EA042272B1 - METHOD FOR OBTAINING POLYMORPHIC FORM OF ROBENACOXIB - Google Patents

Description

Technical field

The invention relates to methods for producing the D2 polymorphic form of robenacoxib and to pharmaceutical compositions containing it. The polymorph form of robenacoxib obtained by the method of the present invention is characterized by high polymorph purity and high chemical and physical stability.

Prior Art

Robenacoxib is the international nonproprietary name for {5-ethyl-2-[(2,3,5,6tetrafluorophenyl)amino]phenyl}acetic acid, a compound of formula (I):

Robenacoxib belongs to the class of selective cyclooxygenase type 2 (COX-2) inhibitors and is used in particular for the treatment of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Like other COX-2 inhibitors, its mechanism of action is to reduce the production of prostaglandins (PGs; from English: prostaglandins) from arachidonic acid. By blocking the formation of prostaglandins, robenacoxib reduces pain and inflammation caused by musculoskeletal disease, surgery, or osteoarthritis.

Robenacoxib is available on the market under the trade name Onsior in the form of tablets with dosages of 5 mg, 6 mg, 10 mg, 20 mg, 40 mg, or in the form of injection with a concentration of robenacoxib equal to 20 mg/ml.

It is indicated for the treatment of acute pain and inflammation associated with musculoskeletal disorders, chronic osteoarthritis, and orthopedic or soft tissue surgery.

Robenacoxib is a free acid according to European Medicines Agency (EMA) information regarding Onsior. It readily dissolves in aqueous solution at alkaline pH values greater than 8. At acidic pH values, robenacoxide is practically insoluble in aqueous solution; solubility in pure water is low. In acidic solutions, the active substance readily decomposes to form lactam. It was reported that robenacoxib exists in various polymorphic forms, that the more stable form at room temperature was chosen, and that it was shown to be chemically and physically stable under stability recording conditions.

The present inventors have designated the polymorph present in the commercial product as D2.

The polymorphic forms of robenacoxib have not yet been described in detail in the literature. In the founding patent EP1007505B1, the melting point of robenacoxib, crystallized from cyclohexane, is in the range from 165°C to 169°C.

Only a small number of methods for the preparation of robenacoxib have been described in the literature. EP 1007505B1 discloses the purification of Robenacoxib and its analogues by chromatographic purification using a mixture of ethyl acetate and hexane. Tetrahedron 2004, Vol:60, Nr:50, pages: 11571-11586, describes a precipitation process at a pH value ranging from 3 to 4 in a medium that contains ethanol, aqueous NaOH and HCl. The authors of the present invention found that the methods disclosed in the prior art, lead to the formation of a polymorphic form, which was designated as D1.

Therefore, there continues to be a need for an improved, robust, well-defined process that is reproducible on a large scale and that produces the D2 polymorph in high yields, high purity and no traces of unwanted forms.

Polymorphic forms are of particular interest due to the provision of essentially pure compounds, providing accurate determination of physico-chemical properties and possible favorable pharmacological characteristics, such as increased solubility, stability and particle size. However, there still remains a need for a reliable method for obtaining a polymorph that is substantially free of other polymorphs, hydrated forms, and an amorphous form.

The inventors of the present invention have found that Form D2 made in substantially pure

- 1 042272 form, is resistant to any transformations and is stable under the technological conditions of such processes as grinding, pressing or mixing with excipients.

Accordingly, it is an object of the present invention to provide a reliable method for obtaining the D2 polymorph in a substantially pure form in high yields, which would have the desired pharmacological properties for the preparation of stable pharmaceutical compositions.

Brief description of graphic materials

Fig. 1 shows an X-ray diffraction pattern (XRDP) from the D1 polymorph of robenacoxib.

Fig. 2 shows an x-ray diffraction pattern (XRDP) from the D2 polymorph of robenacoxib.

Fig. 3 shows an x-ray diffraction pattern (XRDP) from a mixture of the D1 and D2 polymorphs of robenacoxib.

Fig. 4 shows a differential scanning calorimetry (DSC) curve of Robenacoxib in the D1 polymorph.

Fig. 5 shows a scanning electron microscope (SEM) image of Robenacoxib in the D1 polymorph.

Fig. 6 shows a scanning electron microscopy (SEM) image of robenacoxib in the D1 polymorph.

Fig. 7 shows a differential scanning calorimetry (DSC) curve of robenacoxib in the D2 polymorph.

Fig. 8 shows a scanning electron microscopy (SEM) image of robenacoxib in the D2 polymorph.

Fig. 9 shows a scanning electron microscopy (SEM) image of robenacoxib in the D2 polymorph.

Information confirming the possibility of carrying out the invention.

According to a first embodiment of the present invention, there is provided a process for preparing a stable and substantially crystallographically pure D2 polymorph of robenacoxib.

The term substantially crystallographically pure means that the polymorph contains less than 30% by weight of other polymorphs, amorphous form or solvates, preferably less than 10% by weight, more preferably less than 5% by weight, most preferably less than 2% by weight; even more preferably, this form does not contain any other polymorphic form, amorphous form or solvate form at all. Polymorphic purity is determined by X-ray powder diffractometry (eg based on the intensity of the peaks).

X-ray powder diffraction results can be obtained, for example, using a PANalytical X'Pert PRO diffractometer using CuKa radiation with a wavelength of 1.541874 A. The D1 polymorph of Robenacoxib is characterized by an X-ray powder diffraction pattern with the following peaks (°2θ plus/minus 0, 2°) and interplanar spacing d [A]:

No. Position [°2θ.] d-distance [A] 1 5.8 15.32 2 11.6 7.66 3 16.6 5.33 4 17.8 4.97 5 20.5 4.32

The D1 polymorph is also characterized by an X-ray powder diffraction pattern with the following peaks (°2θ plus/minus 0.2°) and interplanar spacing d [A]:

No. Position [°2θ.] d-distance [A] 1 5.8 15.32 2 8.8 10.04 3 11.6 7.66 4 16.6 5.33 5 16.8 5.27 6 17.8 4.97 7 20.5 4.32 8 22.5 3.95 9 26.9 3.32 10 29.1 3.06

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The D1 polymorph of robenacoxib has an XRPD spectrum which is essentially shown in FIG. 1.

Thermogram of polymorph form D1, obtained by differential scanning calorimetry (DSC), shows an endothermic peak (melting) with an initial temperature of 165°C and a peak temperature (Tpeak) of about 167°C. The D1 polymorph is also characterized by the DSC thermogram depicted in FIG. 5.

The D1 polymorph is characterized as an anhydrous and non-hygroscopic crystalline material with a water content of less than about 1% by weight, more preferably less than 0.5% by weight, and most preferably less than 0.2% by weight.

The D1 polymorph is also characterized by a rod-shaped particle morphology, although other morphologies are possible. It is also possible for smaller particles to stick to larger ones and form agglomerates.

Scanning electron microscopy (SEM) images of Robenacoxib in the D1 polymorph are shown in FIG. 5 and FIG. 6.

The D2 polymorph of robenacoxib is characterized by an X-ray powder diffraction pattern with the following peaks (°2θ plus/minus 0.2°) and interplanar spacing d [A]:

No. Position [°2θ.] d-distance [A] 1 6.0 14.81 2 10.1 8.78 3 17.0 5.22 4 22.5 3.96 5 29.1 3.06

The D2 polymorph may optionally also be characterized by an X-ray powder diffraction pattern with the following peaks (°2θ plus/minus 0.2°) and interplanar spacing d [A]: _______________________________________________________________________________

No. Position [°2θ.] d-distance [A] 1 6.0 14.81 2 10.1 8.78 3 16.5 5.36 4 17.0 5.22 5 17.9 4.95 6 20.6 4.32 7 22.5 3.96 8 24.9 3.57 9 29.9 2.99 10 29.1 3.06

The D2 polymorph of robenacoxib may optionally also have an XRPD spectrum as shown in FIG. 2.

The thermogram of the D2 polymorph obtained by differential scanning calorimetry (DSC) characteristically shows an endothermic peak (melting) with an initial temperature of about 120° C., which corresponds to the solid state transition of the D2 polymorph to the D1 form, and an endothermic peak D1) with an initial temperature of 169°C and a Tpeak of about 171°C. The D2 polymorph may also optionally be characterized by the DSC thermogram depicted in FIG. 7.

High temperature microscopy was performed to confirm solid phase transitions of the D2 form of robenacoxib. A solid phase transition from form D2 to form D1 was observed in the temperature range from 110°C to 130°C, which corresponds to the DSC thermogram of form D2. Then, at a temperature of about 170° C., the melting of the particles of form D1, obtained as a result of the above solid-state transition from form D2 to form D1, was observed.

The D2 polymorph is typically characterized as an anhydrous and non-hygroscopic crystalline material with a water content of less than about 1% by weight, more preferably less than 0.5% by weight, and most preferably less than 0.2% by weight.

The D2 polymorph is also characteristically characterized by an acicular particle morphology, although other morphologies are possible. Individual particles of the D2 polymorph can aggregate to form agglomerates. Scanning electron microscopy (SEM) images of Robenacoxib in the D2 polymorph are shown in FIG. 8 and FIG. 9.

- 3 042272

The process for preparing the substantially crystallographically pure D2 polymorph of robenacoxib of the present invention comprises:

(i) dissolving robenacoxib in a suitable solvent system A at a temperature ranging from 0° C. to the reflux temperature of said organic solvent system;

(ii) optionally filtering the resulting crystallization mixture;

(iii) optionally cooling the crystallization mixture to a temperature in the range of 0°C to 50°C or 40°C to -10°C, for example 38°C to -9°C, 36°C to -7° C, from 33°C to -6°C or from 30°C to -5°C, preferably from 30°C to 0°C, more preferably in the range from 10°C to 5°C, (iv) then

a. adding anti-solvent B to the crystallization mixture to initiate precipitation at a crystallization temperature ranging from 50°C to 0°C or from 40°C to -10°C, for example from 38°C to -9°C, from 36°C to -7°C, 33°C to -6°C or 30°C to -5°C, preferably 30°C to 0°C, more preferably in the range of 10°C to 5°C, or

b. adding a crystallization mixture to antisolvent B to initiate precipitation at a crystallization temperature in the range of 50°C to 0°C or 40°C to -10°C, e.g. 38°C to -9°C, 36°C to -7°C, from 33°C to -6°C or from 30°C to -5°C, preferably from 30°C to 0°C, more preferably in the range from 10°C to 5°C, (v ) optionally holding the suspension for a holding time at the crystallization temperature and/or cooling the resulting suspension, wherein the suspension is preferably cooled to a temperature below the crystallization temperature and holding the suspension at said temperature for the holding time, (vi) isolating and drying the crystallized D2 polymorph of robenacoxib .

The present inventors have found that the crystallization temperature during crystallization must be carefully controlled to ensure a reproducible process resulting in a substantially crystallographically pure D2 polymorph of robenacoxib.

The term crystallization temperature, when used in the context of the present invention, refers to the temperature of the crystallization mixture at which nucleation is induced, ie the crystallization start temperature. In the case of a precipitation process, the crystallization temperature can be controlled by controlling the temperature of the crystallization mixture. In an embodiment of the present invention, it is also possible to change the crystallization temperature within the temperatures indicated above, that is, to initiate crystallization at a first temperature selected within at least one of the above temperature ranges, and then to maintain the resulting suspension at a second temperature within at least one of the above temperature ranges. It is also possible to make two or more temperature changes or even a continuous temperature change during crystallization, provided that all selected temperatures during crystallization and holding are within at least one of the above temperature ranges.

In an embodiment of the present invention, the crystallizable mixture is maintained at the crystallization temperature for a holding time necessary for crystal formation to be at least 10 minutes, preferably ranging from 10 minutes to 20 hours, and more preferably ranging from 0.5 hours until 10 o'clock. After the specified residence time at the crystallization temperature, the crystalline particles of robenacoxib are optionally cooled to a temperature below the crystallization temperature, or separated from the mother liquor using standard isolation methods, such as filtration or centrifugation.

A suitable solvent system A can be selected from C1-C6 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, amyl alcohol and 1-hexanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, nitriles, such as acetonitrile, amides such as dimethylformamide (DMF; from English: dimethylformamide), sulfoxides such as dimethyl sulfoxide, and mixtures thereof. The preferred solvent system A contains acetone. Most preferably, the solvent system A consists of acetone.

The anti-solvent B may be selected from water, ethers such as dioxane, diisopropyl ether or tetrahydrofuran (THF; tetrahydrofuran), esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, C6-C8 aliphatic or cyclic hydrocarbons, such as hexane, n-heptane, cyclohexane, halogenated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as toluene, xylene, or mixtures thereof. The preferred antisolvent B is water.

Robenacoxib is preferably dissolved in solvent system A at temperatures ranging from 10° C. to the reflux temperature of solvent system A, more preferably from 25° C. to reflux temperature. According to another embodiment of the present invention, the dissolution is carried out at a temperature in the range from 20°C to 50°C, preferably from 25°C to 40°C.

- 4 042272

The term reflux temperature of a solvent system, when used in the context of the present invention, refers to a temperature ranging from the boiling point of a specific solvent to a boiling point of plus 15°C, i.e. the reflux temperature of ethanol is in the range of 78°C to 93°C. If a mixture of solvents is used, then the term reflux temperature of the solvent system, when used in the context of the present invention, may refer to a temperature ranging from the boiling point of the specific solvent mixture to the boiling point of plus 15°C.

The amounts of robenacoxib and solvent system A used correspond to a solute:solvent weight ratio of less than 1:20, preferably less than 1:10, more preferably less than 1:7, most preferably less than 1:6, even more preferably less than 1:5, preferably more than 1:200, and more preferably more than 1:100. In some embodiments, the implementation of the present invention, the mass ratio is such that the resulting solution is highly concentrated, although it is possible to obtain a clear solution. According to such embodiments of the present invention, for each mass part of robenacoxib, 20 mass parts of solvent or less are used, preferably 10 mass parts of solvent or less, more preferably 7 mass parts of solvent or less, even more preferably 6 mass parts of solvent or less, and most preferably 5 mass parts of the solvent or less.

The volume ratio of solvent system A to solvent system B may vary from 1:10 to 10:1, preferably from 5:1 to 1:5, more preferably from 2:1 to 1:2.

During step (iv), the nucleation temperature of the crystallization mixture can be controlled in the following ways:

a) a solution of robenacoxib in a suitable solvent system A is gradually cooled to the crystallization temperature of the crystallization mixture and/or a solvent B of the same temperature is added to the mixture, or vice versa, or

b) to a solution of robenacoxib in a suitable solvent system A having a temperature above the crystallization temperature, solvent B having a temperature below the crystallization temperature is added in a controlled manner to maintain the crystallization temperature of the solvent mixture, or

c) to a solution of robenacoxib in a suitable solvent system A having a temperature below the crystallization temperature, solvent B having a temperature above the crystallization temperature is added in a controlled manner to maintain the crystallization temperature of the solvent mixture, or

d) a solution of robenacoxib in a suitable solvent system A having a temperature above the crystallization temperature is added in a controlled manner to solvent B having a temperature below the crystallization temperature to maintain the crystallization temperature of the solvent mixture, or

e) a solution of robenacoxib in a suitable solvent system A, having a temperature below the crystallization temperature, is added in a controlled manner to solvent B, having a temperature above the crystallization temperature, to maintain the crystallization temperature of the solvent mixture.

In the above embodiments b) to e), it is preferable that the higher temperature is in the range of 20°C to 40°C, more preferably 22°C to 30°C, and preferably the lower temperature is in the range from 0°C to 10°C, more preferably from 2°C to 8°C.

Another aspect of the present invention is a process for preparing a substantially crystallographically pure D2 polymorph of robenacoxib of the present invention, which comprises crystallization from a solvent system wherein the crystallization temperature is below 50°C or in the range of 40°C to -10°C, for example 38° C to -9°C, 36°C to -7°C, 33°C to -6°C or 30°C to -5°C, preferably 30°C to 0°C, more preferably at between 10° C. and 5° C., wherein crystallization at the crystallization temperature is induced by cooling the crystallization mixture or evaporating the solvent from the crystallization mixture.

Another aspect of the present invention is a process for preparing the substantially crystallographically pure D2 polymorph of robenacoxib, which comprises:

(i) dissolving or suspending robenacoxib in a suitable solvent system at a temperature ranging from 0° C. to the reflux temperature of the crystallization mixture;

(ii) optional cooling of the crystallization mixture to a crystallization temperature below 50°C, or optional evaporation of the solvent to initiate crystallization at a temperature below 50°C (in this case and elsewhere in this publication, references to solvent evaporation are not limited to the specific amount of solvent to be evaporated and may mean partial or complete evaporation), or the optional addition of one or more seed crystals form D2 of robenacoxib at a temperature below 50°C,

(iii) maintaining the crystallization mixture for a holding time at the crystallization temperature, optionally with the addition of one or more form D2 seed crystals of robenacoxib, and (iv) isolating and drying the crystallized form D2 polymorph of robenacoxib.

The crystallization temperature during steps (ii) and (iii) is preferably below 40°C, such as 38°C or less, 36°C or less, or 33°C or less, more preferably below 25°C, even more preferably below 15°C, most preferably below 10°C, it is also preferably above -10°C, more preferably above -5°C, and even more preferably is in the range from 7°C to 3°C or from 0°C to -3°C.

In some embodiments of the present invention, the meaning of the term crystallization temperature is the same as defined above for the anti-solvent embodiment.

A suitable solvent system may be selected from C1-C6 alcohols such as methanol, 1-propanol, 2-propanol, aromatic hydrocarbons such as toluene, xylene, nitriles such as acetonitrile. The preferred solvent system contains or consists of toluene. Most preferably, the solvent system consists of toluene.

The mixture to be crystallized is maintained at the crystallization temperature for a holding time necessary for crystal formation of at least 10 minutes, preferably in the range of 10 minutes to 20 hours, and most preferably in the range of 0.5 hours to 10 hours. After the specified residence time at the crystallization temperature, the crystalline particles of robenacoxib are optionally cooled or separated from the mother liquor using standard isolation techniques, such as filtration or centrifugation.

The crystallization process in the context of this aspect of the present invention can be induced using a primary and/or secondary crystallization mechanism.

Primary crystallization during step (ii) can be induced by cooling and stirring the crystallization mixture at predetermined crystallization temperatures until crystals begin to precipitate, or by concentrating the crystallization mixture by evaporating the solvent.

In the case of secondary crystallization, the mixture to be crystallized is seeded by adding crystals of robenacoxib in the pure D2 polymorph. The crystallizable mixture is seeded by adding robenacoxib crystals at least once during the cooling time or holding time when the temperature of the crystallizable mixture is within the specified crystallization temperature range to prevent excessive supersaturation with robenacoxib and resulting spontaneous crystallization in unwanted polymorphs. Seeding can be repeated to ensure the continued presence of crystalline robenacoxib during cooling and/or holding; the crystallizable mixture can also be seeded semi-continuously until crystallization begins. Robenacoxib seed crystals can be added in powder form or in the form of a suspension in any type of liquid.

Stirring of the crystallizable mixture can be performed using a magnetic or mechanical stirrer. In large portions of the mixture, it is preferable to use a mechanical agitator. The mechanical agitator can be selected from impeller, propeller, turbine, paddle or anchor type agitators.

When used in the context of the present invention, the term drying refers to the removal of residual solvents, for example by heating and/or using a vacuum.

In addition, the purity of the material obtained by the method of the present invention is more than 98 area% by high performance liquid chromatography (HPLC), preferably more than 99% by HPLC. The analytical method used to determine the purity of Robenacoxib was a gradient HPLC method using an XSelect CSH column with C18 stationary phase or a suitable alternative and a UV detector with detection at 274 nm. The mobile phase was a combination of water, acetonitrile and formic acid.

In addition, the method of the present invention can be used for large scale production. The process was confirmed to be reliable on a large scale and to provide a high yield of robenacoxib in the pure D2 polymorph.

The process of the present invention provides uniform particles in the form of easily filterable acicular morphologies or particles of other morphologies that are suitable for direct incorporation into the formulation. However, the resulting product, if necessary, can be further subjected to grinding, milling or micronization.

For grinding, the grinding equipment is usually hydraulic mill, jet mill, ball mill, roller mill or hammer mill.

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A hydraulic mill, or micronizer, is a particularly preferred type of mill due to its ability to provide small size particles with a narrow size distribution, ie micronized material. As is known to those skilled in the art, micronizers utilize the kinetic energy of collisions between particles suspended in a fast moving fluid stream (typically air or nitrogen) to break up particles. The jet mill is the preferred hydraulic mill. The suspended particles are injected under pressure into the recirculating particle stream. The fine particles move to the top of the mill and are entrained in a vent connected to a particle size classifier such as a cyclone. The starting material must first be ground to a particle size in the range of 30 µm to 100 µm, which can be done using a standard ball, roller or hammer mill.

The starting material, in particular the material containing robenacoxib or consisting of robenacoxib, with adjusted particle size, for example by grinding, may have an average particle size in the range from about 10 μm to about 500 μm.

The material is fed into the micronization system at a variable feed rate using a screw feeder or a vibrating feeder. The jet mill operates under controlled air or nitrogen pressure. Micronization can also be done with an impact pin mill. The material is fed into the grinding system at a variable feed rate using a screw feeder or a vibrating feeder. The mill runs at an adjustable speed.

The D2 polymorph of the present invention is preferably characterized by a small particle size defined by an average particle size in the range of 1 µm to 200 µm, preferably 1 µm to 100 µm, more preferably 1 µm to 50 µm, most preferably 1 µm to 30 µm .

Determination and control of particle characteristics, in particular particle size distribution, is very important for controlling the quality and processing characteristics of the product. When used in the context of the present invention, the term average particle size refers to the volume average particle diameter. The diameter and volume average diameter can be determined by laser light scattering using, for example, a Malvern Mastersizer MS 2000, MS 3000 or equivalent equipped with a liquid dispersion unit. Particle sizes are determined by measuring the angular distribution of laser radiation scattered by a homogeneous suspension of particles. Particles to be subjected to particle size measurement are first suspended in a suitable non-polar dispersing agent and then subjected to size measurement in a Malvern Mastersizer. Typically, 100 mg to 800 mg of the substance is dispersed in 5-10 ml of a dispersing agent. The particle size distribution can also be determined in another way, that is, by analyzing images obtained by scanning electron microscopy (SEM; from English: scanning electron microscope). The image analysis process to determine particle size distribution consists of visually counting all crystals visible in an SEM image that contains at least 200 particles. The measured size of each particle is the size of the largest cross section of the corresponding particle.

The method of the present invention is a reliable, reproducible and scalable crystallization method that generates robenacoxib in pure D2 crystalline form. The constant polymorphic purity of the drug substance and drug product, as well as the ability to control the content of the amorphous form in the drug substance, ensure the quality and reliability of the product.

Robenacoxib, used in appropriate methods to obtain the D2 polymorph, can be obtained by any method known to those skilled in the art. The preparation of robenacoxib is described, for example, in EP1007505B1, CN102311355, EP1216226, Tetrahedron 2004, Vol 60, Nr 50, pages 11571-11586. Preferably, robenacoxib is used which is of high purity, preferably 98% or more, more preferably 99% or more, even more preferably 99.5% or more, and most preferably 99.7% or more.

The D2 polymorph of robenacoxib obtained by the method of the present invention can be included in pharmaceutical compositions or formulations as an active ingredient. It is of particular advantage that this polymorph is unexpectedly stable under the conditions of standard manufacturing processes used to prepare pharmaceutical compositions.

The pharmaceutical compositions are preferably solid pharmaceutical compositions in the form of tablets containing the D2 polymorph of robenacoxib together with excipients such as microcrystalline cellulose, powdered cellulose, crospovidone, povidone, magnesium stearate and optionally a flavoring such as artificial beef flavor and yeast powder. .

In an alternative embodiment of the present invention, the pharmaceutical compositions

- 7 042272 are solid pharmaceutical compositions containing the D2 polymorph form of robenacoxib, which are intended to be dissolved before use to obtain pharmaceutical compositions in the form of a solution, preferably an injectable solution containing robenacoxib,

Macrogol 400, ethanol, Poloxamer 188 anhydrous, citric acid monohydrate, sodium metabisulphite, sodium hydroxide and water for injection.

The following examples illustrate the present invention and do not limit it in any way.

Description of exemplary embodiments of the invention

The compounds of the present invention were characterized by their X-ray powder diffraction patterns (obtained with a PANalytical X'Pert PRO diffractometer using CuKa radiation at a wavelength of 1.541874 A).

In the examples below, robenacoxib was used as starting material with a purity of 99.8%. Robenacoxib used as starting material was a mixture of the D1 polymorph and the D2 polymorph.

SEM images were obtained under high vacuum on a CarlZeiss Ultra Plus scanning electron microscope. The accelerating voltage was in the range of 1 kV to 2 kV, and the working distance was in the range of 2.1 mm to 5.3 mm.

Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC 1 scanning calorimeter. Samples weighing approximately 3 mg were scanned from 20° C. to 270° C. at a heating rate of 10° C./min under nitrogen (40 ml/min) in aluminum cups covered with perforated lids.

Thermogravimetric (TG; thermogravimetric) analysis was performed on a Mettler Toledo TGA/DSC1 analyzer. Samples weighing from about 7 mg to about 15 mg were heated from 20° C. to 220° C. at a heating rate of 10° C./min under nitrogen in aluminum crucibles covered with perforated lids.

Dynamic vapor sorption analysis was performed on a ProUmid GmbH, SPS 1 μ dynamic vapor sorption analyzer. Up to 100 mg of samples were exposed to relative humidity (RH; from English: relative humidity), increasing from 0% to 90% and then returning from 90% to 0%, in two cycles at 25°C in steps of 10% RH. The minimum time was chosen to be 360 minutes for each stage.

High temperature microscopy was performed using a Mettler FP82MT stage with FP90 controller mounted on a Nicon Eclipse E600 microscope. The table has been accurately calibrated to 3 temperature points. The samples were placed on a coverslip and a second coverslip was placed on top of the sample. The samples were heated to 170° C. until the melting temperature was reached using a temperature rise rate of 10° C./min. During the heating of the table, all samples were examined visually.

Comparative example 1.

Ethyl acetate and hexane in a volume ratio of 40:60 (1 ml) were loaded into a glass reactor at room temperature. Robenacoxib (0.11 g) was added to the reactor and the mixture was heated to 70° C. until robenacoxib dissolved. The solvent was evaporated. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 50 mg of material. The resulting product was the D1 polymorph.

Comparative example 2.

17.5 mg of robenacoxib was loaded into a glass reactor and 0.5 ml of cyclohexane was added to form a suspension. The suspension was heated to 80° C. and another 2.5 ml of cyclohexane was added. The suspension was gradually cooled to room temperature over 3 hours. The resulting product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 110 mg of material. The resulting product was the D1 polymorph.

Comparative example 3.

0.80 g of robenacoxib was loaded into a glass reactor. Added 9 ml of ethanol and 0.5 ml of water and heated the mixture to reflux (78°C). 0.95 g (0.7 ml) of a 30 wt% NaOH solution was slowly added dropwise, and the mixture was heated at reflux temperature for one hour. The solution was cooled to 40° C. and 0.5 M HCl solution was slowly added until a pH of 3 to 4 was reached. The resulting suspension was cooled to 20° C. and the product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 740 mg of material. The resulting product was the D1 polymorph.

Method for obtaining polymorphic form D2 using a solvent/antisolvent system.

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Example 1

0.25 g of robenacoxib was loaded into a glass reactor and 1.75 ml of water was added. Separately prepared a solution of 0.25 g of robenacoxib in 1.75 ml of acetone. The latter was added to the suspension in a glass reactor, heated to 40°C and stirred for 8 hours. Then the suspension was cooled to 25°C and stirred for the next 5 hours. The product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 440 mg of material. The resulting product was the D2 polymorph.

Example 2

ml of water was loaded into a glass reactor. Separately prepared a solution of 0.5 g of robenacoxib in 2 ml of acetone. The solution was added to water in a glass reactor at room temperature. Then the resulting suspension was heated to 40°C and stirred for 8 hours at the same temperature, after which the suspension was cooled to room temperature and stirred for another 5 hours. The product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 340 mg of material. The resulting product was the D2 polymorph with an average particle size of about 380 µm as determined by scanning electron microscopy. SEM images of the product are shown in FIG. 8.

Example 3

Prepared a solution of 0.25 g of robenacoxib in 2 ml of acetone. The solution was then slowly added to a reactor containing 3 ml of water cooled to 5°C while maintaining the temperature of the crystallized mixture at 5°C. The suspension thus obtained was then stirred for 3 hours, after which the product was isolated using a Buchner funnel. Received 140 mg of material. The resulting product was the D2 polymorph.

Example 4

Prepared a solution of 1.5 g of robenacoxib in 6 ml of acetone. The solution was then slowly added dropwise to a reactor containing 9 ml of water cooled to 5°C, maintaining the temperature of the crystallized mixture at 5°C. The suspension thus obtained was then stirred at this temperature for 4 hours, after which the product was isolated using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 1.1 g of material. The resulting product was the D2 polymorph, with an average particle size ranging from 5 µm to 10 µm as determined by scanning electron microscopy.

Example 5

A solution of 0.54 g of robenacoxib in 2 ml of acetone was prepared at room temperature. The solution was slowly added dropwise to 3 ml of water heated to 30°C. The suspension was then slowly cooled to room temperature over 4 hours and the product was isolated using a Buchner funnel. Received 400 mg of material. The resulting product was the D2 polymorph.

Example 6

A solution of 0.52 g of robenacoxib in 2 ml of acetone was prepared at room temperature. The solution was slowly added dropwise to 3 ml of water heated to 40°C. The suspension was then slowly cooled to room temperature over 4 hours and the product was isolated using a Buchner funnel. Received 410 mg of material. The resulting product was a mixture of the D1 and D2 polymorphs.

Example 7

A solution of 0.52 g of robenacoxib in 2 ml of acetone was prepared at room temperature. The solution was slowly added dropwise to 3 ml of water heated to 50°C. The suspension was then slowly cooled to room temperature over 4 hours and the product was isolated using a Buchner funnel. Received 420 mg of material. The resulting product was a mixture of the D2 and D1 polymorphs.

Example 8

A solution of 10.04 g of robenacoxib in 40 ml of acetone was prepared at room temperature. The solution was added to 60 ml of water cooled to 5°C. The suspension was stirred at the same temperature for 4 hours. The product was isolated using a Buchner funnel and dried in a vacuum dryer at reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 9.3 g of material. The resulting product was the D2 polymorph, with an average particle size ranging from 5 µm to 10 µm as determined by scanning electron microscopy. SEM images of the product are shown in FIG. 9.

Example 9

0.50 g of robenacoxib was charged into a 25 ml round bottom flask, and 2.27 ml of methyl isobutyl ketone (MIBK; from English: methyl isobutyl ketone) was added to obtain a solution at room temperature. Then the solution was cooled to 5°C. Then 4.5 ml of dichloromethane was slowly added dropwise to give a suspension. The resulting suspension was filtered and the product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 0.07 g of the product. The resulting product was the D2 polymorph.

Example 10

1.01 g of robenacoxib was charged into a 5 ml round bottom flask, and 4 ml of acetone was added to obtain a solution at room temperature. Meanwhile, 6 ml of water was charged into a 25 ml round bottom flask and cooled to 5°C. A solution of robenacoxib in acetone was slowly added dropwise to chilled water and stirred for 4 hours at 5°C. The suspension was then filtered and washed with 5 ml of chilled water. The product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 0.88 g of the product. The resulting product was the D2 polymorph.

Example 11.

1.01 g of robenacoxib was charged into a 25 ml round bottom flask, and 4 ml of acetone was added to obtain a solution at room temperature. Meanwhile, 6 ml of water was charged into a 10 ml round bottom flask and cooled to 5°C. Then, chilled water was slowly added dropwise to the solution and stirred for 4 hours at a temperature of 5°C. The suspension was then filtered and washed with 5 ml of chilled water. The product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 0.84 g of the product. The resulting product was the D2 polymorph.

Example 12.

12.03 g of robenacoxib was charged into a 100 ml round bottom flask and 48 ml of acetone was added to obtain a solution at room temperature. After complete dissolution of robenacoxib, the solution was loaded into the reactor. Then 72 ml of water cooled to 5°C was slowly added to the solution. After completion of the addition, the suspension was cooled to 0°C and stirred overnight. The suspension was then filtered and washed with 10 ml of chilled water. The product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 11.69 g of the product. The resulting product was the D2 polymorph, with an average particle size of about 45 µm as determined by scanning electron microscopy.

The method for obtaining polymorphic form D2, which is different from the method using the solvent/antisolvent system.

Example 13

0.5 g of Robenacoxib in the D1 polymorph and 5 ml of toluene were added to a glass reactor. Then the suspension was heated to 40°C and stirred for 8 hours at the same temperature, after which the suspension was cooled to room temperature and stirred for another 5 hours. The resulting product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 370 mg of material. The resulting product was the D2 polymorph.

Example 14

0.72 g of robenacoxib was dissolved in 5 ml of methanol in a glass reactor. The solution was heated to 40°C and then slowly cooled to -10°C. The material began to crystallize between 0°C and -10°C. The resulting product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 110 mg of material. The resulting product was the D2 polymorph.

Example 15

In a glass reactor, 0.51 g of Robenacoxib in the D1 polymorph was suspended in 5 ml of toluene at room temperature and rapidly cooled to 5°C. The suspension was stirred at the same temperature overnight. The resulting product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 460 mg of material. The resulting product was the D2 polymorph.

Example 16

In a glass reactor, 0.58 g of robenacoxib was dissolved in 5 ml of 2-propanol at room temperature. The solution was then rapidly cooled to 5° C. and stirred at the same temperature overnight. The resulting product was isolated by suction filtration using a Buchner funnel. The isolated product was dried in a vacuum dryer under reduced pressure (500 mbar (50,000 Pa)) and a temperature of 25° C. overnight. Received 150 mg of material. The resulting product was the D2 polymorph.

Example 17.

0.50 g of robenacoxib was charged into a 25 ml round bottom flask, and 10 ml of acetonitrile was added to obtain a solution at room temperature. The solution was then cooled to 5°C to obtain

- 10 042272 suspension and stirred for 1 hour. The resulting suspension was filtered and the product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 0.07 g of the product. The resulting product was the D2 polymorph.

Example 18.

0.53 g of robenacoxib was charged into a 25 ml round bottom flask, and 1.85 ml of acetone was added to obtain a solution at room temperature. Then the solution was cooled to 5°C. Thereafter, 3.7 ml of toluene was slowly added dropwise to the solution. Since the solution remained clear even after adding 6 times the amount of anti-solvent (total 22.2 ml), the solvent was slowly (partially) evaporated under nitrogen. The product was placed in a vacuum dryer at 22° C. and 500 mbar (50,000 Pa). Received 0.24 g of the product. The resulting product was the D2 polymorph.

Example 19.

10.03 g of robenacoxib and 100 ml of toluene were charged into a 100 ml reactor to form a suspension at room temperature. The suspension was then cooled to 5° C. and stirred overnight. After that, the suspension was filtered and the product was placed in a vacuum dryer at 22°C and 500 mbar (50,000 Pa). Received 9.16 g of the product. The resulting product was the D2 polymorph, with an average particle size of about 109 µm as determined by scanning electron microscopy.

Claims (6)

1. A process for the preparation of a crystallographically substantially pure D2 polymorph of robenacoxib, comprising the steps of: (i) dissolving robenacoxib in a suitable solvent system A at a temperature in the range of 0° C. to the reflux temperature of said organic solvent system; (ii) then a. adding antisolvent B to the crystallization mixture to initiate precipitation at a crystallization temperature in the range of 50°C to 0°C or 40°C to -10°C, or b. adding the crystallization mixture to antisolvent B to initiate precipitation at a crystallization temperature in the range of 50° C. to 0° C. or 40 ^° C. to -10° C., (iii) recovering and drying the crystallized D2 polymorph of robenacoxib; where solvent system A is selected from the group consisting of: C1-C6 alcohols selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, amyl alcohol and 1-hexanol, ketones selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles, selected from the group consisting of acetonitrile, amides selected from the group consisting of dimethylformamide (DMF), sulfoxides selected from the group consisting of dimethyl sulfoxide, and mixtures thereof; where antisolvent B is selected from the group consisting of: water, ethers selected from the group consisting of dioxane, diisopropyl ether and tetrahydrofuran (THF), esters selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate, C6-C8 aliphatic or cyclic hydrocarbons selected from the group consisting of hexane, n-heptane and cyclohexane, halogenated hydrocarbons selected from the group consisting of dichloromethane, aromatic hydrocarbons selected from the group consisting of toluene and xylene, and mixtures thereof ; where the term crystallographically substantially pure means that the polymorph form contains less than 30 wt.% of other polymorphs, amorphous form or solvates, where the polymorph purity is determined by X-ray powder diffractometry, and where the D2 polymorph form of robenacoxib is characterized by an X-ray powder diffraction pattern obtained using CuKa -radiation and containing signals with peak positions at the following 2θ values: 6.0°, 10.1°, 17.0°, 22.5° and 29.1°. 2. The method of claim 1 wherein the solvent system A is acetone and the anti-solvent B is water. 3. The method according to claim 1 or 2, where the crystallization temperature is in the range from 30°C to 0°C. 4. A process for the preparation of a crystallographically substantially pure D2 polymorph of robenacoxib, comprising the steps of: (i) dissolving or suspending robenacoxib in a suitable solvent system at a temperature in the range of 0° C. to the reflux temperature of the crystallization mixture; (ii) keeping the mixture to crystallize for a holding time at a temperature - 11 042272 crystallization, and (iii) isolate and dry the crystallized D2 polymorph of robenacoxib; where the solvent system is selected from the group consisting of: C1-C6 alcohols selected from the group consisting of methanol, 1-propanol and 2-propanol, aromatic hydrocarbons selected from the group consisting of toluene and xylene, and nitriles selected from the group consisting of acetonitrile; where the term crystallographically substantially pure means that the polymorph form contains less than 30 wt.% of other polymorphs, amorphous form or solvates, where the polymorph purity is determined by X-ray powder diffractometry, and where the D2 polymorph form of robenacoxib is characterized by an X-ray powder diffraction pattern obtained using CuKa -radiation and containing signals with peak positions at the following 2θ values: 6.0°, 10.1°, 17.0°, 22.5° and 29.1°. 5. The method of claim 4 wherein the solvent system is toluene. 6. The method according to any one of claims 1 to 5, further comprising the step of combining the crystallized D2 polymorph of robenacoxib with one or more pharmaceutically acceptable excipients to obtain a pharmaceutical composition.