890 



1 )J-]SCK I FT I( )XS OF ANTIBIOTICS 



Aqueous suspension of precipitate acidified to pH 



I to 4, and NaCl and butanol added. Cooling gives 

 hydrochloride crystals (33). IV. Precipitated 

 from broth-filtrate at pH 8.5 to 9.5 on addition of 

 CaS04 , BaCh , or MgCh . Extracted into water 

 at pH 1.5 and filtered. Filtrate adjusted to pH 

 8.0. This insoluble polyvalent metallic ion salt may 

 be slurried with butanol or acetone at pH 2.0, 

 filtered, and precipitated from the organic solvent 

 by adding water and raising the pH to 4.2 (40). 

 V. Precipitated from acidified broth-filtrate with 

 such arylazosulfonic acid dyes as Polar yellow 

 5G, metanil yellow, Wool blue black 6B, or orange 



II (36). VI. Adsorbed from broth on IRC-50 

 (H''" i)hase) and eluted with A' HCl in 60 per cent 

 methanol. Can also be adsorbed on Dowex 1, 

 Dowex 50, or IR-112, and eluted with dilute alkali 

 (25). VII. Purified by countercurrent distribu- 

 tion using water-saturated butanol at pH 3.0 and 

 a butanol-saturated aqueous solution of the anti- 

 biotic (25). VIII. See I under chlortetraeycline, 

 "Method of Extraction." 



Chemical and physical properties. Amphoteric 

 substance. Trihydrale of free base: Yellow ortho- 

 rhombic (25) or equant to tabular (32) crystals; 

 m.p. 170-175°C (decomposition) (25). Swells and 

 yellows at 165-170°C. Very soluble in methanol. 

 Soluble in ethanol, butanol, ethyl acetate, and 

 chloroform. Soluble to less than 1 mg per ml in 

 watei', benzene, and diethyl ether. Insoluble in 

 petroleum ether. Least soluble in water at pH 

 6.0 (25, 32). Anhydrous tetracycline: m.p. 160-168°C 

 (25). Ultraviolet absorption spectrum maxima: in 

 0.1 N HCl: 220 (E = 13,000), 268 (e = 18,040), 

 und 355 niM (f = 13,320j; in 0.01 M methanolic 

 HCl: 268 (log 6 = 4.27) and 363 m/z (log e = 4.14); 

 in 0.01 M methanolic NaOH:246 (log e = 4.24) and 

 372 mM (log 6 = 4.20), or at 245, 265, and 382 m/z (3, 

 20); in methanol: 235 {E^^n. 188), 269 (El'^^n, 271), 

 298.5 (E'Tcm 128), and 365 m^ (fi'llm 272) (25). Infra- 

 red spectrum given in references 9, 25, and 33. 

 \a]t = -239° (c = 1 per cent in methanol) (2). 

 Gives an orange-yellow solution in Ehrlich's 

 yy-dimethylamino-benzaldehyde reagent (oxytet- 

 racyline gives a blue-green precipitate and super- 

 natant, and chlortetraeycline, a canary-yellow 

 solution). In H2SO4 it gives a stable violet color 

 (oxy tetracycline gives a cherry-red solution, chlor- 

 tetraeycline, a purple solution rapidly changing to 

 greenish l)lackj (9). Separation of the tetracyclines 

 by paper chromatography has been reported (5). 

 Rf values of tetracycline in various systems given 

 in reference 26. Crystallographic data given in 

 references 9, 25, and 32. Somewhat more stable 

 than oxytetracycline and much more stal)le than 

 chlortetraeycline in aqueous solution (13). Most 



stable at acid pH (5, 8). C22H2408X2-3H20: C = 

 52.9%; H = 6.2%; N = 5.5%; H2O = 10.9% (2). 

 pKa = 8.3 and 10.2 (2). Structural formula of 

 tetracvcline: 



H3C 



OH 



N(CH3)2 



OH 

 CONH2 



OH O 



OH O 



Hydrochloride: Bright yellow crystals. Darken 

 gradually; melt with evolution of gas at 214°C 

 (2, 20). Soluble in water to 100 to 200 mg per ml. 

 Very soluble in niethanol and ethanol; slightly 

 soluble in 2-methoxymethanol and n-butanol; 

 relatively insoluble in other organic solvents (32, 

 33). Infrared spectrum given in reference 25. 

 [a];:' = -257.9° (c = 0.5 per cent in 0.1 N HCl) (2) 

 or [ajn = —283° (c = 0.65 per cent in water) (9). 

 Xa and K salts: Yellow crystals (33). Ca salt: 

 Yellow crystals. Soluble in water to 890 ^g per ml 

 at pH 8.55 (32, 33). Mg salt: Soluble in water to 

 1 mg per ml at pH 7.0 (32 j. 



Biological activity: Antibacterial activity is 

 essentially the same as that of chlortetraeycline 

 and oxytetracycline (5, 8, 9). Not active on fila- 

 mentous fungi or yeasts (8) . Cross-resistance with 

 the other tetracyclines (12). In vivo: Active in 

 animals on Streptococcus mitis, Staph, aureus, D. 

 pneumoniae, Listerella monocytogenes, B. anthracis, 

 Pasteurella multocida, K. pneumoniae, and Sal. 

 typhosa infections. Moderately active on Strepto- 

 coccus pyogenes, Sal. gallinarum, and M. tubercu- 

 losis infections (6, 12). Under certain contlitions, 

 potentiates experimental infections with ('. albi- 

 cans and Staph, aureus in mice (14). Active on 

 Toxoplasma gondii in mice (11), natural psittaco- 

 sis infections in parakeets and pigeons (18), feline 

 pneumonitis organism in chick embryos (23), and 

 that of primary atypical pneumonia (Eaton) in 

 cotton rats (15). Concentrations of 1:8000 in- 

 hibit the reproduction of the nematode Anguil- 

 lula aceti. At 1:10,000 ascarid motility is stimu- 

 lated, followed by a period of depressed activity. 

 High concentrations are toxic (41). Some control 

 of crown-gall (Agrobacterium tumefaciens) of roses 

 (27). Active on bacterial wilt of sweet corn {Bac- 

 terium stewartii) (28). Inclusion in the diet im- 

 proves feed efficiency, but not gain rates in pigs 

 (10). Increases weight gain and feed efficiency in 

 chicks (22). Tetracycline localizes in tumor and 

 bone tissue and persists there, probably in the 

 form of a loosely l)onn(l complex with a peijlide 

 (29). 



