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WO2011050865A1 - Procédé pour la fabrication de la forme cristalline a du linézolide - Google Patents

Procédé pour la fabrication de la forme cristalline a du linézolide Download PDF

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Publication number
WO2011050865A1
WO2011050865A1 PCT/EP2010/001214 EP2010001214W WO2011050865A1 WO 2011050865 A1 WO2011050865 A1 WO 2011050865A1 EP 2010001214 W EP2010001214 W EP 2010001214W WO 2011050865 A1 WO2011050865 A1 WO 2011050865A1
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WO
WIPO (PCT)
Prior art keywords
linezolid
process according
antisolvent
solution
solvent
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.)
Ceased
Application number
PCT/EP2010/001214
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English (en)
Inventor
Raymond Jozef Hubertus Westheim
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Synthon BV
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Synthon BV
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Filing date
Publication date
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Priority to PCT/EP2010/066348 priority Critical patent/WO2011051384A1/fr
Priority to EP10773295A priority patent/EP2493867A1/fr
Publication of WO2011050865A1 publication Critical patent/WO2011050865A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 the 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.
  • the crystalline Form III of WO 2005/035530 is of certain importance in 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 WO2005/035530, 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 by 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
  • WO2005/035530 appeared to be identical with the product of WO 95/07271 (Form I) during prosecution.
  • 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 linezolid, in particular the 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 rapid and controlled precipitation of the solid linezolid from a solution thereof in an organic solvent by means of an antisolvent kept at a preselected temperature.
  • a process for crystallizing linezolid, especially in the crystalline Form A comprising a step of dissolving linezolid in an organic solvent to obtain a solution followed by a step of adding the obtained solution into an antisolvent kept at a pre-selected temperature and, optionally, seeded with crystals of the desired crystalline form of linezolid, especially linezolid Form A.
  • 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 organic solvent is selected from an aliphatic alcohol, a cyclic ether or an aliphatic ester and mixtures thereof.
  • the organic solvents are essentially anhydrous.
  • the antisolvent is a] an aliphatic hydrocarbon, which preferably is a hexane such as n-hexane, a heptane such as n-heptane, a cyclohexane and/or petroleum ether; b] an aliphatic ether , which preferably is methyl-tert.butyl ether; and mixtures thereof.
  • the temperature of the solution is within the range from 50 °C up to the reflux temperature.
  • a first preferred aspect of the process of the invention is the pre-selected temperature of the antisolvent within the range from -20°C to +25°C, preferably at a temperature lower than 0°C.
  • the pre-selected temperature of the antisolvent less than 15 °C, preferably less than 10 °C lower than the boiling temperature of the antisolvent and is preferably higher than 80°C.
  • the process of the present invention based on a technique in which a hot solution of linezolid in a solvent is brought into a contact with an anti-solvent (i.e. with a liquid in which the linezolid is practically insoluble) at a defined, pre-determined temperature with a defined, pre-determined speed, and ,optionally, in the presence of seeds of the desired crystalline form of linezolid , allows to form crystals of linezolid under reliable and well controllable conditions, which are particularly important in a large scale production.
  • an anti-solvent i.e. with a liquid in which the linezolid is practically insoluble
  • the process of the present invention is particularly useful for making the crystalline Form A of linezolid and, therefore, it is discussed hereinunder in details in respect to this form. It is not meant, however, that the invention is limited to processes of making the Form A only.
  • the "Form A" of linezolid is a crystalline form of linezolid that is characterized by a XRPD powder diffraction pattern comprising , inter alia, the 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) .
  • XRPD powder diffraction pattern comprising , inter alia, the 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 WO
  • the Form A of linezolid produced by the process of the present invention has an excellent batch-to-batch uniformity in the size and shape of the formed crystals. Importantly, the process provides for crystals of a relatively small average size, which is advantageous and very suitable property for formulation into pharmaceutical compositions.
  • the linezolid Form A crystals produced by the process of the present invention are advantageously substantially free from other crystalline forms of linezolid, particularly from the Form II of linezolid, which can be otherwise very easily formed by any process of "classical crystallization".
  • 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 linezolid starting material useful for making the solution can be in any physical form of 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 mixtures obtained after the chemical synthesis of linezolid (an example is, e.g., WO 95/07271) or after liberation of 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 solvent.
  • the solvent is essentially anhydrous, i.e. it does not comprise water or may comprise only traces of water . This is because of a risk of forming linezolid hydrates, which should be limited or avoided.
  • the organic solvent is advantageously a polar organic solvent, more advantageously that of having less than 10 carbon atoms; suitable examples comprise, alone or in an admixture: an aliphatic ester, e.g. ethyl acetate, an aliphatic alcohol, e.g. methanol , ethanol , 1-propanol, isopropanol or 1-butanol , a cyclic ether, e.g. 1 ,4-dioxane.
  • the solution is provided by dissolving linezolid in the solvent preferably at an enhanced temperature.
  • the solution may be filtered hot to remove undesired solid particles, optionally in the presence of a surface active material, e.g. activated carbon, for to improve colour and clarity of the solution.
  • a surface active material e.g. activated carbon
  • the useful antisolvent is a liquid, in which the linezolid is essentially insoluble.
  • the antisolvent comprises an aliphatic and/or alicyclic hydrocarbon, preferably the hydrocarbon with 5 to 10 carbon atoms, or an aliphatic ether, preferably that of 4 to 10 carbon atoms.
  • the antisolvent is a hexane such as n-hexane, a heptane such as n- heptane, a cyclohexane, methyl-teri. -butyl ether and/or petroleum ether, and mixtures thereof.
  • the antisolvent is free from the traces of water.
  • the process of the present invention can be essentially performed by two techniques: a) Contacting with a cold antisolvent with seeding
  • the enhanced temperature, at which the solution of linezolid in the solvent is provided comprises any temperature within the range from 50 °C up to the reflux temperature.
  • the suitable concentration of linezolid in the solvent is so selected that the solution can be kept at the chosen temperature without any danger of nucleation at said temperature.
  • the concentration comprises a range of between 2- 100 ml of the solvent per 1 gram of linezolid.
  • the antisolvent Prior to any addition of the linezolid solution, the antisolvent is temperated and kept cold at a predetermined temperature below +25° C under stirring. Typically, the temperature of the antisolvent is within the range between -20°C to +25°C, preferably between -15 and 0°C.
  • the mutual ratio between the antisolvent and the solvent is from 1 : 1 to 10 : 1 (v/v), advantageously from 2 : 1 to 7 : 1 (v/v) .
  • the antisolvent is seeded with seeds of the desired Form A of linezolid. These seeds may be obtained by heating Iinazolid (produced following US 5,688,792) at 130°C to 140°C under nitrogen atmosphere for 4 hours). This is important as no spontaneous nucleation is allowed. Typically, the relative amount of the seeds in respect to the weight of the linezolid in the solution is 1- 25 %. Seeds of other crystalline forms of linezolid, such as seeds of linezolid Form I and Form III, may be obtained using processes known in the art.
  • the rate of the addition of the solution into the antisolvent is not specifically limited and is advantageously so selected that the whole volume of the solution is poured into the stirred antisolvent in 30 minutes or less. Care is to be taken that the cooling speed is sufficient to maintain the temperature of the formed mixture at the predetermined value.
  • the actual temperature during the period of contacting the solution with the antisolvent does not exceed + 5°C from the predetermined temperature. Care is also to be taken that the nucleation does not start prior to the contact of the solution with the antisolvent.
  • the pipelines and valves coming into the contact with the hot solution should be advantageously pre-heated to a suitable temperature.
  • the order of contacting the solution with the antisolvent cannot be reversed, i.e. the antisolvent may not be added to the hot solution.
  • the linezolid rather precipitates as the Form II.
  • the precipitate is formed practically immediately after contacting of both fluids.
  • 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 the Form II of linezolid and/or from any hydrated form thereof.
  • the precipitated product can be isolated from the mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by a fresh antisolvent, and dried. b) contacting with a hot antisolvent, preferably without seeding
  • linezolid When linezolid is dissolved in an alcoholic solvent, particularly in a propanol or butanol solvent (e.g. in 1 -propanol or 1 -butanol) at a reflux temperature, whereby a very concentrated solution of linezolid, e.g of more than 100 mg/ml and typically of about 200-400 mg/ml, is obtained, it is advantageous that such concentrated solution is contacted with the antisolvent at a near-to-reflux temperature.
  • near-to-reflux temperature is less than 15 degrees Celsius, preferably less than 10 degrees Celsius lower than is the boiling temperature of the antisolvent.
  • the temperature both of the solvent and of the antisolvent is higher than 80°C.
  • n-heptane when used as the antisolvent, it is typically temperated to about 90°C prior to contacting with the hot linezolid solution.
  • the antisolvent is advantageously used in a volume ratio from 1 : 1 to to 10 : 1 advantageously from 2 : 1 to 7 : 1 in respect to the volume of the solvent.
  • the rate of the addition of the solution into the antisolvent is not specifically limited and is advantageously so selected that the whole volume of the solution is poured into the stirred antisolvent in 30 minutes or less. Care is to be taken as the reaction mixture may temporarily boil during the mixing.
  • the suspension is then cooled to a temperature of 25 °C or less, whereby the rate of cooling is not specifically prescribed, and is kept at this temperature preferably for a period not exceeding 3 hours.
  • the solid material is isolated from the mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by a fresh antisolvent, and dried.
  • This technique may be also modified in such a way that when linezolid is present as a solution in a solvent, which is other than the alcoholic solvent (e.g. an ethyl acetate reaction mixture after making the linezolid by a synthesis) , it is advantageous to replace the solvent by the alcoholic solvent .
  • the original reaction solvent may be distilled off and replaced by the corresponding amount of the alcohol.
  • 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, hydroxyethyl cellulose, macrocrystalline 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 phosphate.
  • 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 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.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of ethyl acetate at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 100 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 20 minutes of stirring at a temperature between -10 and 0° C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield : 0.32 g.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of ethanol at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 100 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 10 minutes of stirring at a temperature between -10 and 0 °C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield : 0.50 g.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of 2-propanol at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 50 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 10 minutes of stirring at a temperature between -10 and 0° C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield : 0.50 g.
  • Linezolid Form III 2.0 g was dissolved in 10 ml of 1-propanol at reflux. The hot solution was added slowly but at once to 10 ml of hot n-heptane, stirred at 90 °C and containing approximately 25 mg of Linezolid Form A as seeds. The suspension was rapidly cooled down to 0 °C using ice-water and stirred at 0 °C for about 2.5 hour. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried overweekend at 40 °C. The yield was 1.80 g (90%).
  • Linezolid Form III 2.0 g was dissolved in 5 ml of 1-butanol at reflux. The hot solution was added slowly but at once to 10 ml of hot n-heptane, stirred at 90 °C (containing no seeds of Form A. As a result, a solid was formed. The suspension was rapidly cooled down to 0°C using ice-water (took about 5 minutes) and stirred at 0 °C for about 1 hour. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40 °C. The yield was 1.83 g (92%).
  • Linezolid Form III 100 g was dissolved in 250 ml of 1-butanol at reflux. The hot solution was added slowly to 500 ml of hot n-heptane, mechanically stirred at 90 °C (200 rpm). The anti-solvent was not seeded prior to mixing. The suspension was cooled down to 20 °C using a water bath and stirred at 20 °C for 30-60 min (150 rpm). The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40 °C. The yield was 97.32 g (97%).
  • the solution from the Step I comprising a solution of approximately 2.0 g of crude linezolid in 130 ml of ethyl acetate was heated to reflux. At reflux, 10 ml of 1-butanol was added. Then, ethyl acetate was distilled off, leaving a concentrated yellow solution in 1-butanol with a small residual amount of ethyl acetate.
  • This hot solution was slowly added to 10 ml of n- heptane, stirred at 90 °C. To the mixture, a few mg of linezolid Form A and 10 ml of hot n- heptane was added. As a result, slow crystallisation took place.

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

Abstract

L'invention porte sur un procédé pour la fabrication de linézolide cristallin, comprenant une étape de dissolution de linézolide dans un solvant organique pour obtenir une solution suivie par une étape d'ajout de la solution obtenue dans un antisolvant maintenu à une température présélectionnée et éventuellement ensemencée de cristaux de la forme cristalline du linézolide souhaitée.
PCT/EP2010/001214 2009-10-28 2010-02-23 Procédé pour la fabrication de la forme cristalline a du linézolide Ceased WO2011050865A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/EP2010/066348 WO2011051384A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide
EP10773295A EP2493867A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP2009/007919 2009-10-28
PCT/EP2009/007919 WO2011050826A1 (fr) 2009-10-28 2009-10-28 Procédé de fabrication d'une forme cristalline de linézolide

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WO2011050865A1 true WO2011050865A1 (fr) 2011-05-05

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PCT/EP2009/007919 Ceased WO2011050826A1 (fr) 2009-10-28 2009-10-28 Procédé de fabrication d'une forme cristalline de linézolide
PCT/EP2010/001214 Ceased WO2011050865A1 (fr) 2009-10-28 2010-02-23 Procédé pour la fabrication de la forme cristalline a du linézolide
PCT/EP2010/066348 Ceased WO2011051384A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013120496A1 (fr) 2012-02-14 2013-08-22 Pharmathen S.A. Procédé pour la préparation de linézolide sous forme cristalline et de sels de celui-ci
CN103893138A (zh) * 2012-12-28 2014-07-02 成都国弘医药有限公司 一种含有利奈唑胺晶型ⅲ的片剂
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

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WO2013072923A1 (fr) * 2011-09-19 2013-05-23 Cadila Healthcare Limited Procédé de préparation de linézolide cristallin
CN102399200B (zh) * 2011-12-14 2013-12-04 浙江新东港药业股份有限公司 一种利用悬浮结晶法制备利奈唑胺晶型ⅰ的方法
EP2852580A1 (fr) * 2012-01-24 2015-04-01 Jubilant Life Sciences Ltd. Procédé amélioré de préparation de la forme cristalline stable i du linézolide, pratiquement exempte de solvant résiduel
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

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Publication number Priority date Publication date Assignee Title
WO2013120496A1 (fr) 2012-02-14 2013-08-22 Pharmathen S.A. Procédé pour la préparation de linézolide sous forme cristalline et de sels de celui-ci
CN103893138A (zh) * 2012-12-28 2014-07-02 成都国弘医药有限公司 一种含有利奈唑胺晶型ⅲ的片剂
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

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