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1. WO2011050826 - PROCÉDÉ DE FABRICATION D'UNE FORME CRISTALLINE DE LINÉZOLIDE

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[ EN ]

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 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. 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-(mo holin-4- l)phen l)-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.

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), amorphous form (WO 2007/026369) and hydrated forms (US 2006/01 1350, EP 2033960).

Among the solid state forms of linezolid, 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

crystallization from an ester solvent.

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

WO2005/035530 appeared to be identical with the product of WO 95/07271 (Form I) during prosecution. 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 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.

According to a first aspect of the present invention, there is provided 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 seeded with crystals of the desired crystalline form of linezolid, especially linezolid Form A.

According to particular aspect, 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.

According to another particular aspect, the organic solvent is selected from an aliphatic alcohol, a cyclic ether or an aliphatic ester and mixtures thereof. Advantageously, the organic solvents are essentially anhydrous.

According to yet another particular aspect, 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.

Advantageously, the temperature of the solution is within the range from 50 °C up to the reflux temperature.

Yet advantageously, the pre-selected temperature of the antisolvent is within the range from -20°C to +25°C, preferably at a temperature lower than 0°C.

Detailed description of the invention

The known processes of making the crystalline linezolid by a "classical" crystallization, i.e. the processes characterized by providing a solution of linezolid at an enhanced temperature and cooling the solution until a crystalline solid starts to precipitate therefrom, have the principal disadvantage in that these processes are hardly controllable, particularly in the 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 crystals. What is even more important, undesired crystalline forms of linezolid may be formed by crystallization instead of the desired form .

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 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.

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.

Throughout the disclosure and claims, 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) . Such pattern may be obtained when measured with CuKal 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 crystal structure, but rather differences in technique, sample preparation, impurities, etc.

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. According to one particular aspect of the invention, 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". 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.

In the first step of the process of the present invention, a solution of linezolid in a suitable solvent is provided.

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.

Typically, the solvent is an organic solvent. According to an important aspect, 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 or isopropanol, a cyclic ether, e.g. 1,4-dioxane.

The solution is provided by dissolving linezolid in the solvent preferably at an enhanced temperature. The enhanced temperature 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. In an example, the concentration comprises a range of between 10- 100 ml of the solvent per 1 gram of linezolid.

Whenever necessary or appropriate, 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.

In the second step, the obtained solution is contacted with the antisolvent, which is kept cold at a pre-selected temperature.

The useful antisolvent is a liquid, in which the linezolid is essentially insoluble.

Advantageously, 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. In an example, the antisolvent is a hexane such as n-hexane, a heptane such as n-heptane, a cyclohexane, methyl-tert. -butyl ether and/or petroleum ether, and mixtures thereof. Preferably, the antisolvent is free from the traces of water.

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.

Typically, 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) .

Immediately before contacting the linezolid solution with the antisolvent, the antisolvent is 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). 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 linezoid, such as seeds of linezoid 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. Advantageously, 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. Thus, the pipelines and valves coming into the contact with the hot solution should be advantageously pre-heated to a suitable temperature.

It should be noted that the order of contacting the solution with the antisolvent cannot be reversed, i.e. the antisolvent may not be added to the hot solution. In such reversed process, the linezolid rather precipitates as the Form II.

By controlled addition of the above linezolid solution into the stirred and seeded antisolvent, 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.

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, hydroxyethyl 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 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.

Example 1

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.

Example 2

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.

Example 3

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.

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.