EP2683696A1 - Process for making crystalline form a of linezolid - Google Patents

Process for making crystalline form a of linezolid

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Publication number
EP2683696A1
EP2683696A1 EP20110707846 EP11707846A EP2683696A1 EP 2683696 A1 EP2683696 A1 EP 2683696A1 EP 20110707846 EP20110707846 EP 20110707846 EP 11707846 A EP11707846 A EP 11707846A EP 2683696 A1 EP2683696 A1 EP 2683696A1
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EP
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Application
Patent type
Prior art keywords
linezolid
process according
solvent
temperature
antisolvent
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Withdrawn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
EP20110707846
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German (de)
French (fr)
Inventor
Raymond Jozef Hubertus Westheim
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Synthon BV
Original Assignee
Synthon BV
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Filing date
Publication date

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic 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
    • C07D263/16Heterocyclic 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2

Abstract

The invention relates to a process for making crystalline linezolid 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 precipitation, said step preferably comprising adding, upon maintaining the temperature of at least 80°C, an antisolvent to said solution in an amount sufficient to induce precipitation of linezolid.

Description

PROCESS FOR MAKING CRYSTALLINE FORM A OF LINEZOLID

BACKGROUND OF THE INVENTION

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. In the above-marketed compositions, linezolid is present as a free base.

Hereinunder, the name linezolid will be used as the generic name for N-(3-(3-fluoro-4- (morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)acetamide, unless indicated to the contrary.

Linezolid was first disclosed in WO 95/07271 (EP 0717738, US 5,688,792) of the Upjohn Company.

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

(WO 2006/004922, US 2006/0142283), an amorphous form (WO 2007/026369) and hydrated forms (US 2006/0111350, EP 2033960).

Among the solid state forms of linezolid, 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

crystallization from an ester solvent. US 7,649,096 disclosed a process, in which a solution comprising linezolid dissolved in an organic solvent is treated with an antisolvent, whereby the solvent is then removed by distillation.

As many crystalline forms of linezolid have been disclosed in the literature, there is a risk of misinterpretation of data from different sources. For instance, the Form III of

WO 2005/035530 appeared to be identical with the product of WO 95/07271 (Form I) during prosecution of the patent application. For reasons of clarity the 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. In respect to the prior art, 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.

SUMMARY OF THE INVENTION

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.

According to a first aspect of the present invention, there is provided 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. Most preferably, 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.

According to a particular aspect, the organic solvent is an aliphatic alcohol with a boiling point higher than 80°C. Advantageously, the organic solvent is essentially anhydrous.

According to another particular aspect, the antisolvent is an aliphatic hydrocarbon with a boiling point higher than 80°C.

Optionally, the solution is seeded with crystals of the crystalline Form A of linezolid.

Optionally, 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. According to yet another particular aspect, 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.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the disclosure and claims, 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) . Such pattern may be obtained when measured with CuK l radiation (λ = 1.54060 A). 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 2005/035530. "Substantially corresponds" is meant to cover variations/differences in the pattern that would not be understood by a worker skilled in the art to represent a difference in the crystal structure, but rather differences in the technique, sample preparation, impurities, etc.

The known processes of making the crystalline linezolid Form A by a "classical" crystallization, i.e. the processes characterized by providing a solution of linezolid at an enhanced temperature and cooling the solution whereby a crystalline solid starts to precipitate from the solution during said cooling, have the principal disadvantage that these processes are hardly controllable, particularly in large scale production. Dependent on the nature of the solvent, the concentration of the linezolid therein, the chemical purity of the compound, the speed of cooling and intensity of stirring, the crystals can precipitate from the supersaturated solution at different temperatures and with different speed, which can lead to undesirably low batch-to-batch uniformity in the shape and size of the crystals. What is even more important: undesired crystalline forms of linezolid may be formed by such crystallization along with or instead of the desired Form A.

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. Apparently, the Form A is the only thermodynamically stable form at such temperatures. In the broadest sense, 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. As 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.

There are two principal means or techniques how to assure this crystallization:

a) to reduce the volume of the solvent at the temperature higher than 80°C,

b) to decrease the solubility of linezolid in the solvent at a temperature higher than 80°C by adding an antisolvent to said solution.

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. Thus, this technique is preferred and is disclosed in detail below. It should be understood that 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. In some aspects, 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. In this respect, 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. Importantly, the process provides for crystals of excellent flowability, which is an advantageous and very suitable property for the formulation into pharmaceutical compositions.

In the first step of the process of the present invention, a solution of linezolid in a suitable solvent is provided at a temperature of 80°C and higher. Whenever necessary or appropriate, 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.

Typically, the "solvent" is an organic liquid having a boiling point of at least 80°C, preferably at least 90°C. According to an important aspect, 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.

In the second step, 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.

Advantageously, 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. In a preferred embodiment, the antisolvent is a heptane such as n-heptane. Preferably, the antisolvent is free from traces of water.

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. Typically, such temperature of the antisolvent is from 60 to 90°C. Typically, 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).

Optionally, but not necessarily, 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. Advantageously, the actual temperature of the mixture during the whole period of contacting the solution with the antisolvent does not drop below 80°C.

By controlled addition of the above antisolvent into the stirred hot solution, the precipitate is formed rapidly after contacting of both fluids. To avoid impurification of the formed product by other polymorphic form(s), it is advantageous to stir the formed mixture at a temperature higher than 80°C for at least 15 minutes and preferably for at least 1 hour after termination of antisolvent addition. It was proven (by spiking the crystallization mixture with Form II crystals) that other polymorphic forms, whenever undesirably formed, may be converted into Form A under these conditions of stirring.

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. For instance, a suitable pharmaceutical composition may comprise the linezolid Form A and at least one pharmaceutically acceptable excipient.

Pharmaceutically acceptable 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; and polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Carbopol® (B.F.

Goodrich), Eudragit® (Rohm), polycarbophil, and chitosan polymers. 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 an antibacterial agent, in treating various diseases caused by some types of bacteria, by

administering an effective amount thereof to a patient in need of such treatment. In particular, it is useful in the treatment of diabetic food infections caused by Gram-positive bacteria. Typically the effective amounts range from 1 mg to 500 mg, expressed as the amount of linezolid base, per day.

The invention will be further described with reference to the following non- limiting examples.

EXAMPLES

Example 1

10.0 g of linezolid was suspended in 40 ml of 1-butanol, stirred magnetically and heated up. Around 86°C, all solid was dissolved. At 90°C, 80 ml hot n-heptane of 90°C was added via a hose and using little nitrogen pressure, taking about 1 minute. During addition, a solid was formed and the temperature dropped to 84°C. The suspension was stirred at 84-91°C for about 1 hour (reflux), cooled to 30°C in a 75 minute period and further cooled to 20°C in an additional 40-45 minutes. The mixture was filtered over a P3-glass filter (reduced pressure). The solid was washed twice with n-heptane and vacuum-dried overnight at 40°C. A white to off-white solid with a nice flowability was obtained (small, shiny crystals). The yield was 8.86 g (89%). XRPD showed only peaks of Form A. Example 2

10.0 g of linezolid was suspended in 40 ml of 1-butanol, stirred magnetically and slowly heated to 90°C. At 90°C, 80 ml warm n-heptane of 60°C was added via a hose and using little nitrogen pressure. Initially, addition was quite fast, during which the temperature dropped to 80°C. Then, the addition was slowed down and the temperature slowly rose to 85°C. The formed suspension was stirred at about 90°C for about 1 hour (reflux). The suspension was slowly cooled to 20°C in 100-105 minutes. The mixture was filtered over a P3-glass filter (reduced pressure). The solid was washed twice with n-heptane and vacuum-dried overnight at 40°C. A white to off-white solid with a nice flowability was obtained (small, shiny crystals). The yield was 8.84 g (88%). XRPD showed only peaks of Form A.

Example 3

100 g of linezolid was suspended in 400 ml of 1-butanol, stirred mechanically (150 rpm) and slowly heated to 90°C. At this temperature, 800 ml warm n-heptane of 60-65°C was added via a hose and using little nitrogen pressure. Addition took about 15 minutes and the temperature dropped to around 85°C. Furthermore, a solid was formed. The suspension was stirred at about 90°C for about 1 hour (reflux). The suspension was then slowly cooled to 20°C in 110-120 minutes. The solid was filtered over a P3-glass filter (reduced pressure), washed three times with n-heptane and vacuum-dried overnight at 40°C. A white to off-white, free flowable solid was obtained (shiny crystals). The yield of the solid was 96.61 g (97%). XRPD showed only peaks of Form A. In the above examples, the XRPD spectra were recorded on Bruker-AXS D8 vario (Θ/2Θ geometry, reflection mode, Vantec PSD detector) at the following settings:

Start angle (20): 2.0 o

End angle (26 : 35.0 °

Scan step width: 0.02 °

Scan step time: between 0.7-11.0 seconds

Radiation type: Cu

Radiation wavelengths I .54060 A (Κα,ι), primary monochromator used

Exit slit: 6.0 mm

Focus slit: 0.2 mm

Divergence slit: Variable (V20)

Antiscatter slit: I I .8 mm

Receiving slit: 20.7 mm

The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

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 linezolide Form A at such temperature, wherein the Form A of linezolid is characterized by an XRPD powder diffraction pattern comprising 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, when measured with CuKal radiation (λ = 1.54060 A). The process according to claim 1 , wherein 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 process according to claim 1-2, wherein the organic solvent is an aliphatic alcohol with a boiling point higher than 80°C, preferably 1-butanol.
The process according to claims 1-3, wherein the antisolvent is an aliphatic hydrocarbon with a boiling point higher than 80°C, preferably n-heptane.
The process according the claims 1-4, wherein both the solvent and the antisolvent are essentially anhydrous.
The process according to claims 1-5, wherein the concentration of linezolid in the solvent is within a range of between 50-500 g/1, preferably 100-400 g/1.
The process according to claims 1-6, wherein the mutual ratio between the antisolvent and the solvent is from 1 : 1 to 10: 1 (v/v), preferably from 2: 1 to 5: 1 (v/v).
The process according to claims 1-7, wherein the solution is seeded with crystals of the crystalline Form A of linezolid.
9. The process according to claims 1-8, wherein 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.
10. The process according to claims 1-9 further comprising a step, wherein the solvent- antisolvent mixture comprising the linezolid crystals is cooled to an ambient temperature and the crystals are isolated by filtration or centrifugation.
11. The process according to claim 10, wherein the time of cooling is less than 2 hours.
12. The process according to claim 1 , wherein the precipitating step comprises reducing the volume of the solvent at the temperature higher than 80°C.
13. The process according to claims 1-12, wherein the crystallization provides the crystalline Form A of linezolid, which is essentially free from any other crystalline form of linezolid.
EP20110707846 2011-03-09 2011-03-09 Process for making crystalline form a of linezolid Withdrawn EP2683696A1 (en)

Priority Applications (1)

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014101064A1 (en) * 2012-12-27 2014-07-03 上海创诺医药集团有限公司 Method for preparing linezolid crystalline form i
WO2015068121A1 (en) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Process for preparation of crystalline form i of linezolid and its compositions

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (en) 1993-09-09 1995-03-16 The Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
DE60111497T2 (en) 2000-02-02 2006-05-18 Pharmacia & Upjohn Co. Llc, Kalamazoo Linezolid krystall form ii
US6444813B2 (en) 2000-02-02 2002-09-03 Pharmacia & Upjohn Company Linezolid-crystal form II
DE09163348T1 (en) 2003-10-16 2010-01-07 Symed Labs Ltd., Hyderabad Crystalline form of Linezolid
CA2572054A1 (en) 2004-06-29 2006-01-12 Teva Pharmaceutical Industries Ltd. Crystalline form iv of linezolid
EP1745028A2 (en) 2004-06-29 2007-01-24 Teva Pharmaceutical Industries Ltd Solid forms of linezolid and processes for preparation thereof
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 (en) 2005-08-29 2007-03-08 Symed Labs Limited A novel amorphous form of linezolid
EP2033960A3 (en) 2007-09-04 2009-04-29 Dipharma Francis S.r.l. Linezolid crystalline hydrate form and linezolid salts
WO2009063505A3 (en) 2007-10-08 2009-11-12 Usv Limited Process for preparation of (s) (n-[[3-[3-fluoro-4-(4-morpholinyl) hen l -2-oxo-5-oxazolidin l methyl]acetamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012119653A1 *

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