Stable monohydrate of df2755a and method for its preparation

Abstract

The present invention relates to stable monohydrates of the compound DF2755A, to processes for their manufacture, to pharmaceutical compositions and medical uses thereof. The monohydrate of the compound DF2755A of the present invention is physically, chemically and optically stable, and thus is particularly advantageous for pharmaceutical applications.

Description

Technical Field

[0001] The present invention relates to a monohydrate of the compound DF2755A, a method for preparing the monohydrate, and a pharmaceutical composition and medical use thereof. Background Art

[0002] International patent application WO2010031835A2 discloses a class of compounds of formula (I) and their chemical synthesis in the name of the applicant:

[0003]

[0004] Specifically, the above document discloses the compound 2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (wherein in formula (1), Z is CF3; Y is S; R1 and R2 are H) (Example 1), and its 2S enantiomer (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (Example 3) is also known as DF2755Y.

[0005]

[0006] and its sodium salt, sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate (Example 3a), also known as DF2755A:

[0007]

[0008] The compound DF2755A appears particularly promising due to its selective dual potent inhibitory activity against both CXCR1 and CXCR2 receptors and its favorable oral pharmacokinetic profile. It has been found to have potential therapeutic applications in colon cancer, prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, melanoma, inflammatory and postoperative pain, inflammatory-mediated diseases (e.g., bullous pemphigoid, cystic fibrosis, chronic obstructive pulmonary disease, asthma, psoriasis, rheumatoid arthritis, inflammatory bowel disease), and lung cancer (Theranostics 2017; 7(6): 1543-1588; Pharmacological Research 103(2016) 69–79).

[0009] The present inventors have studied the stability of DF2755A with the aim of developing it as a pharmaceutical and have found that the known anhydrous DF2755A obtained in Example 3a of WO2010031835A2 is physically and chemically unstable. More specifically, as will be described in detail in Example 2 below, this form is not only highly hygroscopic (spontaneously absorbing water from the environment, thereby becoming amorphous, partially molten, sticky, and difficult to handle), but also largely converts into undesirable by-products.

[0010] A fundamental requirement for pharmaceutical products is that the active substance must be in a stable crystalline form to ensure consistent processing parameters and the quality, stability and reproducibility of the final pharmaceutical product. Summary of the Invention

[0011] The present inventors have found that the anhydrous solid form of DF2755A is not suitable for pharmaceutical use, particularly for macroscale applications, due to its hygroscopicity and chemical instability.

[0012] Therefore, the present inventors focused on research activities aimed at obtaining a solid form of DF2755A that is physically and chemically stable, easy to handle, industrially advantageous and suitable for pharmaceutical applications.

[0013] After extensive research, the present inventors unexpectedly discovered that under very specific environmental conditions, the unstable anhydrous DF2755A is smoothly converted into a new stable crystalline monohydrate polymorph. Unexpectedly, only the specific process conditions determined by the present inventors and described in this application produced the stable monohydrate polymorph of the present invention, while many other attempts to obtain a stable form of DF2755A produced the same known anhydrous DF2755A form, or a non-stoichiometric unstable hydrate, even when water was present in the crystallization medium.

[0014] As shown by the analytical and stability studies reported in this experimental section, the DF2755A monohydrate polymorph, referred to herein as Form I, is physically and chemically stable. Advantageously, this new crystalline form is non-hygroscopic and does not undergo undesirable chemical transformations.

[0015] Thus, a first aspect of the present invention provides crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate (also referred to herein as "DF2755A monohydrate"), characterized in that it has an X-ray diffraction pattern (XRPD) having peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5° 2θ ± 0.2 degrees 2θ.

[0016] Another aspect of the present invention provides a method for preparing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate monohydrate, preferably crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate monohydrate as defined above, comprising:

[0017] i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate; and

[0018] ii) exposing it to an atmosphere having a relative humidity (RH) of more than 60 wt % and less than 80 wt % at a temperature of 25° C. to 40° C. and at atmospheric pressure, preferably for a period of 12 to 72 hours, thereby providing sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate.

[0019] Another aspect of the present invention provides a method suitable for large-scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, comprising:

[0020] - providing a solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid in a solvent selected from ethyl acetate, isobutyl acetate, propyl acetate, and mixtures thereof, wherein the concentration of the acid in the solution is from 0.08 Kg / l to 0.12 Kg / l;

[0021] - adding sodium base to the solution at a molar ratio of 0.9:1 to 0.95:1 compared to the acid to provide a mixture;

[0022] - adding an antisolvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture, wherein the volume ratio of the antisolvent to the solvent is 0.4:1 to 0.6:1, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate.

[0023] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate crystalline monohydrate, preferably sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate crystalline monohydrate as defined above and at least a pharmaceutically acceptable excipient.

[0024] Another aspect of the present invention provides crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, preferably crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate as defined above, for use as a medicament.

[0025] Another aspect of the present invention provides crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, preferably crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate as defined above, for use in preventing or treating acute or chronic inflammatory-mediated diseases, inflammatory and postoperative pain, interstitial cystitis (IC) / bladder pain syndrome (BPS) and / or cancer.

[0026] Another aspect of the present invention provides a method for preventing or treating acute or chronic inflammatory-mediated diseases, inflammatory and postoperative pain, interstitial cystitis (IC) / bladder pain syndrome (BPS) and / or cancer, which comprises administering to an individual in need thereof an effective amount of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate of the present invention, alone or in combination with another pharmaceutically acceptable excipient.

[0027] definition

[0028] As used herein, the term "comprise" or variations such as "comprising" or "including" should be interpreted as meaning the inclusion of any recited integers (e.g., features, elements, characteristics, attributes, method / process steps, or limitations) or group of integers (e.g., features, elements, characteristics, attributes, method / process steps, or limitations) but not the exclusion of any other integer or group of integers. Thus, the term "comprising" as used herein is inclusive or open-ended and does not exclude additional, unrecited integers or method / process steps.

[0029] As used herein, the term "consisting of" is used to indicate that only the recited integers (e.g., compounds, compositions, features, elements, characteristics, attributes, method / process steps, or limitations) or groups of integers (e.g., compounds, compositions, features, elements, characteristics, attributes, method / process steps, or limitations) are present.

[0030] The phrase "consisting essentially of is used herein to claim the entirety of the recitation and those things that do not materially affect the characteristics or functions of the claimed invention.

[0031] The term "substantially identical" in relation to XRPD diffraction patterns means that variability in the positions and relative intensities of the peaks is taken into account. The ability to determine the basic characteristics of an X-ray diffraction pattern is within the skill of one of ordinary skill in the art. For example, the typical accuracy of 2θ values is within ±0.2° 2θ. Thus, under standard conditions, a diffraction peak that normally appears at 14.9° 2θ may appear between 14.7° and 15.1° 2θ on most X-ray diffractometers. XRPD measurements are typically performed at RT, for example, at a temperature of 20°C, and preferably at a relative humidity of 40%.

[0032] For the purposes of the present invention, the term "pharmaceutically acceptable excipient" refers to a substance that does not have any pharmacological effect itself and does not produce adverse reactions when administered to a mammal, preferably a human.

[0033] For the purposes of the present invention, the term "room temperature" (RT) means a temperature range of 18°C to 25°C.

[0034] For the purposes of the present invention, the term "antisolvent" means a solvent in which the compound is insoluble or poorly soluble.

[0035] The terms "approximately," "around," and "about" herein refer to the range of experimental error that may occur in the measurements. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The measured values of anhydrous DF2755A prepared according to Example 3a of WO2010031835A2 at time 0 are shown. 1 H-NMR spectrum (solvent: D2O);

[0037] Figure 2 Shown is the XRPD pattern of anhydrous DF2755A prepared according to Example 2A measured at time 0 (y-axis: counts);

[0038] Figure 3 The results show that the anhydrous DF2755A prepared according to Example 2A after exposure to uncontrolled ambient humidity at a temperature of about 25°C for 24 hours 1 H-NMR spectrum (solvent D2O) (the signal of the hydroxylated by-product is marked with X);

[0039] Figure 4 shows the XRPD pattern (y-axis: counts) of anhydrous DF2755A prepared according to Example 2A after exposure to humidity (%RH: 50%) at a temperature of about 25°C for 24 hours;

[0040] Figure 5The results show the measured values of DF2755A monohydrate prepared according to Example 3 after 24 hours in a climate chamber at 65% RH and 30°C. 1 H-NMR spectrum (solvent D2O);

[0041] Figure 6 Shown are XRPD patterns of DF2755A monohydrate Form I prepared according to Example 3 measured at time 0 and after 24 hours in a climate chamber at 65% RH and 30° C. (y-axis: counts);

[0042] Figure 7 Shown are DSC analyses of DF2755A monohydrate held at 30°C / 65% RH or 40°C / 75% RH measured at time 0 and after 1, 3, 6, 9, 12, and 18 months.

[0043] Figure 8 Shown is the HPLC chromatogram of DF2755A monohydrate. DETAILED DESCRIPTION

[0044] A first aspect of the present invention provides a crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, characterized in that an X-ray diffraction pattern (XRPD) has peaks at 7.9°, 18.3°, 19.8°, 23.8° and 25.5° 2θ ± 0.2 degrees 2θ (i.e., the error range of the value shown for each peak is ± 0.2 degrees 2θ).

[0045] As a shorthand, this compound is referred to herein as "DF2755A monohydrate."

[0046] DF2755A monohydrate is characterized by Figure 5 of 1 H-NMR spectrum, Figure 6 XRPD and Figure 7 DSC.

[0047] It will be understood by one of ordinary skill in the art that XRPD patterns may be obtained with measurement errors that depend on the measurement conditions employed. It will be understood that the crystalline forms described herein are not limited to crystalline forms that produce X-ray diffraction patterns that are identical to those depicted in the accompanying drawings. Rather, Figure 6 Crystalline forms of DF2755A having X-ray diffraction patterns substantially identical to those shown in FIG. 5 (as defined above) fall within the scope of the present invention.

[0048] The crystalline form of DF2755A monohydrate obtained in the present invention characterized by an X-ray diffraction pattern (XRPD) having peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5° 2θ ± 0.2 degrees 2θ is referred to herein as Form I.

[0049] Preferably, the present crystalline form of DF2755A monohydrate is further characterized by XRPD peaks at 9.3°, 15.5°, 22.1°, 22.3°, 23.0°, and 24.6° 2Θ ± 0.2 degrees 2Θ.

[0050] Other polymorphs of the present DF2755A monohydrate are also within the scope of the present invention.

[0051] All the most relevant XRPD peaks for DF2755A monohydrate are shown in Table 1 below:

[0052] Table 1

[0053] Position [°2θ] Relative strength [%] 7.9 99.9 9.3 8.1 15.5 7.9 17.5 4.1 18.3 16.3 19.8 16.8 22.1 8.2 22.3 8.5 23.0 8.7 23.8 16.8 24.6 9.6 25.5 16.9 27.5 5.1 28.1 5.1 29.1 5.1

[0054] The water content of the DF2755A monohydrate of the present invention as measured by the Karl Fischer method is preferably 5.0 to 6.3 wt%, more preferably 5.0 to 5.5 wt%, even more preferably 5.0 to 5.3 wt%.

[0055] The DF2755A monohydrate of the present invention appears as a white powder.

[0056] The powders are characterized by good rheological properties and are particularly suitable for pharmaceutical applications.As known in the art, the technical properties of powders (PSD, bulk density, flowability, surface area, etc.) and their use in pharmaceutical manufacturing strictly depend on the particle properties.

[0057] Compared with the powder of anhydrous DF2755A, the powder of DF2755A monohydrate obtained by the present method is non-sticky and shows an improved appearance. In addition, the powder properties and morphology of the present monohydrate are particularly advantageous for pharmaceutical formulations.

[0058] Preferably, the DF2755A monohydrate powder of the present invention is characterized by the following particle size distribution intervals as measured by Malvern Mastersizer 3000 using Aero S accessory: D(0.1) = 2.0 μm to 2.5 μm, D(0.5) = 6.5 μm to 8.5 μm, D(0.9) = 20.0 μm to 30.0 μm.

[0059] The bulk density of a powder is the ratio of the mass of an untapped powder sample to its volume. It depends on both the density of the powder particles and the spatial arrangement of the particles in the powder bed.

[0060] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a bulk density measured according to Ph. Eur. 2.9.34 higher than 0.15 g / ml, more preferably higher than 0.16 g / ml, higher than 0.17 g / ml, even more preferably between 0.17 g / ml and 0.20 g / ml.

[0061] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a tap density measured according to Ph. Eur. 2.9.34 of 0.19 to 0.28 g / ml, preferably of about 0.25 g / ml.

[0062] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a compressibility index of 23 to 33.

[0063] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a Hausner Ratio below 1.50, more preferably below 1.45, typically between 1.30 and 1.45.

[0064] As shown in the experimental part, the DF2755A monohydrate powder according to the invention is not hygroscopic (see unchanged water content for at least 12 months under accelerated stability conditions - Table 7).

[0065] Furthermore, the DF2755A monohydrate according to the present invention is chemically and optically stable (see unchanged impurity content and enantiomeric purity in Table 7 in the experimental section). In particular, the byproduct of hydroxylation at position 4 of the thiazole ring, which is produced in significant amounts when anhydrous DF2755A is exposed to ambient, uncontrolled humidity at a temperature of about 25° C. ((2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (referred to herein as DFL23803)), was not detected. Furthermore, the undesired enantiomer (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (referred to herein as DF2703Y) was well below the product specification (see Table 7).

[0066] Thus, according to the present invention, there is provided a composition comprising, consisting essentially of or consisting of DF2755A, preferably a composition comprising, consisting essentially of or consisting of DF2755A monohydrate as described herein.

[0067] Preferably, the total impurity content in the present composition measured by HPLC as described in this experimental part is below 0.5%, more preferably below 0.1%, even more preferably below 0.05% (see for example the data in Table 7).

[0068] Preferably, the present composition comprises DF2755A, or is essentially composed of DF2755A, preferably, comprises DF2755A monohydrate as described above, or is composed of DF2755A monohydrate as described above, wherein the content of the structurally related impurity (2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (DFL23803) determined by HPLC method according to the present specification is less than 0.5%, preferably less than 0.2%, more preferably less than 0.1% (see, for example, the data in Tables 5 and 7).

[0069] In summary, the DF2755A monohydrate of the present invention is superior to the known anhydrous DF2755A and is particularly suitable for large-scale pharmaceutical applications.

[0070] Another aspect of the present invention provides a method for preparing crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, preferably crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate according to any one of the above embodiments of the first aspect of the present invention, comprising:

[0071] i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate; and

[0072] ii) exposing it to an atmosphere having a relative humidity (RH) of more than 60 wt % and less than 80 wt % at a temperature of 25° C. to 40° C. and at atmospheric pressure, preferably for a period of 12 to 72 hours, thereby providing sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate.

[0073] Regarding step i) of the present process, the starting anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (hereinafter also referred to as “anhydrous DF2755A”) is preferably prepared according to the process of the present invention described below.

[0074] Regarding step ii) of the present method, the atmosphere to which the anhydrous DF2755A is exposed may be air, one or more inert gases, or a mixture thereof, preferably the atmosphere is nitrogen.

[0075] Regarding the RH of the atmosphere, the inventors observed that for RH values up to 60%, there was little or no conversion to the monohydrate, whereas for RH values of 80% or higher, the product became deliquescent.

[0076] Preferably, the RH of the atmosphere is 65 wt% to 75 wt%.

[0077] Preferably, the atmosphere temperature is 25°C to 30°C.

[0078] Preferably, the exposure time is from 24 hours to 72 hours.

[0079] A preferred method for preparing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, preferably crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate according to any one of the above-mentioned embodiments of the first aspect of the present invention, comprises:

[0080] i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate, preferably prepared according to the process of the present invention described below; and

[0081] ii) exposing it to an atmosphere having a relative humidity (RH) of 65 to 75 wt % at a temperature of 25 to 30° C. and at atmospheric pressure, preferably for a period of 12 to 72 hours, thereby providing sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate.

[0082] Typically, anhydrous DF2755A is spread on a tray and placed in a climate chamber set at the desired RH and T for the time required to complete the conversion. The conversion can be monitored by Karl Fischer analysis.

[0083] Another aspect of the present invention provides a method suitable for large-scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, comprising:

[0084] - providing a solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (DF2755Y) in a solvent selected from ethyl acetate, isobutyl acetate, propyl acetate, and mixtures thereof, wherein the concentration of the acid in the solution is from 0.08 Kg / l to 0.12 Kg / l,

[0085] - adding sodium base to the solution in a molar ratio of 0.9:1 to 0.95:1 compared to the acid to provide a mixture,

[0086] - adding an antisolvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture, wherein the volume ratio of the antisolvent to the solvent is 0.4:1 to 0.6:1, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate.

[0087] Preferably, the concentration of the acid DF2755Y in the solution is between 0.09 Kg / l and 0.11 Kg / l, more preferably about 0.10 Kg / l.

[0088] Preferably, the solvent is selected from isobutyl acetate, propyl acetate and mixtures thereof, more preferably the solvent is isobutyl acetate.

[0089] Preferably, the sodium base is selected from sodium hydroxide or sodium methoxide, more preferably sodium hydroxide. The sodium base can be added as is, or preferably dissolved in a suitable solvent, preferably in water or an aqueous mixture with a polar solvent (e.g., ethanol or methanol). In a preferred embodiment, the sodium base is aqueous sodium hydroxide.

[0090] Preferably, the sodium base is added in a substoichiometric amount relative to the acid to prevent racemization of the chiral carbon.

[0091] According to the present method, precipitation of anhydrous DF2755A from the solution is performed by adding an antisolvent, preferably selected from toluene, p-xylene and mixtures thereof, more preferably the antisolvent is toluene.

[0092] Preferably, the volume ratio of the antisolvent or mixture thereof to the solvent is about 0.5:1.

[0093] The precipitation is generally carried out under stirring, preferably by cooling at a temperature below 20°C, more preferably below 10°C, even more preferably at about 5°C.

[0094] A preferred method for large-scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate comprises:

[0095] - providing a solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (DF2755Y) in isobutyl acetate, wherein the concentration of the acid in the solution is 0.09 Kg / l to 0.11 Kg / l, preferably about 0.10 Kg / l,

[0096] - adding sodium hydroxide to the solution at a molar ratio of 0.9:1 to 0.95:1 compared to the acid to provide a mixture,

[0097] - Toluene was added to the mixture at a volume ratio of about 0.5:1 compared to the solvent, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate.

[0098] Advantageously, the present method for preparing anhydrous DF2755A by antisolvent precipitation is industrially feasible and avoids the cumbersome and expensive lyophilization procedures shown in the prior art. Compared with the lyophilization methods of the prior art, the present method provides anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate with improved chemical and enantiomeric purity.

[0099] Another aspect of the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate monohydrate, preferably sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate monohydrate according to any one of the above-mentioned embodiments of the first aspect of the present invention; and at least a pharmaceutically acceptable excipient.

[0100] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, its effect on solubility and stability, and the nature of the dosage form.

[0101] The pharmaceutical composition according to the present invention may be in any form suitable for administration to humans and / or animals (preferably humans including infants, children and adults) and can be produced by standard procedures known to those skilled in the art.

[0102] In one embodiment, the pharmaceutical composition of the present invention is an oral solid composition, such as a capsule, pill, tablet, cachet, chewable dosage form, powder, lozenge, granule, orally soluble granule, or as a dry powder to be reconstituted with a liquid medium.

[0103] In one embodiment, the pharmaceutical composition of the present invention is a suspension, emulsion or spray.

[0104] The pharmaceutical composition may additionally comprise one or more pharmaceutically acceptable excipients, such as fillers, binders, glidants, disintegrants, flow regulators, and release agents.

[0105] Suitable excipients are disclosed, for example, in “Handbook of Pharmaceutical Excipients”, 3rd edition, published by AH Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London.

[0106] Suitable fillers are, for example, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate and dibasic calcium phosphate.

[0107] The filler may be present in an amount of 0% to 80% by weight, preferably 10% to 60% by weight, based on the total weight of the composition.

[0108] Suitable binders are, for example, polyvinylpyrrolidone, microcrystalline cellulose hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sugars, dextran, corn starch, gelatin, polyethylene glycol, natural and synthetic gums, pregelatinized starch.

[0109] The binder may be present in an amount of 0% to 80% by weight, preferably 10% to 60% by weight, based on the total weight of the composition.

[0110] Binders are generally used to impart a cohesive quality to tablet formulations.

[0111] Suitable glidants are, for example, alkaline earth metal salts of fatty acids, such as stearic acid, for example magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate.

[0112] The glidant may be present, for example, in an amount of 0% to 2% by weight, preferably in an amount of 0.5% to 1.5% by weight, based on the total weight of the composition.

[0113] Suitable disintegrants are, for example, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinyl pyrrolidone (crospovidone), sodium carboxymethyl glycolate, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, sodium alginate, and sodium bicarbonate.

[0114] The disintegrant may be present in an amount of 0 wt% to 20 wt%, preferably 1 wt% to 15 wt%, based on the total weight of the composition.

[0115] A suitable flow control agent is for example colloidal silicon dioxide.The flow control agent may be present in an amount of 0% to 8% by weight, preferably in an amount of 0.1% to 3% by weight, based on the total weight of the composition.

[0116] A suitable release agent is for example talc.The release agent may be present in an amount of 0% to 5% by weight, preferably in an amount of 0.5% to 3% by weight, based on the total weight of the composition.

[0117] The solid composition may be coated, preferably film-coated.

[0118] Suitable coating agents are, for example, cellulose derivatives, poly(meth)acrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, and / or shellac or natural rubber, such as carrageenan.

[0119] There are many situations in which it will be advantageous or even necessary to deliver the DF2755A monohydrate of the present invention as a solid, for example by placement of a solid implant composition into an appropriate body tissue or cavity.

[0120] The implant may comprise a matrix of biocompatible and bioerodible material in which particles of the DF2755A monohydrate of the present invention are dispersed, or pellets or discrete units in which a liquid mixture of the DF2755A monohydrate of the present invention may be embedded. It is desirable that the matrix will decompose and be completely absorbed by the body. The composition of the matrix is also preferably selected to provide controlled, sustained, and / or delayed release of the DF2755A monohydrate of the present invention over an extended period of time.

[0121] Alternatively, the DF2755A monohydrate of the present invention can be formulated as a solid, semisolid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.

[0122] The present compositions may be applied topically to the skin or mucosa, ie, dermally, epidermally, subcutaneously or transdermally.

[0123] The present composition may be administered sublingually or via a suppository.

[0124] Typical formulations for this purpose include pour-ons, spot-ons, dips, sprays, mousses, shampoos, powders, gels, hydrogels, lotions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, depots, sponges, fibers, bandages, microemulsions, orosoluble granulates. Liposomes may also be used.

[0125] The pharmaceutical compositions of the present invention may be solutions or suspensions for oral or parenteral administration (to be administered, for example, by intramuscular, intraperitoneal or intravenous injection).

[0126] The pharmaceutical compositions of the present invention may be solid compositions for the extemporaneous preparation of solutions for oral or parenteral administration (to be administered, for example, by intramuscular, intraperitoneal or intravenous injection).

[0127] The pharmaceutical composition of the present invention can be prepared by methods known to those skilled in the art.

[0128] The compositions of the present invention may be immediate release, delayed release, modified release, sustained release, pulsed release or controlled release.

[0129] According to a further embodiment, the pharmaceutical composition of the present invention may comprise the DF2755A monohydrate of the present invention and at least another pharmaceutically active ingredient.

[0130] The additional pharmaceutically active ingredient will be determined by the circumstances under which the therapeutic agents of the invention are administered.

[0131] The further medicament active ingredients are, for example, selected from analgesic and / or anti-inflammatory drugs or from anticancer drugs.

[0132] Another aspect of the present invention provides the sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate as described above for use as a medicament.

[0133] Medicinal uses may be curative, preventative or palliative.

[0134] Another aspect of the present invention provides the sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate crystalline monohydrate as described above for use in preventing or treating acute or chronic inflammatory-mediated diseases, inflammatory and postoperative pain, interstitial cystitis (IC) / bladder pain syndrome (BPS) and / or cancer.

[0135] Preferably, the inflammatory-mediated disease is selected from bullous pemphigoid, cystic fibrosis, chronic obstructive pulmonary disease, asthma, psoriasis, rheumatoid arthritis and inflammatory bowel disease,

[0136] Preferably, the cancer is selected from lung cancer, colon cancer, prostate cancer, pancreatic cancer, breast cancer and ovarian cancer, and melanoma.

[0137] The daily dose for humans and animals may vary depending on the basic factors of the respective species or other factors, such as age, sex, weight or degree of disease.

[0138] Another aspect of the present invention provides a method for preventing or treating pain, inflammation and / or cancer, comprising administering a therapeutically effective amount of the DF2755A monohydrate of the present invention to an individual in need thereof, alone or in combination with another pharmaceutically active ingredient.

[0139] According to the present invention, the term "individual" refers to a human or an animal, preferably a human.

[0140] The same preferences described above for the medical use of DF2755A monohydrate also apply to the present method.

[0141] Experimental part

[0142] In the following, some non-limiting examples according to the present invention or comparison are provided for illustrative purposes.

[0143] Analysis and test methods

[0144] HPLC assay :

[0145] Instrument: Agilent HP 1100, HP 1200 or equivalent HPLC system with UV detector

[0146] Detector: Wavelength: 220nm

[0147] Column: BDS Hypersyl C18, 250 mm × 4.6 mm, 5 μm (Thermo) or equivalent

[0148] Column temperature: 35°C

[0149] Mobile phase: (A) Buffer solution KH2PO4 0.025 M (pH 3.0). Procedure: Dissolve 3.4 g of potassium dihydrogen phosphate in water and dilute to 1000 ml with water; adjust to pH 3.0 with dilute phosphoric acid or potassium hydroxide solution. (B) Acetonitrile.

[0150] Flow rate: 1.3ml / min

[0151] Injection volume: 10 μl

[0152] Injection interval: 26 minutes

[0153] Diluent: H2O / CH3CN (40 / 60)

[0154] Relative retention time: DF 2755Rt 11.8 minutes

[0155] Gradient: Table 2

[0156] Table 2

[0157] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 60 40 10 60 40 19 40 60 20 60 40 26 60 40

[0158] HPLC enantiomeric purity

[0159] Chromatographic conditions

[0160] Instrument: Agilent HP 1100, HP 1200 or equivalent HPLC system with UV detector

[0161] Detector: Wavelength: 294nm

[0162] Column: Chiralpak AS-RH, 150 mm × 4.6 mm 55 μm (Daicel) or equivalent Column temperature: 35 °C

[0163] Mobile phase: (A) Buffer solution KH2PO4 0.025M (pH 3.0) Procedure: Dissolve 3.4 g of potassium dihydrogen phosphate in water and dilute to 1000 ml with water; adjust to pH 3.0 with dilute phosphoric acid or potassium hydroxide solution; (B) Acetonitrile

[0164] Flow rate: 0.7ml / min

[0165] Injection volume: 10 μl

[0166] Injection interval: 45 minutes

[0167] Diluent: H2O / CH3CN (40 / 60)

[0168] Eluent: 70% mobile phase A, 30% mobile phase B

[0169] 1 H-NMR : Recorded on a Bruker Avance3 400 MHz instrument with tetramethylsilane (TMS) as the internal standard in the specified solvent 1 H-nuclear magnetic resonance (NMR) spectrum.

[0170] XRPD : XRPD analyses were performed with the following instrumentation at RT and under the conditions reported in Table 3 below:

[0171] Table 3

[0172]

[0173]

[0174]

[0175] Water content by Karl Fischer:

[0176] Instrument: Mettler DL38, V30 or equivalent

[0177] Electrode: Double platinum needle electrode DM 143-SC for Karl Fischer titration.

[0178] Titrant: Karl Fischer reagent 5mg H2O / ml

[0179] Solvent: 30 ml of methanol neutralized with Karl Fischer reagent.

[0180] Procedure: Accurately weighed 0.2 g of product is dissolved in solvent and titrated with Karl Fischer reagent.

[0181] Formula: %H2O=(V×e) / (10×w)

[0182] in

[0183] V = ml of Karl Fischer reagent used for titration

[0184] e = equivalent of Karl Fischer reagent (mg H2O / ml)

[0185] w = weight of the sample in g

[0186] Three samples are analyzed and the results averaged. The limit must not exceed 10.0%.

[0187] Particle size distribution Measured by Malvern Mastersizer 3000 using the Aero S attachment.

[0188] Tap density and bulk density The density was determined according to the European Pharmacopoeia (Ph. Eur. 2.9.34) using a density tester ERWEKA SMV102 (Heusenstamm, Germany).

[0189] Compressibility index Calculated according to the following formula:

[0190] CI = 100 x (tap density - bulk density) / tap density.

[0191] Hausnaby Calculated according to the following formula:

[0192] Hr = tap density / bulk density

[0193] Example 1: (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid Preparation of (DF2755Y)

[0194] The title compound was prepared as described under Example 3 of WO2010031835A2.

[0195] Example 2: Anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate Preparation of (Anhydrous DF2755A) (Laboratory Scale)

[0196] The title compound was prepared according to the procedure described under Example 3a of WO2010031835A2 starting from the free acid DF2755Y of Example 1.

[0197] Example 2A (Invention): Anhydrous (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) Preparation of Sodium Propionate (Anhydrous DF2755A) (Pilot Scale)

[0198] The acid DF2755Y (7.9 kg) of Example 1 is loaded into a 200-liter glass chemical reactor and then, at room temperature (rt), 63 liters of isobutyl acetate are added under stirring. Decolorizing carbon (0.4 kg) is added to the dark solution and placed at rt for 20 minutes. The solution is filtered through a FAP5 filter to obtain a completely transparent light yellow solution. The solution is loaded into a 500-liter glass chemical reactor and, at rt, 16 liters of isobutyl acetate are added under stirring. 50% aqueous sodium hydroxide solution (1.3 liters) is added and the resulting solution is mixed at 50°C for 1 hour. The reactor is cooled at 20°C, then toluene (40 liters) is added. After 1 hour under stirring, the product begins to separate out, and the mixture is further stirred at 5°C for 12 hours. The slurry is then centrifuged at 1000rpm for 30 minutes. The isolated product was dried at 40°C under vacuum for about 24 hours to obtain crystalline anhydrous DF2755A (8.1 kg, 96% yield) as a white solid with mp of about 150°C.

[0199] The anhydrous DF2755A thus obtained is obtained by 1 H-NMR (at T0, 1 The H-NMR spectrum is consistent with that of anhydrous DF2755A prepared according to Example 3a of WO2010031835 and is shown in Figure 1 ) and XRPD analysis ( Figure 2 ) for characterization.

[0200] The relevant XRPD peaks for anhydrous DF2755A have the positions and relative intensities shown in Table 4 below:

[0201] Table 4

[0202] Position [°2θ] Relative strength [%] 8.1 100 9.5 67.7 15.7 29.3 18 7.1 18.8 30.1 19.2 57.1 19.8 8.1 22.2 15.1 22.5 21.1 23.5 14.7 24.1 100 24.6 42.5 25.5 10.1 27.7 11.1 28.5 14.9 29.5 13.1

[0203] Stability testing

[0204] A sample of anhydrous DF2755A prepared according to Example 2A was placed in a climate chamber and exposed to 50% RH at about 25°C for 24 hours to provide a sticky hydrated solid having a water content of 17% as measured by Karl Fischer analysis. The solid showed Figure 4 XRPD spectrum of .

[0205] 1H-NMR analysis showed that the hydrated solid contained another compound in significant amounts (about 50% mol / mol), a byproduct of the hydroxylation at position 4 of the thiazole ring of DF2755A (see Figure 3 The relevant signals are marked by X in the figure).

[0206] In summary, anhydrous DF2755A under the conditions tested was both physically and chemically unstable.

[0207] Example 3 (Invention): Preparation of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazole-2- Sodium 1,2-dimethylamino}phenyl)propionate monohydrate Form I (DF2755A monohydrate Form I)

[0208] Anhydrous DF2755A (0.040 kg) prepared according to Example 2A was spread on a tray and placed in a climate chamber at 65% RH at a temperature of 30° C. for 48 hours to provide DF2755A monohydrate Form I (0.039 kg, 93% yield) as a white solid.

[0209] Supplied by HPLC Figure 8 The final product was analyzed by the chromatogram of , and the results are shown in the following Table 5:

[0210] Table 5

[0211]

[0212] As can be seen, the final DF2755A monohydrate has a very high purity and contains the by-product DFL23803 in negligible amounts (0.02%).

[0213] Also by Karl Fischer method (water content: 5.27 wt%), by 1 H-NMR (24 hours after removal from the climate chamber, Figure 5 ) and by XRPD (at time 0 and 24 hours after removal from the climate chamber, Figure 6 ) to analyze the product.

[0214] The relevant XRPD peaks of DF2755A monohydrate at T0 and after 24 hours have the positions and relative intensities shown in Table 6 below:

[0215] Table 6

[0216]

[0217] These analyses confirmed the structure, purity, crystallinity, and stability of DF2755A monohydrate Form I.

[0218] Stability testing

[0219] DF2755A monohydrate was then subjected to stability testing under the following conditions:

[0220] A) at 30°C and 65% RH (up to 18 months) and

[0221] B) At 40°C and 75% RH (accelerated stability up to 12 months).

[0222] The samples were analyzed for appearance, water content, HPLC purity, HPLC assay, HPLC enantiomeric purity, and DSC thermal behavior. The results are shown in Table 7 below:

[0223] Table 7: Stability data under accelerated condition B

[0224]

[0225] Compl: complies; nd: not detected;

[0226] DF2703Y: (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid;

[0227] DFL23803: (2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid,

[0228] and in Figure 7 , wherein under both stability test conditions A) and B), DF2755A monohydrate shows essentially the same DSC graph over time.

[0229] These data indicate that DF2755A monohydrate is completely stable for at least 18 months under Condition A and at least 12 months under Accelerated Condition B (see Figure 7 and Table 7), in particular, no significant amount of hydroxylated by-product DFL23803 and the other enantiomer (2R) DF2703Y was observed to form. Throughout the study period, the results of all analytical tests remained within the specification limits, and there was no evidence of the formation of degradation compounds.

[0230] Example 3A (Invention): Preparation of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazole-2- Sodium 1,2-dimethylamino}phenyl)propionate monohydrate Form I (DF2755A monohydrate Form I)

[0231] Anhydrous DF2755A (8.1 kg) prepared according to Example 2A was spread on a tray and placed in a climate chamber at 75% RH at a temperature of 25° C. for 72 hours to provide DF2755A monohydrate Form I (8.5 kg, 100% yield) as a white solid. The product had a water content of 5.27 wt % by Karl Fischer and an XRPD consistent with DF2755A monohydrate Form I.

[0232] DF2755A Monohydrate Form I powder exhibits the following rheological properties:

[0233] - Particle size distribution: D(0.1) = 2.09 μm, D(0.5) = 7.86 μm, D(0.9) = 25.42 μm;

[0234] -Tap density: 0.256 g / ml;

[0235] - Bulk density: 0.178 g / ml;

[0236] - Compressibility index: 30.7;

[0237] -Hausnerby: 1.44.

[0238] Example 4 (comparative): Preparation of DF2755A monohydrate by crystallization in the presence of water (failed)

[0239] The preparation of Example 2A was repeated on a 100 g scale in the presence of water in order to directly obtain the monohydrate polymorph.

[0240] In particular, during the salt formation step, the solution was cooled at 20° C. and then toluene and 6% of water were added. After 1 hour, the product began to precipitate and the resulting solid was stirred at 5° C. for another 12 hours.

[0241] However, the product obtained after filtration and drying at 40°C under vacuum for about 24 hours was anhydrous DF2755A. 1 H-NMR, HPLC, Karl Fischer and XRPD analyses confirmed the results.

[0242] Example 5 (Comparative): Preparation of Stable Stoichiometric Hydrate DF2755A by Controlled Hydration (Failed)

[0243] A sample of anhydrous DF2755A prepared according to Example 2A was placed in a climate chamber under the following conditions:

[0244] Example 5A: 24 hours, 25°C 50% RH

[0245] Example 5B: 24 hours, 25°C 60% RH

[0246] Example 5C: 72 hours, 25°C 60% RH

[0247] At the end of the hydration experiment, the 1 All samples analyzed by H-NMR, HPLC, Karl Fischer, and XRPD showed non-stoichiometric hydrates rather than DF2755A monohydrate.

Claims

1. A crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, characterized in that The X-ray diffraction pattern (XRPD) has peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5° 2Θ ± 0.2 degrees 2Θ.

2. The crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate according to claim 1, having a water content of 5.0 to 6.3 wt%, preferably 5.0 to 5.5 wt%, and more preferably 5.0 to 5.3 wt%, as measured by the Karl Fischer method.

3. The sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate crystalline monohydrate according to claim 1 or 2, characterized in that The X-ray diffraction pattern (XRPD) also has peaks at 9.3°, 15.5°, 22.1°, 22.3°, 23.0°, and 24.6° 2Θ ± 0.2 degrees 2Θ.

4. The crystalline monohydrate of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate according to any one of the preceding claims, characterized in that One or more of the following powder characteristics: - particle size distribution measured by Malvern Mastersizer 3000 using Aero S accessory with D(0.1)=2 to 2.5 μm, D(0.5)=6.5 to 8.5 μm, D(0.9)=20 to 30 μm; - a bulk density measured according to Ph. Eur. 2.9.34 of 0.17 g / ml to 0.20 g / ml; - a tap density measured according to Ph. Eur. 2.9.34 of 0.19 g / ml to 0.28 g / ml; - Compressibility index of 23 to 33; -Hausner Ratio below 1.

50.

5. A composition comprising, consisting essentially of, or consisting of the crystalline monohydrate according to any one of claims 1 to 4.

6. The composition according to claim 5, wherein the content of (2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid determined by HPLC method according to the instructions is less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%.

7. A method for preparing sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate crystalline monohydrate, comprising: i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate; and ii) exposing it to an atmosphere having a relative humidity (RH) of more than 60 wt % and less than 80 wt % at a temperature of 25° C. to 40° C. and at atmospheric pressure, preferably for a period of 12 to 72 hours, thereby providing sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate. The method according to claim 7 , wherein the RH of the atmosphere is 65 wt % to 75 wt %.

9. The method according to claim 7 or 8, wherein the temperature is 25°C to 30°C, and preferably, the time is 24 hours to 72 hours.

10. The method according to any one of claims 7 to 9, wherein the anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate of step i) is prepared according to the method according to claim 11 or 12.

11. A method for preparing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate, comprising: - providing a solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid in a solvent selected from ethyl acetate, isobutyl acetate, propyl acetate, and mixtures thereof, wherein the concentration of the acid in the solution is from 0.08 Kg / l to 0.12 Kg / l, - adding sodium base to the solution at a molar ratio of 0.9:1 to 0.95:1 compared to the acid to provide a mixture; - adding an antisolvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture, wherein the volume ratio of the antisolvent to the solvent is 0.4:1 to 0.6:1, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propionate.

12. The method according to claim 11, wherein: - the concentration of the (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid in the solution is 0.09 Kg / l to 0.11 Kg / l; - the solvent is isobutyl acetate; - the sodium base is sodium hydroxide, preferably aqueous sodium hydroxide; - the antisolvent is toluene; - the volume ratio of the antisolvent to the solvent is about 0.5:1; and - The precipitation is carried out by cooling at a temperature below 20°C, preferably below 10°C.

13. A pharmaceutical composition comprising a therapeutically effective amount of sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate according to any one of claims 1 to 4 and at least a pharmaceutically acceptable excipient.

14. Sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate according to any one of claims 1 to 4 for use as a medicament.

15. Sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate crystalline monohydrate according to any one of claims 1 to 4, for use in preventing or treating acute or chronic inflammatory-mediated diseases, inflammatory and postoperative pain, interstitial cystitis (IC) / bladder pain syndrome (BPS) and / or cancer.

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