Claims
- 1. A method for forming a crystalline echinocandin nucleus salt from its mixed broth or partially purified process streams comprising in the following order the steps of;providing a solution comprising an echinocandin nucleus or amorphous salt thereof, an aldehyde impurity and a solvent; concentrating said solution by means of a nanofiltration process to form a concentrate; adding a derivatizing agent which selectively interacts with said aldehyde impurity; adjusting the pH of said concentrate to less than 4.0; adding an acid or metal salt; and cooling said concentrate to form a crystalline echinocandin nucleus salt.
- 2. The method of claim 1 further comprising a step (vii) adding a seed crystal to initiate crystallization.
- 3. The method of claim 1 wherein said echinocandin nucleus is represented by the structure
- 4. The method of claim 3 wherein said derivatizing agent is sodium bisulfite, said acid is hydrogen chloride, and said aldehyde impurity is represented by the structure:
- 5. The method of claim 1 wherein said metal salt is preferably added in three portions at different temperatures.
- 6. A crystalline hydrochloride salt of echinocandin B nucleus prepared by the steps ofproviding a solution comprising echinocandin B nucleus or amorphous salt thereof, an aldehyde impurity and a solvent; concentrating said solution by means of a nanofiltration process to form a concentrate; adding sodium bisulfite; adjusting the pH of said concentrate to less than 4.0; adding a chloride metal salt; and cooling said concentrate.
- 7. The crystalline hydrochloride salt of claim 6 wherein said chloride metal salt is added in three portions which comprises a first portion which is added between about 22 and 28° C., a second portion which is added between about 20 and 15° C. and a third portion which is added between about 12 and 8° C.
- 8. The crystalline hydrochloride salt of claim 7 wherein said first portion contains nearly twice as much chloride metal salt by weight as either said second or third portion.
- 9. A crystalline salt form of a cyclopeptide (CP) echinocandin B nucleus represented by the formula CP—NH3+A−, (CP—NH3+)2A−2, or (CP—NH3+M+)A−2 wherein CP—NH3+ is represented by the structure A− is chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, hydrogen oxalate, hydrogen tartrate, benzoate, methanesulfonate, or p-toluenesulfonate; M+ is ammonium, lithium, sodium, potassium or tetraalkylammonium, A−2 is sulfate, oxalate, hydrogen phosphate, tartrate or fumarate; and pharmaceutically acceptable solvates or hydrates thereof.
- 10. A crystalline inner-salt form of a cyclopeptide (CP) echinocandin nucleus represented by the formula (CP—NH3+A−)(M+A−) or ((CP—NH3+)2A−2)(M+2A−2) wherein CP—NH3+ is represented by the structure A− is chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, hydrogen oxalate, hydrogen tartrate, benzoate, methanesulfonate, or p-toluenesulfonate; M+ is ammonium, lithium, sodium, potassium or tetraalkylammonium; A−2 is sulfate, oxalate, hydrogen phosphate, tartrate or fumarate; M+2 is calcium or magnesium; and pharmaceutically acceptable solvates or hydrates thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International Patent Application No. PCT/US00/05494, filed on Mar. 2, 2000, which claims priority to U.S. Provisional Patent Application Ser. No. 60/123,073, filed on Mar. 3, 1999, the contents of each of which are incorporated herein by reference in their entirety.
US Referenced Citations (14)
Foreign Referenced Citations (34)
Number |
Date |
Country |
0 031 221 |
Jul 1981 |
EP |
0031221 |
Jul 1981 |
EP |
0 359 529 |
Mar 1990 |
EP |
0 359 529 |
Mar 1990 |
EP |
0 447 186 |
Sep 1991 |
EP |
0 448 353 |
Sep 1991 |
EP |
0 448 353 |
Sep 1991 |
EP |
0 460 882 |
Dec 1991 |
EP |
0 460 882 |
Dec 1991 |
EP |
0 460 882 |
Dec 1991 |
EP |
0 462 531 |
Dec 1991 |
EP |
0 462 531 |
Dec 1991 |
EP |
0 561 639 |
Sep 1993 |
EP |
0 561 639 |
Sep 1993 |
EP |
WO 9631228 |
Oct 1996 |
WO |
WO 9637509 |
Nov 1996 |
WO |
WO 9637510 |
Nov 1996 |
WO |
WO 9637511 |
Nov 1996 |
WO |
WO 9637512 |
Nov 1996 |
WO |
WO 9705163 |
Feb 1997 |
WO |
WO 9727864 |
Aug 1997 |
WO |
WO 9906062 |
Feb 1999 |
WO |
WO 9943337 |
Sep 1999 |
WO |
WO 0011023 |
Mar 2000 |
WO |
WO 0011023 |
Mar 2000 |
WO |
WO 0012540 |
Mar 2000 |
WO |
WO 0034315 |
Jun 2000 |
WO |
WO 0034315 |
Jun 2000 |
WO |
WO 0035944 |
Jun 2000 |
WO |
WO 0035945 |
Jun 2000 |
WO |
WO 0051564 |
Sep 2000 |
WO |
WO 0051567 |
Sep 2000 |
WO |
WO 0052036 |
Sep 2000 |
WO |
WO 0052037 |
Sep 2000 |
WO |
Non-Patent Literature Citations (3)
Entry |
Ibrahim, F. S. et al., (1995) “The Effect of pH, sugars and calcium ion concentration on the thermal stability of whey proteins” Egyptian J. Dairy Sci. 23:177-178. |
Nail, S. L. and Gatlin, L. A. (1993) “Chapter 3: Freeze drying: Principles and practice” Pharmaceutical Dosage Forms, Parenteral Medications, vol. 2, 2nd Edition, edited by Kenneth, E. A. et al., Marcel Dekker, Inc., pp. 163-233. |
Etter, M.C. and Baures, P.W. (1988) “Triphenylphosphine Oxide as a Crystallization Aid,” J. Am. Chem. Soc. 110:639-640. |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/123073 |
Mar 1999 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
PCT/US00/05494 |
Mar 2000 |
US |
Child |
09/944309 |
|
US |