WO2012119653A1 - Procédé de préparation de la forme cristalline a du linézolid - Google Patents

Procédé de préparation de la forme cristalline a du linézolid Download PDF

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Publication number
WO2012119653A1
WO2012119653A1 PCT/EP2011/053555 EP2011053555W WO2012119653A1 WO 2012119653 A1 WO2012119653 A1 WO 2012119653A1 EP 2011053555 W EP2011053555 W EP 2011053555W WO 2012119653 A1 WO2012119653 A1 WO 2012119653A1
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WO
WIPO (PCT)
Prior art keywords
linezolid
process according
solvent
antisolvent
temperature
Prior art date
Application number
PCT/EP2011/053555
Other languages
English (en)
Inventor
Raymond Jozef Hubertus Westheim
Original Assignee
Synthon Bv
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 Synthon Bv filed Critical Synthon Bv
Priority to EP11707846.9A priority Critical patent/EP2683696A1/fr
Priority to PCT/EP2011/053555 priority patent/WO2012119653A1/fr
Publication of WO2012119653A1 publication Critical patent/WO2012119653A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the present invention relates to an improved process for making the compound linezolid, especially in its specific crystalline form called Form A.
  • Linezolid is a pharmaceutically active compound useful as an antibacterial agent, e.g. for the treatment of diabetic food infections caused by Gram-positive bacteria. It is represented by formula (I).
  • the marketed pharmaceutical compositions are a sterile isotonic solution for an i.v. infusion, a tablet for oral administration and an aqueous suspension for oral administration. They are marketed, i.e., under brand name ZYVOX by Pfizer.
  • the molecule of linezolid has one asymmetric carbon in the molecule allowing for 2 enantiomers; the marketed compound is the (S)-enantiomer.
  • linezolid is present as a free base.
  • Linezolid exhibits polymorphism.
  • Various solid state forms of linezolid have been disclosed in the prior art: crystalline Form I (J.Med. Chem. 39(3), 673 (1996)), Form II (WO 01/057035, US 6,559,305), Form III (WO 2005/035530) and many others
  • the crystalline Form III of WO 2005/035530 is of certain importance in the pharmaceutical industry as it is a sufficiently stable, good crystalline form with a good processability and compatibility with pharmaceutical excipients, particularly for making solid state dosage forms.
  • the Form III was obtained in the original WO 2005/035530, e.g., by heating linezolid at 130-140°C, refluxing in a solvent such as toluene or xylene or by crystallization from a seeded solution in a solvent.
  • the WO 2009/063505 obtained the crystalline linezolid (which corresponds to the Form III when evaluating of the disclosed XRPD pattern) by crystallization from various polar aprotic organic solvents, preferably from dioxane/di-isopropyl ether mixture, or by a rapid
  • WO 2005/035530 appeared to be identical with the product of WO 95/07271 (Form I) during prosecution of the patent application.
  • Form A solid state form of linezolid resulting from the processes described in the present application is denoted Form A throughout the specification and is defined by its X-ray powder diffraction (XRPD) data.
  • XRPD X-ray powder diffraction
  • it can either correspond to previously denoted Form I or to Form III. While several production processes of making the crystalline linezolid are known in the art, an improvement in this respect is still desirable.
  • the present invention relates to the discovery of a new process for making the crystalline
  • Form A of linezolid as defined hereinafter, which process is useful in a reliable production on an industrial scale.
  • the process is characterized by a controlled precipitation of the solid linezolid from a solution thereof in an organic solvent at a preselected temperature by means of an antisolvent added to the solution at this preselected temperature.
  • a process for crystallizing linezolid in the crystalline Form A comprising a step of dissolving linezolid in an organic solvent at a temperature of at least 80°C to obtain a solution, followed by a step of precipitating linezolid Form A from the solution at the same temperature.
  • the precipitating comprises adding, upon maintaining the temperature of at least 80°C, an antisolvent to said solution in an amount sufficient to induce precipitation of linezolid.
  • the organic solvent is an aliphatic alcohol with a boiling point higher than 80°C.
  • the organic solvent is essentially anhydrous.
  • the antisolvent is an aliphatic hydrocarbon with a boiling point higher than 80°C.
  • the solution is seeded with crystals of the crystalline Form A of linezolid.
  • the so obtained suspension of linezolid crystals in the solvent-antisolvent mixture is stirred at a temperature higher than 80°C for at least 15 minutes and preferably for at least 1 hour.
  • the solvent-antisolvent mixture comprising the linezolid Form A crystals is cooled to an ambient temperature and the crystals are isolated by filtration or centrifugation.
  • the formed linezolid Form A is substantially free from other solid state forms of linezolid, particularly from the Form II and/or from hydrated forms.
  • the "Form A" of linezolid is a crystalline form of linezolid that is characterized by an XRPD powder diffraction pattern comprising, inter alia, principal peaks at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees 2 theta ( ⁇ 0.2 degrees 2 theta) .
  • the XRPD pattern of the Form A obtained by the process of the present invention substantially corresponds to that as disclosed for the Form III in
  • the process of the present invention is based on the finding that linezolid selectively and reliably crystallizes from a solution in the desired Form A, if the temperature, at which the crystals are formed, is higher than 80°C.
  • the Form A is the only thermodynamically stable form at such temperatures.
  • the invention provides a process of making linezolid Form A, wherein linezolid is dissolved in a solvent to obtain a solution and crystallizes from said solution at a temperature higher than 80°C.
  • the Form A is the only stable crystalline form of linezolid at said temperature, it is thereby assured that the precipitated linezolid is polymorphically pure, i.e. it does not comprise any crystalline form other than the Form A.
  • the second technique in which a hot solution of linezolid in a solvent is brought into contact with an antisolvent (i.e. with a liquid in which the linezolid is practically insoluble) at a defined, pre-determined temperature, allows forming crystals of linezolid Form A under reliable and well controllable conditions, which are particularly important in large scale production.
  • an antisolvent i.e. with a liquid in which the linezolid is practically insoluble
  • this technique is preferred and is disclosed in detail below.
  • the limit of 80°C does not represent a sharp limit, but it rather indicates an average limit value, above which the inventive process provides the desired results.
  • performing the process at lower temperatures e.g. 78°C or 75°C etc., may still be within the inventive concept.
  • the linezolid Form A obtained by the process of the present invention is substantially free from other crystalline forms of linezolid, particularly from the Form II of linezolid, which can otherwise be very easily formed by any process of "classical crystallization", in particular if such crystallization occurs at a temperature below 80°C.
  • the "substantially free” means that less than 10%, and advantageously less than 5% of other crystalline forms are present in the precipitated and/or isolated product comprising the Form A of linezolid.
  • the Form A of linezolid obtained by the process of the present invention exhibits an excellent batch-to-batch uniformity in the size and shape of the formed crystals.
  • the process provides for crystals of excellent flowability, which is an advantageous and very suitable property for the formulation into pharmaceutical compositions.
  • a solution of linezolid in a suitable solvent is provided at a temperature of 80°C and higher.
  • the solution may be pre-filtered hot to remove undesired solid particles, optionally in the presence of a surface active material, e.g. activated carbon, to improve the color and clarity of the solution.
  • the solution is kept at a temperature higher than 80°C, in some embodiments higher than 90°C and yet in other embodiments between 90 and 120°C.
  • the linezolid starting material useful for making the solution can be in any physical form of the linezolid base including the hydrated forms, in any degree of purity.
  • the starting linezolid can also be crude linezolid that is present in the reaction mixture obtained after the chemical synthesis of linezolid (an example is, e.g., WO 95/07271) or after liberation of the linezolid base from a linezolid salt. Processes for obtaining linezolid and its isolated forms are well known in the art.
  • the "solvent" is an organic liquid having a boiling point of at least 80°C, preferably at least 90°C.
  • the solvent is essentially anhydrous, i.e. it does not comprise water or may comprise only traces of water such as less than 0.5%. This is because of a risk of forming linezolid hydrates, which should be limited or avoided.
  • the solvent is advantageously a polar organic solvent and more preferably is an aliphatic alcohol, e.g. 1-butanol.
  • the suitable concentration of linezolid in the solvent is so selected that the solution can be kept at the chosen temperature without nucleation at said temperature. In an example, the advantageous concentration is in the range of between 50-500 g/1, preferably 100-400 g/1.
  • an antisolvent is added to the linezolid solution upon maintaining the temperature of at least 80°C, in an amount sufficient to induce precipitation of linezolid from the solvent-antisolvent mixture at this temperature.
  • the "antisolvent” is a liquid, in which the linezolid is essentially insoluble.
  • the antisolvent comprises at least one aliphatic and/or alicyclic hydrocarbon, having a boiling point of at least 80°C, preferably at least 90°C.
  • the antisolvent is a heptane such as n-heptane.
  • the antisolvent is free from traces of water.
  • the antisolvent Prior to any addition of the linezolid solution, the antisolvent is advantageously temperated at a predetermined temperature for easier maintaining the desired temperature during contacting with the solution.
  • a predetermined temperature for easier maintaining the desired temperature during contacting with the solution.
  • such temperature of the antisolvent is from 60 to 90°C.
  • the mutual ratio between the antisolvent and the solvent is from 1 : 1 to 10:1 (v/v), advantageously from 2: 1 to 5: 1 (v/v).
  • the crystallization medium may be seeded with seeds of the desired Form A of linezolid. These seeds may be obtained by heating linazolid (produced following US 5,688,792) at 130°C to 140°C under nitrogen atmosphere for 4 hours).
  • the rate of the addition of the antisolvent to the solution is not specifically limited. Care is to be taken that the speed is sufficient to maintain the temperature of the formed mixture at the predetermined value.
  • the actual temperature of the mixture during the whole period of contacting the solution with the antisolvent does not drop below 80°C.
  • the precipitate is formed rapidly after contacting of both fluids.
  • the suspension is then cooled to a temperature of 25°C or less.
  • the rate of cooling is not specifically prescribed but the average cooling time should advantageously be less than 2 hours.
  • the solid material is isolated from the cool mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by fresh antisolvent, and dried.
  • the precipitate comprises small and uniform particles of the Form A of linezolid. If the above process conditions are met, the precipitate comprises the product, which is essentially free from Form II of linezolid and/or from any hydrated form thereof.
  • the linezolid Form A prepared by the process of the present invention can be formulated and used in pharmaceutical compositions.
  • a suitable pharmaceutical composition may comprise the linezolid Form A and at least one pharmaceutically acceptable excipient.
  • excipients are known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances such as absorption enhancers, penetration enhancers, surfactants, co-surfactants, and specialized oils.
  • the proper excipient(s) are selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphates, sugars, etc.
  • Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxy ethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose; polyvinylpyrrolidones; polyethylenoxides;
  • polyalkylene glycols such as polyethylene glycol and polypropylene glycol
  • polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Carbopol ® (B.F.
  • Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated polyglycolyzed glycerate.
  • Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium
  • Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars (polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches.
  • the compositions may be formulated into various types of dosage forms, for instance as solutions or suspensions for parenteral or oral administration, as tablets or capsules for oral administration, ointments or lotions for transdermal administration etc. The above lists of excipients and forms are not exhaustive.
  • the linezolid Form A prepared by the process of the present invention is useful as an antibacterial agent, in treating various diseases caused by some types of bacteria, by
  • the effective amounts range from 1 mg to 500 mg, expressed as the amount of linezolid base, per day.
  • Scan step time between 0.7-11.0 seconds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de préparation de la forme cristalline A du linézolid, comprenant une étape de dissolution du linézolid dans un solvant organique à une température d'au moins 80°C pour obtenir une solution, suivie d'une étape de précipitation, ladite étape comprenant, de préférence, l'ajout, avec maintien d'une température d'au moins 80°C, d'un antisolvant à ladite solution en une quantité suffisante pour induire la précipitation du linézolid.
PCT/EP2011/053555 2011-03-09 2011-03-09 Procédé de préparation de la forme cristalline a du linézolid WO2012119653A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP11707846.9A EP2683696A1 (fr) 2011-03-09 2011-03-09 Procédé de préparation de la forme cristalline a du linézolid
PCT/EP2011/053555 WO2012119653A1 (fr) 2011-03-09 2011-03-09 Procédé de préparation de la forme cristalline a du linézolid

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Application Number Priority Date Filing Date Title
PCT/EP2011/053555 WO2012119653A1 (fr) 2011-03-09 2011-03-09 Procédé de préparation de la forme cristalline a du linézolid

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014101064A1 (fr) * 2012-12-27 2014-07-03 上海创诺医药集团有限公司 Procédé de préparation de la forme i cristalline de linézolide
WO2015068121A1 (fr) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Procédé pour la préparation de la forme cristalline i de linézolide et ses compositions

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
WO2001057035A1 (fr) 2000-02-02 2001-08-09 Pharmacia & Upjohn Company Facies de cristaux de linezolide (forme ii)
US6559305B1 (en) 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
WO2005035530A1 (fr) 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid
WO2006004922A1 (fr) 2004-06-29 2006-01-12 Teva Pharmaceutical Industries Ltd. Forme cristalline iv de linezolide
US20060111350A1 (en) 2004-06-29 2006-05-25 Judith Aronhime Solid forms of linezolid and processes for preparation thereof
US20070015753A1 (en) * 2005-07-15 2007-01-18 Glenmark Pharmaceuticals Limited Process for the preparation of a crystalline form of (S)-N [[3-(3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide
WO2007026369A1 (fr) 2005-08-29 2007-03-08 Symed Labs Limited Nouvelle forme amorphe du linezolid
EP2033960A2 (fr) 2007-09-04 2009-03-11 Dipharma Francis S.r.l. Formule d'hydrate cristalline de linézolide et sels de linézolide
WO2009063505A2 (fr) 2007-10-08 2009-05-22 Usv Limited Processus de préparation de (s) (n-[[3-[3-fluoro-4-(4-morpholinyle) hen l -2-oxo-5-oxazolidine l méthyl]acétamide

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
EP0717738A1 (fr) 1993-09-09 1996-06-26 PHARMACIA & UPJOHN COMPANY Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
WO2001057035A1 (fr) 2000-02-02 2001-08-09 Pharmacia & Upjohn Company Facies de cristaux de linezolide (forme ii)
US6559305B1 (en) 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
WO2005035530A1 (fr) 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid
WO2006004922A1 (fr) 2004-06-29 2006-01-12 Teva Pharmaceutical Industries Ltd. Forme cristalline iv de linezolide
US20060111350A1 (en) 2004-06-29 2006-05-25 Judith Aronhime Solid forms of linezolid and processes for preparation thereof
US20060142283A1 (en) 2004-06-29 2006-06-29 Judith Aronhime Crystalline form IV of linezolid
US20070015753A1 (en) * 2005-07-15 2007-01-18 Glenmark Pharmaceuticals Limited Process for the preparation of a crystalline form of (S)-N [[3-(3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide
US7649096B2 (en) 2005-07-15 2010-01-19 Glenmark Pharmaceuticals Limited Process for the preparation of a crystalline form of (S)-N [[3-(3-fluoro-4(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide
WO2007026369A1 (fr) 2005-08-29 2007-03-08 Symed Labs Limited Nouvelle forme amorphe du linezolid
EP2033960A2 (fr) 2007-09-04 2009-03-11 Dipharma Francis S.r.l. Formule d'hydrate cristalline de linézolide et sels de linézolide
WO2009063505A2 (fr) 2007-10-08 2009-05-22 Usv Limited Processus de préparation de (s) (n-[[3-[3-fluoro-4-(4-morpholinyle) hen l -2-oxo-5-oxazolidine l méthyl]acétamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J.MED.CHEM., vol. 39, no. 3, 1996, pages 673

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014101064A1 (fr) * 2012-12-27 2014-07-03 上海创诺医药集团有限公司 Procédé de préparation de la forme i cristalline de linézolide
WO2015068121A1 (fr) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Procédé pour la préparation de la forme cristalline i de linézolide et ses compositions

Also Published As

Publication number Publication date
EP2683696A1 (fr) 2014-01-15

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