REVIEW Institute of Pharmacy1, Faculty of Medicine, University of Tartu, Estonia; Department of Dosage Form Technology2, Faculty of Pharmacy, Riga Stradins University, Latvia; Department of Drug Technology and Social Pharmacy3; Department of Pharmacognosy4, Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Pharmacognosy5, National University of Pharmacy, Kharkiv, Ukraine; Department of Pharmacognosy and Pharmaceutical Botany6, Faculty of Pharmacy, Nicolae Testemitanu State University of Medicine and Pharmacy, Republic of Moldova; Faculty of Pharmacy7, Hue University of Medicine and Pharmacy, Hue University, Vietnam Dragendorff’s reagent: Historical perspectives and current status of a versatile reagent introduced over 150 years ago at the University of Dorpat, Tartu, Estonia A. RAAL1,*, A. MEOS1, T. HINRIKUS1, J. HEINÄMÄKI1, E. ROMĀNE2, V. GUDIENĖ3, V. JAKŠTAS4, O. KOSHOVYI5, A. KOVALEVA5, C. FURSENCO6, T. C HIRU6, H. T. NGUYEN7 Received March 25, 2020, accepted April 23, 2020 *Corresponding author: A. Raal, Nooruse 1, Tartu 50411, Estonia [email protected] Pharmazie 75: 299-306 (2020) doi: 10.1691/ph.2020.0438 The well-known Dragendorff’s reagent (DR) was introduced by an Estonian-German Professor Johann Georg Noel Dragendorff (1836–1898) in the middle of the 19th century (1866). Dragendorff, who was a full-time professor in pharmacy at the university of Dorpat (Tartu) used his reagent originally for the rapid screening of herbal products to find traces of alkaloids. DR is a solution of potassium bismuth iodide composing of basic bismuth nitrate (Bi(NO3)3), tartaric acid, and potassium iodide (KI), and when contact with alkaloids DR produces an orange or orange red precipitate. In this review article, we make a short historical overview on the biography and scientific research work of Professor Dragendorff at the University of Dorpat. The chemistry, method of preparation, mechanism of action, and practical uses of DR in various disciplines in various European countries including the Baltic countries (Estonia, Latvia, Lithuania), Finland, Ukraine, Moldova, and in Asia (Vietnam), are also discussed. Over several decades, DR and its modifications have found uses in many new applications and disciplines, and a number of commercial DRs are also currently available on the market. Today, DR is used for example in the production of surfactants, where non-ionic surfactant is precipitated in water solution with modified DR (KBiI4+BaCl2+glacial acetic acid). Total six different potassium iodobismuthate (DR) solutions are also presented in the European Pharmacopoeia. In conclusion, DR (after more than 150 years of its invention in Estonia) has still an important role in pharmaceutical and related sciences all over the world. 1. Introduction Dragendorff`s reagent (DR) was introduced by Johann Georg Noel Dragendorff (1836–1898), who acted as a full-time professor in Pharmacy at the University of Dorpat, Tartu, Estonia (Fig. 1). DR was described for the first time in 1865/1866 (Fig. 2), thus it has more than a 150-year history as a reagent (Dragendorff 1866; Past et al. 2009). Since then, DR has been widely applied e.g., in phar- macy, medicine, forensic chemistry and related sciences all over the world. DR is a color reagent to detect alkaloids in a test sample. Alkaloids, if present in the solution of the sample, react with DR and yield an orange or orange red precipitate. The reagent is a solution of potassium bismuth iodide prepared from basic bismuth nitrate (Bi(NO3)3), tartaric acid, and potassium iodide (KI). In this review article, we make a historical overview on the biog- raphy of Professor J. Georg N. Dragendorff and his scientific research work, when he acted as a full-time professor in pharmacy at the University of Dorpat, Tartu, Estonia. The chemistry, method of preparation, mechanism of action, and practical uses of DR in various disciplines and in various European countries including the Baltic countries (Estonia, Latvia, Lithuania), Finland, Ukraine, Moldova, and in Asia (Vietnam), are also discussed. 1.1. University of Dorpat (Tartu) The University of Dorpat, UD (since 1919, University of Tartu) (Fig. 3) was founded in 1632 by the Swedish King Gustav II Adolf Fig. 1: Professor Georg Dragendorff Pharmazie 75 (2020) 299 REVIEW Siller, a Baltic-German chemist, Carl Schmidt, acted as a full-time professor of pharmacy for a short period of time (1850–1852). His research interests included also human physiology. During 1852 and 1864, the professorship of Pharmacy at the UD was hold by Carl Claus. The greatest progress in pharmacy, however, was obtained thanks to Professor J. Georg N. Dragendorff (1864–1894) (Hinrikus et al. 2005; 2007; Raal et al. 2009). 1.2. Professor J. Georg N. Dragendorff Johann Georg Noel Dragendorff (1836–1898) (Fig. 1) was born in Rostock, Germany in the family of medical doctor. He worked Fig. 2: Description of Dragendorff’s reagent (DR) in Pharmaceutische Zeitschrift as a student in Friedrich Witte Pharmacy and passed the pharmacy für Russland 5 (1866), 82-85. exam in 1856. He graduated from the University of Heidelberg in 1858 and worked later at the Universities of Heidelberg, Rostock, and Munich (Germany). He lived a short time in St. Petersburg, (1594–1632). At the UD, pharmacy was adopted as an independent Russia (1862–1864), and edited there the journal Pharmaceutische discipline in 1802. The rapid early-stage development of phar- Zeitschrift für Russland (The Russian Pharmaceutical Journal). In macy as a teaching subject and research discipline was fostered 1864, J. Georg N. Dragendorff came to Tartu starting his scientific by several outstanding scientists acting at the UD. Within the career at the UD for the next thirty years. In 1894, Dragendorff years 1802–2010, in total 6736 students studied pharmacy at the returned to his home town Rostock (Germany), and worked there UD (later University of Tartu), and 4184 of them were graduated in his small in-house laboratory at home. The reason for his deci- (total 583 individuals interrupted their studies). No information, sion to leave Tartu was the beginning of a russification period at the however, is available about the graduation of the remaining 1969 UD. J. Georg N. Dragendorff died in 1898 at the age of 62 after a students in the archives (Kapp et al. 2012). serious heart disease (Tankler et al. 2002; Hinrikus and Raal 2011). Fig. 4: Dragendorff’s laboratory in Dorpat Fig. 3: University of Dorpat (Tartu). Gravure by August Clara, 1821 In 1799, Russian Tsar Paul I approved the university plan, which In Tartu, Dragendorff focused his teaching and research activities also scheduled the joint professorship in chemistry and pharmacy. solely on pharmacy, pharmacognosy and forensic chemistry for In 1800, the chemist Philipp Arzt came from Tallinn to Tartu as the 30 years. He wrote numerous textbooks and monographs, and first professor of Chemistry and Pharmacy. Unfortunately, Philipp supervised a total of 90 master’s and 87 doctoral theses in the Arzt drowned in August 1802, and thus the position was void fields of pharmaceutical chemistry, pharmacology, pharmacog- for the next one-two years. After this, a German chemist, Alex- nosy, forensic, environmental and food chemistry, physiology and ander Nicolaus Scherer (1772–1824), was nominated as the first bacteriology. The abovementioned number of master and doctoral professor of theoretical and applied chemistry to the UD. After dissertations written under his supervision will probably remain as Scherer, the following scientists hold a professorship in chemistry insurmountable forever (Hinrikus et al. 2005; Tankler et al. 2002). and pharmacy at the UD: David Hieronymus Grindel from Riga, In those times, it was quite usual that research work and doctoral Latvia (1805–1814), Ferdinand Giese from Harkiv, Ukraine (1814– dissertations in pharmacy were interdisciplinary combining espe- 1821), and Gottfried Osann from Weimar, Germany (1823–1828). cially pharmacy with forensic chemistry. The key attribute to the G. Osann was a well-known chemist and researcher of the plat- successful research work of Dragendorff and his students was their inum ore of the Urals, and his scientific work led Carl Claus to success in implementing both qualitative and quantitative analytical discover Ruthenium (Hinrikus et al. 2005, 2007; Raal et al. 2009). methods for alkaloids, glycosides and the other biologically active Professor Friedemann Goebel from Jena, Germany, hold the substances (Tankler et al. 2002; Hinrikus et al. 2005, 2007; Raal et professorship in Chemistry and Pharmacy 1828–1851, and during al. 2009). Unfortunately, the UD had serious financial difficulties his time research work developed a lot at the UD. Furthermore, he by the time of Dragendorff’s stay in Estonia, limiting the research made an initiative for establishing an independent professorship in work of his group. In those times, many Russian universities and pharmacy at the UD, and this professorship was obtained by the act universities abroad had much more resources and funding than in October 19th in 1842. The first Professor of pharmacy, Eduard the UD. On the other hand, Dragendorff noticed that the limited Siller, came to Tartu from Europe via St. Petersburg in summer funding resulted in the higher commitment of the students to make 1843 and remained until 1850. The studies at the UD started a scientific research work. He also showed that all difficulties and in August of the same year, and this can be considered as the challenges related to resources can be overcome with a bright and beginning of a higher pharmaceutical education in Estonia. After strong personality (Raal et al. 2006; Kapp et al. 2012). 300 Pharmazie 75 (2020) REVIEW In the 30-year period under Dragendorff, the UD became one Then, an ion-exchange reaction takes place between ammonium of the most important higher-education and research centers in salt and potassiumtetraiodo bismuthate leading to the formation of Europe. Hermann Thoms, a former Professor of pharmaceutical an insoluble complex salt.