TREA

Cephalosporin salts and injectable compositions

Follow

Information

  • Patent Grant
  • 4994451
  • Patent Number
    4,994,451
  • Date Filed
    Monday, December 11, 1989
    35 years ago
  • Date Issued
    Tuesday, February 19, 1991
    33 years ago
Information
Abstract
Crystalline sulfuric, di-nitric, mono-hydrochloric, di-hydrochloric, and di- and sesqui-orthosphosphoric acid addition salts of 7-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoxyiminoacetamido]-3-[(1-methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylate are stable even at elevated temperatures. The crystalline sulfuric acid addition salt is made by forming an admixture of (a) at least one molar equivalent of sulfuric acid with (b) zwitterion in an amount so as to be present in the admixture at a concentration of greater than 25 milligrams/ml, causing crystallization, separating the crystals, washing and drying. The crystalline monohydrochloride, dihydrochloride, and orthophosphate salts are prepared by dissolving the zwitterion in the appropriate amount of acid, causing crystallization by adding acetone and isolating the crystals. Physical admixtures of the salts with certain bases in proportions to give a pH ranging from about 3.5 to about 7 on dilution with water provide injectable compositions on dilution.
Description
Claims
  • 1. Temperature stable crystalline salts of 7-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoxyiminoacetamido]-3-[(1-methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylate selected from the group consisting of the sulfuric, di-nitric, mono-hydrochloric, and di-hydrochloric acid addition salts, and orthophosphoric acid addition salts containing 1.5-2 molar equivalents of H.sub.3 PO.sub.4, or solvates thereof in physical admixture with a pharmaceutical acceptable non-toxic organic or inorganic base selected from the group consisting of sodium salts with weak non-toxic anions, N-methylglucamine, lysine and arginine in proportions to provide a pH of about 3.5 to about 7 on dilution of the admixture with water to injectable concentration.
  • 2. A physical admixture as recited in claim 1 wherein the salt and the base are present in proportions to provide a pH of about 4 to about 6 on dilution of the admixture with water to injectable concentration.
  • 3. A physical admixture as recited in claim 2 wherein the base is L(+) lysine.
  • 4. A physical admixture as recited in claim 2 wherein the base is L(+) arginine.
REFERENCE TO RELATED APPLICATION

This application is a divisional of co-pending application Ser. No. 144,899 filed Jan. 19,1988, now U.S. Pat. No. 4,910,301 which in turn is a continuation-in-part of application Ser. No. 901,088 filed Aug. 27, 1986, now abandoned which is a continuation-in-part of Ser. No. 762,235 filed Aug. 5, 1985, now abandoned.

US Referenced Citations (13)
Number Name Date Kind
1445803 Spickett et al. Aug 1976
3984403 Fujisawa et al. Oct 1976
3988466 Takagi et al. Oct 1976
4104469 Naito et al. Aug 1978
4180658 Kaplan et al. Dec 1979
4235900 LaVia et al. Nov 1980
4329453 Brodie et al. May 1982
4354023 Falciani et al. Oct 1982
4406899 Aburaki et al. Sep 1983
4434163 Lombardino et al. Feb 1984
4749694 Fix et al. Jun 1989
4797423 Benanti et al. Jan 1989
4880795 Angerbauer Nov 1989
Divisions (1)
Number Date Country
Parent 144899 Jan 1988
Continuation in Parts (2)
Number Date Country
Parent 901088 Aug 1986
Parent 762235 Aug 1985