WO2004101547A1 - Procedes de purification de gatifloxacine et nouvelle forme de gatifloxacine - Google Patents

Procedes de purification de gatifloxacine et nouvelle forme de gatifloxacine Download PDF

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Publication number
WO2004101547A1
WO2004101547A1 PCT/IN2003/000191 IN0300191W WO2004101547A1 WO 2004101547 A1 WO2004101547 A1 WO 2004101547A1 IN 0300191 W IN0300191 W IN 0300191W WO 2004101547 A1 WO2004101547 A1 WO 2004101547A1
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WO
WIPO (PCT)
Prior art keywords
process according
gatifloxacin
acid
amine
solvent extraction
Prior art date
Application number
PCT/IN2003/000191
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Jonnala Sambi Reddy
Original Assignee
Hetero Drugs Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Drugs Limited filed Critical Hetero Drugs Limited
Priority to AU2003304118A priority Critical patent/AU2003304118A1/en
Priority to PCT/IN2003/000191 priority patent/WO2004101547A1/fr
Publication of WO2004101547A1 publication Critical patent/WO2004101547A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to methods for the purification of gatifloxacin.
  • the present invention also relates to a stable novel crystalline form of gatifloxacin hemihydrate.
  • the object of the present invention is to provide simple and effective methods for the purification of gatifloxacin.
  • the another object of the present invention is to provide a stable novel crystalline form of gatifloxacin hemihydrate, process for preparing it and a pharmaceutical composition containing it.
  • the present invention provides simple and effective methods for purifying gatifloxacin that contains impurities such as 1-Cyclopropyl-6-fluoro-1 ,4- dihydro-8-hydroxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (hydroxy impurity), 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(1- piperazinyl)-4-oxo-3-quinolinecarboxylic acid (desmethyl piperazine impurity), 1- Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(2,5-dimethyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid (2,5-dimethyl piperazine impurity), 1-Cyclopropyl- 6-fluoro-1 ,4-dihydro-8-methoxy-7-(3,5-dimethyl-1-piperazinyl)
  • a method for purification of gatifloxacin which comprises the steps of: a) lowering the pH of the suspension of impure gatifloxacin in water sufficiently to effect dissolution of the solids; b) treating the aqueous solution formed in step (a) to remove impurities; and c) recovering substantially pure gatifloxacin from the aqueous solution of step (b) by raising the pH and by collecting the resulting crystals.
  • the organic solvents of limited or no water solubility which may be used for the solvent extraction include esters, e.g., alkyl esters such as ethyl acetate, isopropyl acetate, isobutyl acetate; ethers, e.g., dialkyl ethers such as isopropyl ether; ketones, e.g., dialkyl ketones such as methyl isobutyl ketone; hydrocarbons, e.g., aromatic hydrocarbons such as toluene and chlorinated solvents, e.g., chloroform, methylene dichloride.
  • esters e.g., alkyl esters such as ethyl acetate, isopropyl acetate, isobutyl acetate
  • ethers e.g., dialkyl ethers such as isopropyl ether
  • ketones e.g., dialkyl ketones such as methyl isobuty
  • Adsorbents useful for adsorption technique include activated carbon and diatomaceous earth.
  • the pH of the solution is raised, preferably to about 6 to
  • the impurities present in the solution formed in step (a) is removed by the techniques such as solvent extraction or adsorption; or combination thereof.
  • the organic solvents of limited or no water solubility which may be used for the solvent extraction include esters, e.g., alkyl esters such as ethyl acetate, isopropyl acetate, isobutyl acetate; ethers, e.g., dialkyl ethers such as isopropyl ether; ketones, e.g., dialkyl ketones such as methyl isobutyl ketone; hydrocarbons, e.g., aromatic hydrocarbons such as toluene and chlorinated solvents, e.g., chloroform, methylene dichloride.
  • Adsorbents useful for adsorption technique include activated carbon and diatomaceous earth.
  • the pH of the solution is lowered, preferably to about 6 to 8, more preferably to about 6.5 to 7.5 by using an acid like mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid; or organic acid, e.g., acetic acid, formic acid, trifluoro acetic acid.
  • an acid like mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid; or organic acid, e.g., acetic acid, formic acid, trifluoro acetic acid.
  • Hydrochloric acid is the preferred acid.
  • the resulting crystals may be collected by filtration or centrifugation.
  • the mixture of gatifloxacin, the ester solvent and water is heated to 50°C to 80°C and gatifloxacin hemihydrate form H6 is isolated at about 10°C to 30°C.
  • Gatifloxacin in any hydrated form excepting gatifloxacin hemihydrate form H6 or gatifloxacin prepared by any previously known method may be used in the method.
  • Water should be used in such a quantity that the total content of water in the mixture is 0.5 to 1.2 moles per mole of gatifloxacin.
  • a hydrated form of gatifloxacin or gatifloxacin prepared by a known method may be used in the process.
  • a pharmaceutical composition comprising gatifloxacin hemihydrate form H6 and pharmaceutically acceptable carrier or diluent.
  • Figure 1 is a x-ray powder diffraction spectrum of gatifloxacin hemihydrate form H6. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper -K ⁇ radiation.
  • the present invention provides simple and effective methods for purifying gatifloxacin that contains impurities such as 1-Cyclopropyl-6-fluoro-1 ,4- dihydro-8-hydroxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (hydroxy impurity), 1-CycIopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-7-(1- piperazinyl)-4-oxo-3-quinolinecarboxylic acid (desmethyl piperazine impurity), 1- Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(2,5-dimethyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid (2,5-dimethyl piperazine impurity), 1-Cyclopropyl- 6-fluoro-1 ,4-dihydro-8-methoxy-7-(3,5-dimethyl-1-piperazin
  • the method of purification involves first treating aqueous suspension of gatifloxacin containing various contaminants from the production procedure, with an acid so that the solids are in solution.
  • a suspension containing about 5 to 50 % by weight of gatifloxacin in water may be used.
  • the pH of an impure aqueous suspension containing gatifloxacin may vary from about 5 to 8.5.
  • This aqueous suspension is treated with an acid like mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid; or organic acid, e.g., acetic acid, formic acid, trifluoro acetic acid. Hydrochloric acid is the preferred acid.
  • the acid is added to the suspension until solution of the solids is obtained. This generally occurs when the pH of the solution is below 4, preferably about 1 to 4 and more preferably about 2 to 4.
  • the organic solvents of limited or no water solubility which may be used for the solvent extraction include esters, e.g., alkyl esters such as ethyl acetate, isopropyl acetate, isobutyl acetate; ethers, e.g., dialkyl ethers such as isopropyl ether; ketones, e.g., dialkyl ketones such as methyl isobutyl ketone; hydrocarbons, e.g., aromatic hydrocarbons such as toluene and chlorinated solvents, e.g., chloroform, methylene dichloride.
  • esters e.g., alkyl esters such as ethyl acetate, isopropyl acetate, isobutyl acetate
  • ethers e.g., dialkyl ethers such as isopropyl ether
  • ketones e.g., dialkyl ketones such as methyl isobuty
  • the pH of the treated aqueous solution is raised to within the range of 6 to 8, preferably about pH 6.5 to 7.5.
  • the product then crystallizes in the form of easily filtered particles.
  • the recovery of substantially pure gatifloxacin by this method is excellent; yields of over 95% being achieved.
  • the substantially pure gatifloxacin may be collected by filtration or centrifugation.
  • the increase in pH is effected by treating the solution with a base like alkali metal hydroxide, e.g., sodium hydroxide, potassium hydroxide; alkali metal carbonates, e.g., sodium carbonate; basic phosphates, e.g., alkali metal phosphate such as trisodium phosphate; ammonia; or an organic amine, e.g., lower alkyl amines like butyl amine, diethyl amine, trimethyl amine lower, triethyl amine, lower alkanol amine, like ethanol amine; strongly basic heterocyclic amines, like N-methyl morpholine or piperidine.
  • Sodium hydroxide is the preferred base.
  • This aqueous suspension is treated with a base like alkali metal hydroxide, e.g., sodium hydroxide, potassium hydroxide; alkali metal carbonates, e.g., sodium carbonate; basic phosphates, e.g., alkali metal phosphate such as trisodium phosphate; ammonia; or an organic amine, e.g., lower alkyl amines like butyl amine, diethyl amine, trimethyl amine lower, triethyl amine, lower alkanol amine, like ethanol amine; strongly basic heterocyclic amines, like N-methyl morpholine or piperidine.
  • Sodium hydroxide is the preferred base.
  • the base is added to the suspension until solution of the solids is obtained. This generally occurs when the pH of the solution is above 9.5, preferably about 9.5 to 11.5 and more preferably to about 10 to 11.
  • the solution containing the impurities in solution is amenable to the removal of the impurities by.
  • the techniques such as organic solvent extraction or adsorption; or combination thereof. These techniques may be employed in any conventional manner.
  • the pH is lowered to within the range of 6 to 8, preferably about pH 6.5 to 7.5.
  • the product then crystallizes in substantially pure form.
  • the crystals may be collected by filtration or centrifugation. The recovery of pure gatifloxacin by this method is excellent; yields of over 95% being achieved.
  • the decrease in pH is effected by treating the solution with an acid like mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid; or organic acid, e.g., acetic acid, formic acid, trifluoro acetic acid.
  • an acid like mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid; or organic acid, e.g., acetic acid, formic acid, trifluoro acetic acid.
  • Hydrochloric acid is the preferred acid.
  • Gatifloxacin hemihydrate form H6 is characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 7.8, 9.2, 9.5, 9.8, 11.4, 12.3, 12.9, 13.6, 19.8, 20.1, 21.2, 21.9, 24.4, 25.4 and 25.9 degrees.
  • Typical x-ray diffraction spectrum of Gatifloxacin hemihydrate form H6 is shown in figure 1.
  • a process for preparation of gatifloxacin hemihydrate form H6 there is provided.
  • gatifloxacin an ester solvent and a suitable amount of water are mixed and gatifloxacin hemihydrate form H6 is isolated from the mixture.
  • Gatifloxacin in any hydrated form excepting gatifloxacin hemihydrate form H6 or gatifloxacin prepared by any previously known method may be used in the method.
  • anhydrous gatifloxacin is formed in the process.
  • the mixture of gatifloxacin, the ester solvent and water is heated to about 50°C to 80°C, maintained at this temperature for about 10 minutes to 10 hours, contents are cooled and separated gatifloxacin hemihydrate form H6 is collected by filtration or centrifugation.
  • Suitable ester solvents are ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate.
  • Ethyl acetate is the preferred solvent.
  • Water should be used in such a quantity that the total content of water in the mixture is 0.5 to 1.2 moles per mole of gatifloxacin.
  • a hydrated form of gatifloxacin or gatifloxacin prepared by a known method may be used in the process.
  • a pharmaceutical composition comprising gatifloxacin hemihydrate form H6 and pharmaceutically acceptable carrier or diluent.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des procédés de purification de gatifloxacine. Cette invention concerne en outre une nouvelle forme cristalline stable de semi-hydrate de gatifloxacine.
PCT/IN2003/000191 2003-05-19 2003-05-19 Procedes de purification de gatifloxacine et nouvelle forme de gatifloxacine WO2004101547A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003304118A AU2003304118A1 (en) 2003-05-19 2003-05-19 Purification methods of gatifloxacin and a novel form of gatifloxacin
PCT/IN2003/000191 WO2004101547A1 (fr) 2003-05-19 2003-05-19 Procedes de purification de gatifloxacine et nouvelle forme de gatifloxacine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000191 WO2004101547A1 (fr) 2003-05-19 2003-05-19 Procedes de purification de gatifloxacine et nouvelle forme de gatifloxacine

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WO2004101547A1 true WO2004101547A1 (fr) 2004-11-25

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980470A (en) * 1986-01-21 1990-12-25 Kyorin Pharmaceutical Co., Ltd. 8-alkoxyquinolonecarboxylic acid and salts thereof
EP0805156A1 (fr) * 1994-12-21 1997-11-05 Kyorin Pharmaceutical Co., Ltd. Hydrate d'acide 8-alcoxyquinolonecarboxylique ayant une excellente stabilite et procede de fabrication
WO2001057017A1 (fr) * 2000-02-01 2001-08-09 Kyorin Pharmaceutical Co., Ltd. Sel de sulfate de quinolone d'acide carboxylique et son utilisation
US20020052379A1 (en) * 2000-09-13 2002-05-02 Raghavan Krishnaswamy S. Gatifloxacin pentahydrate
WO2003094919A2 (fr) * 2002-05-10 2003-11-20 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines de gatifloxacine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980470A (en) * 1986-01-21 1990-12-25 Kyorin Pharmaceutical Co., Ltd. 8-alkoxyquinolonecarboxylic acid and salts thereof
EP0805156A1 (fr) * 1994-12-21 1997-11-05 Kyorin Pharmaceutical Co., Ltd. Hydrate d'acide 8-alcoxyquinolonecarboxylique ayant une excellente stabilite et procede de fabrication
WO2001057017A1 (fr) * 2000-02-01 2001-08-09 Kyorin Pharmaceutical Co., Ltd. Sel de sulfate de quinolone d'acide carboxylique et son utilisation
US20020052379A1 (en) * 2000-09-13 2002-05-02 Raghavan Krishnaswamy S. Gatifloxacin pentahydrate
WO2003094919A2 (fr) * 2002-05-10 2003-11-20 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines de gatifloxacine

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