EP1638520A2 - Solvates de cefprozil - Google Patents

Solvates de cefprozil

Info

Publication number
EP1638520A2
EP1638520A2 EP04737046A EP04737046A EP1638520A2 EP 1638520 A2 EP1638520 A2 EP 1638520A2 EP 04737046 A EP04737046 A EP 04737046A EP 04737046 A EP04737046 A EP 04737046A EP 1638520 A2 EP1638520 A2 EP 1638520A2
Authority
EP
European Patent Office
Prior art keywords
cefprozil
solvate
dimethylacetamide
crystalline
solution
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04737046A
Other languages
German (de)
English (en)
Inventor
Yatendra Kumar
Neera Tewari
Shailendra Kumar Singh
Bishwa Prakash Rai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1638520A2 publication Critical patent/EP1638520A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine

Definitions

  • the field of the invention relates to solvates of cefprozil.
  • the invention also relates to processes for preparing the solvates of cefprozil, crystalline cefprozil from said solvates and pharmaceutical compositions that include the crystalline cefprozil.
  • Cefprozil is a cephalosporin antibiotic for oral administration and is disclosed in U.S. Patent No. 4,520,334. Chemically, cefprozil is 7/3[(D)-2-amino-2-(4-hydroxyphenyl) acetamido]-3-(Z)-l-propenyl]-ceph-3-em-4-carboxylic acid. Cefprozil has a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms.
  • U.S. Patent No. 4,694,079 discloses a crystalline dimethylformamide solvate of cefprozil characterized by a specific powder X-Ray diffraction pattern and its conversion to cefprozil via lyophilization from an aqueous solution.
  • cefprozil forms good crystalline solvates with N- methylpyrrolidone and N,N-dimethylacetamide. These solvates are easily crystallized out from the reaction mixture, and their conversion to cefprozil requires very mild conditions yielding pure cefprozil.
  • the solvates serve as useful intermediates for preparing cefprozil.
  • an N,N-dimethylacetamide solvate of cefprozil In another general aspect, there is provided an N,N-dimethylacetamide solvate of cefprozil. In another general aspect there is provided a process for the preparation of the N- methylpyrrolidone solvate of cefprozil. The process includes obtaining a solution of cefprozil in one or more solvents; adding N-methylpyrrolidone at a pH of about 4.5 to about 6.5; and isolating the N-methylpyrrolidone solvate of cefprozil.
  • N,N-dimethylacetamide solvate of cefprozil includes obtaining a solution of cefprozil in one or more solvents; adding N,N-dimethylactamide at a pH of about 4.5 to about 6.5; and isolating the N,N-dimethylacetamide solvate of cefprozil.
  • a process for the preparation of the crystalline cefprozil from N-methylpyrrolidone solvate or N,N-dimethylacetamide solvate of cefprozil includes obtaining a solution of N-methylpyrrolidone solvate or N,N-dimethylacetamide solvate of cefprozil in one or more solvents; stirring the solution at a temperature of from about 20 0 C to about 6O 0 C; and isolating the crystalline cefprozil.
  • the solvent may be one or more of acetonitrile, ketone, alcohol, cyclic ether, water, or mixtures thereof.
  • the ketone may include one or more of acetone and ethylmethyl ketone.
  • the alcohol may include one or more of methanol, ethanol, denatured spirit, propanol, and isopropanol.
  • the cyclic ether may include one or more of dioxane and tetrahydrofuran. Isolating the solvate or crystalline cefprozil includes one or more of filtration, filtration under vacuum, decantation and centrifugation.
  • the process may include further drying of the product obtained.
  • the solution of cefprozil may be obtained by dissolving a salt of cefprozil, or adding a base to a suspension of cefprozil in a solvent.
  • the solution may be obtained directly from the reaction in which cefprozil is formed.
  • slurry containing the solvate or crystalline cefprozil may be cooled prior to isolation to obtain better yields and the product may be washed with a suitable solvent.
  • a pharmaceutical composition that includes a therapeutically effective amount of a crystalline cefprozil; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the inventors have developed new solvates of cefprozil, and in particular, the N- methylpyrrolidone solvate and N, N-dimethylacetamide solvates of cefprozil.
  • the N-methylpyrrolidone solvate of cefprozil may be characterized by a crystalline structure containing cefprozil and N-methyl pyrrolidone in a molar ratio of 1 : 1.5.
  • N-methylpyrrolidone solvate of cefprozil may also be characterized by the X-ray powder diffraction peaks at about 6.24, 6.48 and 18.64 degrees two-theta.
  • the N,N-dimethylacetamide solvate of cefprozil may be characterized by a crystalline structure containing cefprozil and N,N-dimethylacetamide in a molar ratio of 2:1.5.
  • N,N-dimethylacetamide solvate of cefprozil may also be characterized by X-ray powder diffraction peaks at about 6.48, 7.08, 8.46 and 18.78 degrees two-theta. It may be further characterized by X-ray powder diffraction peaks at about 18.32, 20.06, 21.64, 22.16 and 24.7 degrees two-theta.
  • the inventors have developed processes for the preparation of the N- methylpyrrolidone and N,N-dimethylacetamide solvates of cefprozil.
  • the inventors also have developed a process for the preparation of a crystalline cefprozil from N- methylpyrrolidone or N,N-dimethylacetamide solvates of cefprozil.
  • the inventors also have developed pharmaceutical compositions that contain the crystalline cefprozil, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
  • the N-methylpyrrolidone solvate of cefprozil is prepared by a process comprising obtaining a solution of obtaining a solution of cefprozil in one or more solvents; adding N-methylpyrrolidone at a pH of about 4.5 to about 6.5; and isolating the N-methylpyrrolidone solvate of cefprozil.
  • the N,N-dimethylacetamide solvate of cefprozil is prepared by a process comprising obtaining a solution of obtaining a solution of cefprozil in one or more solvents; adding N,N-dimethylacetamide at a pH of about 4.5 to about 6.5; and isolating the N,N-dimethylacetamide solvate of cefprozil.
  • the solution of cefprozil may be obtained by dissolving a salt of cefprozil, or adding a base to a suspension of cefprozil in a solvent.
  • a solution may be obtained directly from the reaction in which cefprozil is formed.
  • Suitable bases include alkali metal salts of carboxylic acids, such as sodium acetate and potassium acetate; organic amines, such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, and dicyclohexylamine; ammonium hydroxide; alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; and alkali metal bicarbonates such as sodium bicarbonate.
  • carboxylic acids such as sodium acetate and potassium acetate
  • organic amines such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, and dicyclohexylamine
  • ammonium hydroxide alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • alkali metal bicarbonates such as sodium bicarbonate.
  • the above bases may also be used for adjusting the pH of the solution of cefprozil to about 4.5 to about 6.5.
  • the pH may range from about 5.5 to about 6.5.
  • N-methylpyrrolidone, or N,N-dimethylacetamide may be used for preparing the solvates, hi particular, 1.5 moles of N-methylpyrrolidone, or 0.75 moles of N,N-dimefhylacetaniide may be added per mole of cefprozil used.
  • the volumes of N-methylpyrrolidone, or N,N-dmiethylacetamide may be added in an amount ranging from one to 10 times the volume of the solution of cefprozil. For example, three to six volumes of N-methylpyrrolidone, or N,N-dimethylacetamide may be used.
  • the solvents for preparing the solvates may be any water miscible organic solvents in admixture with water.
  • suitable solvents include ketones such as acetone and ethylmethyl ketone; acetonitrile; alcohols, such as methanol, ethanol, propanol, and isopropanol; cyclic ethers, such as dioxane and tetrahydrofuran; and mixture(s) thereof.
  • the cefprozil or its salts can be obtained by methods known in the art including those described in U.S. Patent Nos. 4,520,022; 4,727,070; 5,608,055; 6,060,268; 6333409, and 2002/120136. In particular, it was prepared according to our co-pending PCT Patent Application Serial Nos. PCT/IB03/04439, andPCT/IB2004/000850.
  • the starting cefprozil may be obtained as a solution directly from the reaction in which cefprozil is formed, for example as disclosed in the patents/ patent applications listed above, and used as such without isolation.
  • the solvate precipitates out of the solution or the reaction mixture spontaneously.
  • the precipitation may also be facilitated by adding seeds of the solvate.
  • the precipitation may also be induced by reducing the temperature.
  • the precipitated solvate may be isolated by conventional methods such as filtration, filtration under vacuum, decantation or centrifugation.
  • the product obtained may be further or additionally dried.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the N-methylpyrrolidone or N,N-dimethylacetamide solvates of cefprozil are converted to crystalline cefprozil.
  • the crystalline cefprozil is prepared by obtaining a solution of N-methylpyrrolidone solvate or N 5 N- dimethylacetamide solvate of cefprozil in one or more solvents; stirring the solution at a temperature of from about 2O 0 C to about 6O 0 C; and isolating the crystalline cefprozil.
  • the solvents may be any water miscible organic solvents in admixture with water.
  • suitable solvents include ketones such as acetone and ethylmethyl ketone; acetonitrile; alcohols, such as methanol, ethanol, propanol, and isopropanol; cyclic ethers, such as dioxane and tetrahydrofuran; and mixture(s) thereof.
  • the crystalline cefprozil product may be obtained as a monohydrate or a hemihydrate of cefprozil.
  • the conversion of the solvates to crystalline cefprozil in the desired form may be facilitated by adding seeds of the desired form of crystalline cefprozil or by reducing the temperature.
  • the crystalline cefprozil obtained may be isolated by conventional methods such as filtration, filtration under vacuum, decantation or centrifugation.
  • the product obtained may be further or additionally dried.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the resulting crystalline cefprozil may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. hi these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the NMR spectra were obtained on a Bruker (DRX 300) 300 MHz instrument.
  • the chemical shifts are expressed in ppm values (parts per million downfield from tetramethylsilane).
  • Solution B Potassium (D)-N-[l-methoxycarbonyl propen-2-yl]- ⁇ -amino-p- hydroxyphenylacetate (dane salt, 14Ig) was stirred in methylene chloride (600ml). N,N - dimethylacetamide (DMAc, 400ml) was added and the slurry was stirred at -35 to - 4O 0 C. N-methylmorpholine(0.8g) and ethylchloroformate(56.5g) were added, the mixture stirred for 1.5 hours at -35 to -4O 0 C and then cooled to -65 0 C.
  • DMAc dimethylacetamide
  • the solution A was added into the solution B at -65°C and stirred for 1 hour at
  • IR in KBr pellet (cm "1 ) - 3422, 3217, 3025, 1764, 1697, 1558, 1518, 1400, 1349, and 1263.
  • IR in KBr pellet (cm "1 ) - 3420, 3216, 3028, 1779, 1699, 1667, 1567, 1518, 1448, 1400, and 1350.
  • Cefprozil dimethylacetamide solvate (10Og) prepared in Example 2 was stirred in water (200ml) at 40-45 0 C for 120minutes. It was then cooled to 5-8 0 C and filtered to obtain crystalline cefprozil monohydrate.
  • Cefprozil N-methyl-2-pyrrolidone solvate as prepared in Example 3 was stirred in water (150ml) at 45-5O 0 C for 120 minutes. The mixture was cooled to 0-5 0 C and crystalline cefprozil monohydrate was collected by filtration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des solvates de cefprozil. L'invention porte également sur des procédés permettant de préparer les solvates de cefprozil, du cefprozil cristallin à partir desdits solvates et des compositions pharmaceutiques qui comprennent du cefprozil cristallin.
EP04737046A 2003-06-19 2004-06-18 Solvates de cefprozil Withdrawn EP1638520A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN818DE2003 2003-06-19
PCT/IB2004/002040 WO2004110399A2 (fr) 2003-06-19 2004-06-18 Solvates de cefprozil

Publications (1)

Publication Number Publication Date
EP1638520A2 true EP1638520A2 (fr) 2006-03-29

Family

ID=33548812

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04737046A Withdrawn EP1638520A2 (fr) 2003-06-19 2004-06-18 Solvates de cefprozil

Country Status (2)

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EP (1) EP1638520A2 (fr)
WO (1) WO2004110399A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102344458B (zh) * 2011-09-06 2013-10-16 山东罗欣药业股份有限公司 一种头孢丙烯化合物晶体及其药物组合物
CN103524533B (zh) * 2013-10-10 2016-01-27 珠海金鸿药业股份有限公司 一种头孢丙烯化合物、其分散片、干混悬剂及制备方法
CN110954392A (zh) * 2019-12-26 2020-04-03 广药白云山化学制药(珠海)有限公司 一种酶法制备头孢丙烯中酶蛋白残留的检测方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4520022A (en) * 1983-01-28 1985-05-28 Bristol-Myers Company Substituted vinyl cephalosporins
US4694079A (en) * 1985-07-29 1987-09-15 Bristol-Myers Company 3-propenyl cephalosporin solvates
GB0118764D0 (en) * 2001-08-01 2001-09-26 Biochemie Gmbh Organic compounds
US6537985B1 (en) * 2001-11-30 2003-03-25 Phoenix Scientific, Inc. Antibiotic formulation and a method of making this formulation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
WO2004110399A3 (fr) 2005-02-17
WO2004110399A2 (fr) 2004-12-23

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