wiege der Pharma-Industrie stand in Oppenheim, Oppenheimer Hefte, 2000, 22, 2–21.
[9] R. Böhm and A. Perrin, Buchler GmbH, Braunschweig, personal communication.
[10] www.ck-wein.de/Weingut-Info/Familie/familie.html

The article has been published in German in:

and was translated by W. E. Russey.

From Pharmacy to the Pub — A Bark Conquers the World: Part 2

Interview with Thomas W. Buchler, the fourth generation of the Buchler family to occupy the position of chief executive officer at Buchler & Co., which is still today isolating quinine and other components from cinchona.

From Pharmacy to the Pub — A Bark Conquers the World: Part 3

The long way from the structure determination to the total synthesis is an exciting detective story.

From Pharmacy to the Pub — A Bark Conquers the World: Part 4

Last but not least, besides explaining how quinine helps against malaria, we talk about drinks containing this wonderful alkaloid, no matter wheather stirred or shaken.

 

Other articles by Klaus Roth published by ChemistryViews magazine:

 

 

 

See all articles published by Klaus Roth in ChemistryViews Magazine

 

 

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