USOO5763603A United States Patent 19 11 Patent Number: 5,763,603 Trickes 45 Date of Patent: Jun. 9, 1998 54 CRYSTALLINE TAZOBACTAM, AND ITS 4,912,211 3/1990 Bonfanti................................. 540/222 PRODUCTION AND USE FOREIGN PATENT DOCUMENTS (75) Inventor: Georg Trickes, Loerrach, Germany 63-66187 3/1988 Japan. 73) Assignee: Taiho Pharmaceutical Co., Ltd., OTHER PUBLICATIONS Tokyo, Japan Chemical Patents Index Basic Abstracts Journal, Section (21) Appl. No.: 403829 B:FARMDOC, 1988, Derwent Publications, week 88.18, 29 22 PCT Filed: Nov. 2, 1994 Jun. 1988, 88-122648/18. 86 PCT No.: PCTAJP94/01855 Primary Examiner-Mukund J. Sham Assistant Examiner-Pavanaram K. Sripada S371 Date: Mar 21, 1995 Attorney, Agent, or Firm-Sughrue. Mion. Zinn. Macpeak S 102(e) Date: Mar. 21, 1995 & Seas, PLLC 87 PCT Pub. No.: WO95/12601 57 ABSTRACT Crystalline sodium 20-methyl-2B-(1,2,3-triazol-1-yl) PCT Pub. Date: May 11, 1995 -methylpenan-3o-carboxylate-1,1-dioxide monohydrate 30 Foreign Application Priority Data (crystalline tazobactam sodium monohydrate) obtainable by adding to a concentrated aqueous solution of sodium Nov. 6, 1993 EP European Pat. Off. .............. 93.18.016 20-methyl-23-(1,2,3-triazol-1-yl)-methylpenam-30 (51) Int. Cl. ... ... CO7D 499/00; A61K 31/425 carboxylate-1,1-dioxide (tazobactam sodium) a solvent 52) U.S. Cl. ............................................ 540/310: 514/210 selected from acetone and ethanol in an amount correspond 58) Field of Search .............................. 540/310; 514/210 ing to a solvent to water ratio of between about 95:5 and 99:1 v/v and crystallizing the desired product from the solvent 56) References Cited mixture. The crystalline tazobactam sodium monohydrate exhibits a high B-lactamase inhibitory activity in combina U.S. PATENT DOCUMENTS tion with B-lactam antibiotics. 4,562,073 12/1985 Micetich et al. ........................ 424/114 4,774.238 9/1988 Brown et al. ....... ... 514/192 30 Claims, 4 Drawing Sheets U.S. Patent Jun. 9, 1998 Sheet 1 of 4 5,763,603 FIG. 1 Weight change (%) 25.0 15.0 c - as as a re - a - - - - - - - - - - -a - - - - - - - - - - - - d. are as a sks as - - - - - - as - as all - - - a - -n - - - - - 10.0 - - - - - - - - - - - - - - - - - - - - - - - - - - - 40 50 60 70 80 90 100 Rel. humidity (%) U.S. Patent Jun. 9, 1998 Sheet 2 of 4 5,763,603 FIG.2 Weight change (%) 50.0 X With drying 400 30.0 20.0 10.0 0.0 Rel, humidity (%) U.S. Patent Jun. 9, 1998 Sheet 4 of 4 5,763,603 No. 2THETA d RELI (%). MAX INTEQI WDTH 0.20 8.6645 25.) 665. 3864.75 0.36 2 .300 7.824 86.8 2290. 659.83 0.69 3 3.820 6.4026 8.2 2063. 3733.20 0.56 4 6.300 5.4336 57.4 54. O84.79 0.58 5 6.59 5.2858 28. 743. 4429.26 0.40 6 8.4 4.886), 4.5 096. 740.80 0.53 7 8.459 4.8027 89.2 23SS. 560.33 0.56 8 8.979 4.67.23 46.5 227. 8882.84 0.70 9 2006 4.4.226 000 2639. 1900.20 0.59 O 2.439 4.44 55.0 45. 1027.94 0.65 22.679 3.977 37. 979. 85.03.04 0.204 23.060 3.8538 8.8 497. 2898. 0.37 3 23.34 3.8080 6. 425. 2749.36 0.5) 4 23.600 3.7668 3.7 362. 205.66 0.33 5 24.739 3.5959 67.3 776. 239.30 0.63 6 25.779 3.453 T).7 98. 995.60 0.47 7 26.80 3.40 28.7 758. 479.2 0.46 8 26.42 3.3707 25. 679. 426.59 0.47 9 27.99 3.93 57.4 54. 84.2 0.13 20 28.340 3.467 2.6 333. 3437.5 0.243 29,079 3.0683 39.8 050. 290.46 0.63 22 30.380 2.9398 22.4 59). 430.54 0.7 23 30.640 2.955 3. 346. 204806 0.39 24 3.78 2.8664. 28.6 SS. 4686.6 0.46 25 3.399 2.8467 7.2 455. 2606.58 0.35 26 3.37 27830 8.2 28. 603.78 0.73 27 32.779 2.7300 20.5 S4. 375. 0.63 28 33.26 2.695 9. S03. 3562.67 0.66 9 34.299 2.6.24 4.6 385. 2552.69 0.56 30 34.480 ).599 6. 424. 2592.66 0.44 3. 35.680 ). 544 30.) 197. S869.09 0.73 3) 36:40 2.4768 20.4 537. 3974.05 0.74 33 36.89 2.439) 30.6 808. 5662.38 0.65 34 31.40 2.488 . 309. I4.79 0.3 35 38.320 2.3470 7.4 96. 844.75 0.22 36 39.400 2.285 4.4 380. 342.37 0.94 IENTENSITY 5,763,603 1. 2 CRYSTALLINE TAZOBACTAM, AND ITS 30-carboxylate-1,1-dioxide monohydrate (crystalline tazo PRODUCTION AND USE bactam sodium monohydrate) is characterized by adding to a concentrated aqueous solution of sodium 20-methyl-2,3- TECHNICAL FIELD (1,2,3-triazol-1-yl) -methylpenam-30-carboxylate-1,1- dioxide (tazobactam sodium) a solvent selected from The present invention relates to a novel crystalline peni acetone and ethanolin an amount corresponding to a solvent cillin derivative, crystalline 20-methyl-23-(1,2,3-triazol-1- to water ratio of between about 95:5 v/v and about 99:1 wifv yl)-methylpenam-3o-carboxylic acid-1,1-dioxide, and its and crystallizing the desired product from the solvent mix production and use in a medicine. ture. BACKGROUND ART 10 The tazobactam sodium can be obtained in accordance with a method described, for example, in EPOS 97 446. In EPOS 97 446 certain penicillin derivatives are dis The concentrated aqueous solution of tazobactam sodium closed; in particular, 20-methyl-2B-(11.2,3-triazol-1-yl)- used for this crystallization process should contain about 0.1 methylpenam-3o-carboxylic acid-1.1-dioxide of the for to 0.4 g preferably about 0.25 to 0.35 g of water per g of mula 15 tazobactam equivalent present, The ratio of acetone or ethanol to water is critical. Already at a ratio of 9:1 viv it is not possible to crystallize the product even at -20° C. Suitable ratios for crystallization are about 95:5 to 99:1 viv. Preferred ratios are about 96:4 to 98:2. particularly about 97:3. The crystallization is preferably carried out at a temperature of about -10° to +30° C. more cooH preferably +5° C. to a room temperature, for about 1 to 30 (hereinbelow "tazobactam") and its pharmaceutically hours. acceptable salts, notably the sodium salt, are reported to be 25 The most preferable solvent is acetone. The acetone, in useful as B-lactamase inhibitory agents in combination with the amount dictated by the above recommended acetone to known B-lactam antibiotics, viz. increasing the antimicro water ratio, can be added at once and the mixture be left for bial activity of the B-lactam antibiotics. a sufficient time, e.g. about 10 to 30 hours to crystallize. However, up to the present tazobactam sodium has been However, preferably the acetone to be added is divided in obtained in solid form only in the amorphous state, e.g. as 3 volumes, which are added successively to the concentrated a lyophilisate. Such solid forms are hygroscopic, possess aqueous tazobactam solution a about room temperature. The inferior stability, and their purification require laborious, e.g. first volume is about 23 to 27% of the total acetone volume, lyophilizing procedures. the second volume is about 24 to 28% of the total acetone Thus, there is a need for a crystalline modification of volume and the third volume is about 46 to 52% of the total tazobactam sodium, which overcomes all these drawbacks. 35 acetone volume preferably, the first volume is about 24 to Initial attempts to crystallize the product did not offer the 25% of the total acetone volume, the second volume is about required result: Due to the high solubility of tazobactam 26to 27% of the total acetone volume and the third volume sodium in water it was not expected that the product could is about 48 to 50% of the total acetone volume. The first be crystallized from an aqueous medium. This assumption volume is preferably added together with a small volume of was supported by findings, according to which concentrated methanol so as to postpone crystallization until the addition aqueous tazobactam sodium solutions could not be crystal of the second volume. To that end the methanol added to the lized from methanol due to the solubility of the product in first volume of acetone is preferably about 1 to 4% w/v of the that solvent; moreover, attempts with methyl ethyl ketone acetone totally added. The second volume of acetone will water 95:5 v/v and with ethyl acetate?water 95:5 viv as start crystallization which can be promoted by scratching the solvent failed due to a separation of phases, without crys 45 wall of the vessel or by seeding with a small amount of tallization. Therefore, crystallization in the absence of water tazobactam sodium monohydrate seed crystals. After addi was attempted: Based on a known procedure, tazobactam tion of the third volume of acetone the crystal yield can be was suspended in methanol, and one equivalent of sodium improved by cooling the mixture, e.g.