Stable monohydrate of DF2755A and method for its preparation

Abstract

The present invention relates to a stable monohydrate of compound DF2755A, its preparation method, pharmaceutical composition and medical use thereof. The monohydrate of compound DF2755A of the present invention is physically, chemically and optically stable, and therefore is particularly advantageous for pharmaceutical applications.

Description

[Technical Field]

[0001] The present invention relates to the monohydrate of compound DF2755A, its preparation process, pharmaceutical compositions and medical uses. [Background technology]

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

[0003] [ka]

[0004] and their chemical synthesis are disclosed. In particular, the above document discloses the compound 2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (in formula (I), Z is CF, Y is S, and R and R are H) (Example 1), and its 2S enantiomer, (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid, also known as DF2755Y (Example 3):

[0005] [ka]

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

[0007] [ka]

[0008] Disclose. Compound DF2755A appears particularly promising because it features potent, selective, dual inhibitory activity against both CXCR1 and CXCR2 receptors and a favorable oral pharmacokinetic profile. Therefore, this compound has potential therapeutic applications in colon cancer, prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, melanoma, inflammatory and postoperative pain, and inflammation-mediated diseases such as 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 investigated the stability of DF2755A with the aim of developing this compound as a pharmaceutical agent and found that the known anhydrous DF2755A obtained in Example 3a of WO2010031835A2 is physically and chemically unstable. More specifically, as detailed in Example 2 below, this form is not only highly hygroscopic (it spontaneously absorbs water from the environment, thus becoming amorphous, partially molten, sticky and difficult to handle), but also converts to a significant degree into undesirable by-products.

[0010] A major requirement for pharmaceutical products is that the active substance must have a stable crystalline form, thereby ensuring consistent manufacturing parameters and the quality, stability and reproducibility of the final formulation. Summary of the Invention

[0011] The inventors have found that the anhydrous solid form of DF2755A is not suitable for pharmaceutical applications, especially macroscale applications, due to its hygroscopicity and chemical instability. Therefore, the present inventors have focused their research activities with the aim of obtaining a solid form of DF2755A that is physically and chemically stable, easy to handle, industrially advantageous, and suitable for pharmaceutical applications.

[0012] After extensive research, the inventors have surprisingly found that under very specific environmental conditions, the unstable anhydrous DF2755A smoothly converts to a new stable crystalline monohydrate polymorph. Surprisingly, only the specific process conditions identified by the inventors and described in this application result in the stable monohydrate polymorph of the present invention, while many other attempts to obtain a stable DF2755A form result in the same known anhydrous DF2755A form, even when water is present in the crystallization medium, or result in a non-stoichiometric, unstable hydrate.

[0013] This DF2755A monohydrate polymorph (referred to herein as Form I) is physically and chemically stable as demonstrated by the analytical methods and stability studies reported in this experimental section. Advantageously, this novel crystalline form is not hygroscopic and does not undergo undesired chemical transformations.

[0014] Accordingly, a first aspect of the present invention provides crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate (hereinafter also referred to as "DF2755A monohydrate") characterized by an X-ray diffraction pattern (XRPD) with peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5°2θ±0.2°2θ.

[0015] A further aspect of the present invention is a process 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 as defined above, comprising the steps of: i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; ii) exposing the material to an atmosphere having a relative humidity (RH) of greater than 60% and less than 80% by weight at a temperature of 25°C to 40°C and atmospheric pressure, preferably for 12 to 72 hours, thereby providing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate; The present invention provides a method comprising:

[0016] A further aspect of the present invention is a process suitable for the large-scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate, comprising: - preparing 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 between 0.08 and 0.12 kg / l; - adding a sodium base to the solution in a molar ratio to the acid of 0.9:1 to 0.95:1, thus resulting in a mixture; - adding an anti-solvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture in a volume ratio of 0.4:1 to 0.6:1 relative to the solvent, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; The present invention provides a method comprising:

[0017] A further aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, preferably as defined above, and at least a pharmaceutically acceptable excipient.

[0018] A further aspect of the present invention provides crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, preferably as defined above, for use as a pharmaceutical.

[0019] A further aspect of the present invention provides crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, preferably as defined above, for use in the prevention or treatment of acute or chronic inflammation-mediated diseases, inflammatory and post-operative pain, interstitial cystitis (IC) / painful bladder syndrome (BPS) and / or cancer.

[0020] A further aspect of the present invention provides a method for preventing or treating acute or chronic inflammation-mediated diseases, inflammatory pain and post-operative pain, interstitial cystitis (IC) / painful bladder syndrome (BPS) and / or cancer, comprising the step of administering to an individual in need thereof an effective amount of crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate of the present invention, alone or in combination with another active pharmaceutical ingredient. definition As used herein, the term "comprise," or variations thereof, such as "comprises" or "comprising," should be read as intending to include any stated element (e.g., attribute, element, feature, property, method / process step, or limitation) or group of elements (e.g., attribute, element, feature, property, method / process step, or limitation), but not excluding any other element or group of elements. Thus, as used herein, the term "comprising" is inclusive or open-ended and does not exclude additional, unlisted elements or method / process steps.

[0021] As used herein, the term "consisting of" is used to imply the presence of a stated element (e.g., compound, composition, attribute, element, feature, property, method / process step or limitation) or group of elements (e.g., compound, composition, attribute, element, feature, property, method / process step or limitation) alone.

[0022] The phrase "consisting essentially of" is used herein to require an element(s) that does not materially affect the characteristics or function of the described and claimed invention. The term "substantially identical" in reference to XRPD diffraction patterns means that variations in peak positions and relative intensities of the peaks are allowed for. The ability to confirm the substantial identity of X-ray diffraction patterns is within the purview of one of ordinary skill in the art. For example, typical accuracy of 2θ values ​​is within ±0.2° 2θ. Thus, a diffraction peak that normally appears at 14.9° 2θ may appear between 14.7° and 15.1° 2θ in most X-ray diffractometers under standard conditions. XRPD measurements are typically performed at RT, e.g., at a temperature of 20°C, and preferably at a relative humidity of 40%.

[0023] For the purposes of the present invention, the term "pharmaceutically acceptable excipient" refers to a substance that lacks pharmacological effects of its own and does not produce adverse reactions when administered to a mammal, preferably a human. For the purposes of the present invention, the term "room temperature" (RT) means a temperature range of 18 to 25°C.

[0024] For the purposes of the present invention, the term "antisolvent" means a solvent in which a compound is insoluble or poorly soluble. The terms "approximately," "around," and "about" are used herein to refer to the range of experimental error that may occur in a measurement. [Brief explanation of the drawings]

[0025] [Figure 1]1 shows the H-NMR spectrum (solvent: DO) of anhydrous DF2755A prepared according to Example 3a of WO2010031835A2 measured at time 0. [Figure 2] 1 shows the XRPD pattern (y-axis: counts) measured at time 0 of anhydrous DF2755A prepared according to Example 2A. [Figure 3] 1 shows the H-NMR spectrum (solvent DO) of anhydrous DF2755A prepared according to Example 2A after exposure to uncontrolled ambient humidity at a temperature of about 25° C. for 24 hours (signals of hydroxylated by-products are marked with X). [Figure 4] 1 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. [Figure 5] 1 shows the H-NMR spectrum (solvent DO) of DF2755A monohydrate prepared according to Example 3, measured after 24 hours in a climate chamber at 65% RH and 30° C. [Figure 6] 1 shows the 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). [Figure 7] 1 shows DSC analysis of DF2755A monohydrate maintained at 30° C. / 65% RH or 40° C. / 75% RH measured at time 0 and after 1 month, 3 months, 6 months, 9 months, 12 months, and 18 months. [Figure 8] 1 shows an HPLC chromatogram of DF2755A monohydrate. DETAILED DESCRIPTION OF THE INVENTION

[0026] A first aspect of the present invention provides crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate 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°2θ (i.e., with an error range of ± 0.2°2θ for the value shown for each peak).

[0027] As a shorthand, this compound is designated herein as "DF2755A monohydrate." DF2755A monohydrate is shown in Figure 5 1 Characterized by H-NMR spectrum, XRPD in FIG. 6 and DSC in FIG.

[0028] Those skilled in the art will recognize that XRPD patterns may be obtained with measurement errors that depend on the measurement conditions employed. It will be appreciated that the crystalline forms described herein are not limited to crystalline forms that produce X-ray diffraction patterns exactly identical to those shown in the accompanying drawings. Rather, crystalline forms of DF2755A that give X-ray diffraction patterns (as defined above) substantially in accordance with that shown in Figure 6 are included within the scope of the present invention.

[0029] The crystalline form of DF2755A monohydrate obtained in the present invention, characterized by an X-ray diffraction pattern (XRPD) with peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5°2θ±0.2°2θ, is referred to herein as Form I.

[0030] This crystalline form of DF2755A monohydrate is preferably further characterized by XRPD peaks at 9.3°, 15.5°, 22.1°, 22.3°, 23.0°, and 24.6° 2θ±0.2° 2θ.

[0031] Other polymorphs of the present DF2755A monohydrate are also within the scope of the present invention. All of the most relevant XRPD peaks for DF2755A monohydrate are shown in Table 1 below.

[0032] [Table 1]

[0033] The DF2755A monohydrate of the present invention preferably has a water content measured by the Karl Fischer method of 5.0% by weight to 6.3% by weight, more preferably 5.0% by weight to 5.5% by weight, and even more preferably 5.0% by weight to 5.3% by weight.

[0034] The DF2755A monohydrate of the present invention appears as a white powder. The powders are characterized by good rheological properties and are particularly suitable for pharmaceutical applications. As is known in the art, the technical properties of powders (PSD, bulk density, flowability, surface area, etc.) and their use in pharmaceutical products are strictly dependent on particle characteristics.

[0035] The DF2755A monohydrate powder obtained by this method is non-sticky and exhibits improved appearance compared to that of anhydrous DF2755A. Furthermore, the powder properties and morphology of the monohydrate are particularly advantageous for formulation.

[0036] Preferably, the DF2755A monohydrate powder of the present invention is characterized by the following particle size distribution intervals as measured by a Malvern Mastersizer 3000 using an Aero S accessory: D(0.1) = 2.0-2.5 μm, D(0.5) = 6.5-8.5 μm, D(0.9) = 20.0-30.0 μm.

[0037] The bulk density of a powder is the ratio of the mass of an untapped powder sample to its volume, which depends on both the density of the powder particles and the spatial arrangement of the particles in the powder bed. Preferably, the DF2755A monohydrate powder of the present invention is characterized by a bulk density, measured according to Ph.Eur.2.9.34, of 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 and 0.20 g / ml.

[0038] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a tap density, measured according to Ph.Eur.2.9.34, between 0.19 g / ml and 0.28 g / ml, preferably around 0.25 g / ml.

[0039] Preferably, the DF2755A monohydrate powder of the present invention is characterized by a compressibility index of 23-33. Preferably, the DF2755A monohydrate powder of the present invention is characterized by a Hausner ratio lower than 1.50, more preferably lower than 1.45, typically between 1.30 and 1.45.

[0040] As shown in the experimental section, the DF2755A monohydrate powder of the present invention is not hygroscopic (water content unchanged for at least 12 months under accelerated stability conditions - see Table 7). Furthermore, the DF2755A monohydrate of the present invention is chemically and optically stable (see Table 7 in the Experimental Section for unchanged impurity content and enantiomeric purity). In particular, the hydroxylated by-product at the 4-position of the thiazole ring ((2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (referred to herein as DFL23803), which forms in significant amounts when anhydrous DF2755A is exposed to uncontrolled ambient humidity at a temperature of about 25°C, was not detected. Furthermore, the content of the undesired enantiomer, (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (referred to herein as DF2703Y), is well below the product specifications (see Table 7).

[0041] 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.

[0042] Preferably, the total impurity content in the composition as measured by HPLC is less than 0.5%, more preferably less than 0.1%, and even more preferably less than 0.05%, as described in the experimental section (see, e.g., data in Table 7).

[0043] Preferably, the composition comprises or consists essentially of DF2755A, preferably DF2755A monohydrate, as described above, containing less than 0.5%, preferably less than 0.2%, more preferably less than 0.1% 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) as determined by the HPLC method described herein (see, e.g., data in Tables 5 and 7).

[0044] In conclusion, the DF2755A monohydrate of the present invention is advantageous over the known anhydrous DF2755A and is particularly suitable for large-scale pharmaceutical applications. A further aspect of the present invention is a process 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-described embodiments of the first aspect of the present invention, comprising the steps of: i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; ii) exposing the material to an atmosphere having a relative humidity (RH) of greater than 60% and less than 80% by weight at a temperature of 25°C to 40°C and atmospheric pressure, preferably for 12 to 72 hours, thereby providing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate; The present invention provides a method comprising:

[0045] With respect to step i) of the present process, the starting material 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.

[0046] With regard to 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.

[0047] With respect to the RH of this atmosphere, we observed that at RH values ​​up to 60% there was little or no conversion to the monohydrate, but at RH values ​​of 80% and above the product became deliquescent.

[0048] Preferably, the RH of the atmosphere is 65% by weight to 75% by weight. Preferably, the ambient temperature is 25 to 30°C. Preferably, the exposure time is 24 to 72 hours.

[0049] 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-described embodiments of the first aspect of the present invention, is i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate, preferably prepared according to the method of the present invention described below; ii) exposing the material to an atmosphere having a relative humidity (RH) of 65% to 75% by weight at a temperature of 25°C to 30°C and atmospheric pressure, preferably for 12 to 72 hours, thereby providing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate; Includes:

[0050] Typically, anhydrous DF2755A is spread on trays and left in a climate chamber set at the desired RH for T, the time required to complete the conversion. The conversion can be monitored by Karl Fischer analysis.

[0051] A further aspect of the present invention is a process suitable for the large-scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate, comprising: - preparing 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 0.08-0.12 Kg / L; - adding a sodium base to the solution in a molar ratio to the acid of 0.9:1 to 0.95:1, thus resulting in a mixture; - adding an anti-solvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture in a volume ratio of 0.4:1 to 0.6:1 relative to the solvent, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; The present invention provides a method comprising:

[0052] Preferably, the concentration of acid DF2755Y in the solution is between 0.09 and 0.11 Kg / l, more preferably about 0.10 Kg / l. Preferably, the solvent is selected from among isobutyl acetate, propyl acetate and mixtures thereof, more preferably the solvent is isobutyl acetate.

[0053] Preferably, the sodium base is selected from sodium hydroxide or sodium methoxide, more preferably sodium hydroxide. The sodium base can be added neat or preferably dissolved in a suitable solvent, preferably water or an aqueous mixture with a polar solvent such as ethanol or methanol. In a preferred embodiment, the sodium base is aqueous sodium hydroxide.

[0054] Preferably, the sodium base is added sub-stoichiometrically to the acid to prevent racemization of the chiral carbon. According to the present method, precipitation of anhydrous DF2755A from the solution is carried out by adding an anti-solvent, preferably selected from among toluene, p-xylene and mixtures thereof, more preferably toluene.

[0055] Preferably, the volume ratio of anti-solvent or mixture thereof to solvent is about 0.5:1. Precipitation is typically carried out by cooling under stirring, preferably at a temperature below 20°C, more preferably below 10°C, even more preferably at about 5°C.

[0056] A preferred method suitable for large scale preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate is: - preparing a solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (DF2755Y) in isobutyl acetate, the concentration of the acid in the solution being between 0.09 and 0.11 Kg / l, preferably about 0.10 Kg / l; - adding to a sodium hydroxide solution in a molar ratio to the acid of 0.9:1 to 0.95:1, thus resulting in a mixture; - adding toluene to the mixture in a volume ratio of about 0.5:1 to the solvent, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; Includes:

[0057] Advantageously, the present method for the preparation of anhydrous DF2755A by anti-solvent precipitation is industrially feasible and avoids the cumbersome and expensive lyophilization procedure exhibited in the prior art. The present method provides anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate with improved chemical and enantiomeric purity compared to the prior art lyophilization process.

[0058] A further aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of 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-described embodiments of the first aspect of the invention, and at least a pharmaceutically acceptable excipient.

[0059] 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. The pharmaceutical compositions according to the invention may be in any form suitable for application to humans and / or animals, preferably humans, including infants, children and adults, and may be produced by standard procedures known to those skilled in the art.

[0060] In one embodiment, the pharmaceutical compositions of the present invention are oral solid compositions such as, for example, capsules, pellets, tablets, cachets, chewable dosage forms, powders, lozenges, granules, orally soluble granules, or dry powder forms to be reconstituted with a liquid medium.

[0061] In one embodiment, the pharmaceutical composition of the invention is a suspension, emulsion or spray. The pharmaceutical composition may further contain one or more pharmaceutically acceptable excipients such as fillers, binders, glidants, disintegrants, flow regulating agents and mold release agents.

[0062] 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.

[0063] Suitable fillers are, for example, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate and calcium hydrogen phosphate.

[0064] The filler may be present, for example, in an amount of 0 to 80% by weight, preferably 10 to 60% by weight, of the total weight of the composition. Suitable binders are, for example, polyvinylpyrrolidone, microcrystalline cellulose hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sugars, dextran, corn starch, gelatin, polyethylene glycol, natural and synthetic gums, pregelatinized starch.

[0065] The binder may be present in an amount of 0 to 80% by weight, preferably 10 to 60% by weight, of the total weight of the composition. Binders are commonly used to impart cohesive properties to tablet formulations.

[0066] 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.

[0067] The glidant may be present, for example, in an amount of 0 to 2% by weight, preferably 0.5 to 1.5% by weight, of the total weight of the composition. Suitable disintegrants are, for example, croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, sodium alginate, and sodium bicarbonate.

[0068] The disintegrant may be present in an amount of 0 to 20% by weight, preferably 1 to 15% by weight, of the total weight of the composition. A suitable flow control agent is, for example, colloidal silica. The flow control agent may be present in an amount of 0 to 8% by weight, preferably 0.1 to 3% by weight, of the total weight of the composition.

[0069] A suitable release agent is, for example, talc. The release agent may be present in an amount of 0 to 5% by weight, preferably 0.5 to 3% by weight, of the total weight of the composition. The solid composition may be coated, preferably film coated.

[0070] Suitable coating agents are, for example, cellulose derivatives, poly(meth)acrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, and / or natural gums such as shellac or carrageenan.

[0071] There are many situations in which it may be advantageous or even necessary to deliver the DF2755A monohydrate of the present invention as a solid, for example, by incorporating a solid implant composition into a suitable body tissue or cavity.

[0072] The implant may comprise a matrix of a biocompatible and biodegradable material in which dispersed particles of the DF2755A monohydrate of the present invention or encapsulated droplets or isolated compartments of a liquid mixture of the DF2755A monohydrate are dispersed. Desirably, the matrix is ​​degraded and 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.

[0073] Alternatively, DF2755A monohydrate of the present invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.

[0074] The compositions can be administered topically to the skin or mucosa, that is, dermally, epidermally, subepidermally or transdermally. The compositions may be administered sublingually or in a suppository.

[0075] Typical formulations for this purpose include pour-ons, spot-ons, dips, sprays, mousses, shampoos, powder formulations, gels, hydrogels, lotions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, depots, sponges, fibers, bandages, microemulsions, orally dissolving granules. Liposomes may also be used.

[0076] The pharmaceutical compositions of the present invention may be solutions or suspensions for oral or parenteral administration, for example, by intramuscular, intraperitoneal, or intravenous injection. The pharmaceutical compositions of the present invention may be solid compositions for extemporaneous preparation of solutions for oral or parenteral administration, for example, by intramuscular, intraperitoneal, or intravenous injection.

[0077] The pharmaceutical compositions of the present invention can be prepared by methods well known to those skilled in the art. The compositions of the present invention may be immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release.

[0078] According to a further embodiment, a pharmaceutical composition of the present invention may comprise the DF2755A monohydrate of the present invention and at least another active pharmaceutical ingredient. The other pharmaceutically active ingredients will be determined by the context in which the therapeutic agent of the present invention is to be administered.

[0079] The other pharmaceutically active ingredient is for example selected from among analgesics and / or anti-inflammatory agents or from among anti-cancer agents. A further aspect of the present invention provides the above-mentioned crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate for use as a pharmaceutical.

[0080] The medical use may be curative, preventative or palliative. A further aspect of the present invention provides the above-mentioned crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate for use in the prevention or treatment of acute or chronic inflammation-mediated diseases, inflammatory pain and post-operative pain, interstitial cystitis (IC) / bladder pain syndrome (BPS), and / or cancer.

[0081] Preferably, the inflammation-mediated disease is selected from bullous pemphigoid, cystic fibrosis, chronic obstructive pulmonary disease, asthma, psoriasis, rheumatoid arthritis and inflammatory bowel disease. Preferably, the cancer is selected from lung, colon, prostate, pancreatic, breast and ovarian cancer and melanoma.

[0082] The daily dose for humans and animals may vary depending on the respective species or other factors, such as age, sex, weight or degree of illness. A further aspect of the present invention provides a method for the prevention or treatment of pain, inflammation and / or cancer, comprising the step of administering to an individual in need thereof a therapeutically effective amount of DF2755A monohydrate of the present invention, alone or in combination with another active pharmaceutical ingredient.

[0083] According to the present invention, the term "individual" refers to a human or animal, preferably a human being. The same preferences expressed above for the medical use of DF2755A monohydrate apply to this method as well. [Example]

[0084] The following some non-limiting examples are according to the invention or comparatively and are given for illustrative purposes. Analytical and testing methods HPLC assay: Equipment: Agilent HP 1100, HP 1200 or equivalent HPLC system with UV detector Detector: Wavelength: 220 nm Column: BDS Hypersyl C18, 250 x 4.6 mm, 5 μm (Thermo) or equivalent Column temperature: 35℃ Mobile phase: (A) Buffer solution KH2PO4 0.025M (pH 3.0). Procedure: Dissolve 3.4 g of potassium dihydrogen phosphate in water, dilute to 1000 ml with water, and adjust to pH 3.0 with dilute phosphoric acid or potassium hydroxide solution. (B) Acetonitrile. Flow rate: 1.3ml / min Injection volume: 10μl Time between injections: 26 minutes Diluent: H2O / CH3CN (40 / 60) Relative retention time: DF2755 Rt is 11.8 minutes Gradient: Table 2

[0085] [Table 2]

[0086] HPLC Enantiomeric Purity Chromatography conditions Equipment: Agilent HP 1100, HP 1200 or equivalent HPLC system with UV detector Detector: Wavelength: 294 nm Column: Chiralpak AS-RH, 150 x 4.6 mm, 55 μm (Daicel) or equivalent Column temperature: 35℃ Mobile phase: (A) Buffer solution KH2PO4 0.025M (pH 3.0) Procedure: Dissolve 3.4 g of potassium dihydrogen phosphate in water, dilute to 1000 ml with water, and adjust to pH 3.0 with dilute phosphoric acid or potassium hydroxide solution; (B) Acetonitrile Flow rate: 0.7ml / min Injection volume: 10μl Time between injections: 45 minutes Diluent: H2O / CH3CN (40 / 60) Eluent: 70% mobile phase A, 30% mobile phase B 1 H-NMR: 1 H-nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance3 400 MHz instrument in the solvents specified using tetramethylsilane (TMS) as the internal standard. XRPD: XRPD analyses were performed at RT under the conditions reported in Table 3 below using the following instruments:

[0087] [Table 3-1]

[0088] [Table 3-2]

[0089] Water content according to Karl Fischer: Equipment: Mettler DL38, V30 or equivalent Electrode: Double platinum pin electrode DM143-SC for Karl Fischer titration. Titrant: Karl Fischer reagent 5mgH2O / ml Solvent: 30 ml of methanol pre-neutralized with Karl Fischer reagent. Procedure: An accurately weighed amount of approximately 0.2 g of product was dissolved in a solvent and titrated with Karl Fischer's reagent. Formula: %H2O = (V × e) / (10 × w) (In the formula, V = ml of Karl Fischer reagent used in the titration e = Karl Fischer reagent equivalent (mgH2O / ml) w = sample weight in g The analysis was performed on three samples and the results were averaged. The limit had to be 10.0% or less.

[0090] Particle size distribution was measured by a Malvern Mastersizer3000 using the Aero S accessory. Tapped density and bulk density were determined using a density tester ERWEKA SMV 102 (Heusenstamm, Germany) according to the European Pharmacopoeia (Ph.Eur.2.9.34).

[0091] The compressibility index was calculated according to the following formula: CI = 100 × (tap density - bulk density) / tap density. The Hausner ratio was calculated according to the following formula: Hr = tap density / bulk density Example 1: Preparation of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (DF2755Y) The title compound was prepared as described in Example 3 of WO2010031835A2.

[0092] Example 2: Preparation of anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (anhydrous DF2755A) (laboratory scale) The title compound was prepared starting from the free acid DF2755Y of Example 1 according to the procedure described in Example 3a of WO2010031835A2.

[0093] Example 2A (Invention): Preparation of Anhydrous Sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (Anhydrous DF2755A) (Pilot Scale) The acid DF2755Y from Example 1 (7.9 kg) was placed in a 200-liter glass reactor, followed by the addition of 63 liters of isobutyl acetate under stirring at room temperature (rt). Decolorizing carbon (0.4 kg) was added to the dark solution, which was then left at rt for 20 minutes. The solution was filtered through an FAP5 filter, resulting in a completely clear, pale yellow solution. The solution was placed in a 500-liter glass reactor, followed by the addition of 16 liters of isobutyl acetate under stirring at rt. 50% aqueous sodium hydroxide solution (1.3 liters) was added, and the resulting solution was mixed at 50°C for 1 hour. The reactor was cooled to 20°C, and then toluene (40 liters) was added. After 1 hour of stirring, the product began to precipitate, and the mixture was further stirred at 5°C for 12 hours. The slurry was then centrifuged at 1000 rpm for 30 minutes. The isolated product was dried under vacuum at 40°C for about 24 hours to give crystalline anhydrous DF2755A as a white solid (8.1 kg, 96% yield) with a mp of about 150°C.

[0094] The anhydrous DF2755A thus obtained was 1 H-NMR (T0) is consistent with the spectrum of anhydrous DF2755A prepared according to Example 3a of WO2010031835. 1 It was characterized by H-NMR spectrum (shown in Figure 1) and XRPD analysis (Figure 2).

[0095] The relevant XRPD peaks for anhydrous DF2755A had the positions and relative intensities shown in Table 4 below.

[0096] [Table 4]

[0097] Stability testing A sample of anhydrous DF2755A prepared according to Example 2A was placed in a climate chamber and exposed to 50% RH at approximately 25° C. for 24 hours, thereby providing a sticky, hydrated solid with a water content of 17% as determined by Karl Fischer analysis, which exhibited the XRPD spectrum shown in FIG.

[0098] 1 H-NMR analysis showed that the hydrated solid contained a significant amount (approximately 50% mol / mol) of another compound, namely, a hydroxylated by-product at the 4-position of the thiazole ring of DF2755A (see the relevant signal marked X in Figure 3 ).

[0099] The conclusion was that anhydrous DF2755A was physically and chemically unstable under the test conditions. Example 3 (Invention): Preparation of Sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate Monohydrate Form I (DF2755A Monohydrate Form I) by Controlled Hydration Anhydrous DF2755A (0.040 kg) prepared according to Example 2A was spread on a tray and placed in a climate chamber at 65% RH and 30° C. for 48 hours to provide DF2755A monohydrate Form I as a white solid (0.039 kg, 93% yield).

[0100] The final product was analyzed by HPLC, giving the chromatogram in Figure 8 and the results shown in Table 5 below.

[0101] [Table 5]

[0102] As can be seen, the final DF2755A monohydrate was very pure and contained only a small amount (0.02%) of the by-product DFL23803. The product was analyzed by Karl Fischer method (water content: 5.27% by weight). 1 The samples were analyzed by H-NMR (24 hours after removal from the climate chamber, FIG. 5) and XRPD (time 0 and 24 hours after removal from the climate chamber, FIG. 6).

[0103] The relevant XRPD peaks for DF2755A monohydrate had the positions and relative intensities shown in Table 6 below at TO and after 24 hours.

[0104] [Table 6]

[0105] These analyses confirmed the structure, purity, crystallinity and stability of DF2755A monohydrate Form I. Stability testing DF2755A monohydrate was then subjected to stability testing under the following conditions. A) 30°C and 65% RH (up to 18 months) B) 40°C and 75% RH (accelerated stability up to 12 months).

[0106] The samples were analyzed for appearance, water content, HPLC purity, HPLC assay, HPLC enantiomeric purity, and DSC thermal behavior, and the results of the analysis are shown in Table 7 below.

[0107] [Table 7]

[0108] Compl: Compliant;nd: Not detected; DF2703Y: (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid; DFL23803: (2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid, And in Figure 7, DF2755A monohydrate exhibited virtually the same DSC profile over time under both stability test conditions A) and B).

[0109] From these data, it appears 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 formation of the hydroxylated by-product DFL23803 or significant amounts of the other enantiomer (2R) DF2703Y was observed. All analytical test results remained within specification limits throughout the duration of the study, with no evidence of formation of degradation compounds.

[0110] Example 3A (Invention): Preparation of Sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate Monohydrate Form I (DF2755A Monohydrate Form I) by Controlled Hydration Anhydrous DF2755A (8.1 kg) prepared according to Example 2A was spread on a tray and placed in a climate chamber at 75% RH and 25° C. for 72 hours to provide DF2755A monohydrate Form I as a white solid (8.5 kg, 100% yield). The product had a water content of 5.27 wt % by Karl Fischer method and XRPD consistent with DF2755A monohydrate Form I.

[0111] DF2755A monohydrate form I powder exhibited the following rheological properties: - Particle size distribution: D(0.1)=2.09μm, D(0.5)=7.86μm, D(0.9)=25.42μm; - Tap density: 0.256g / ml; - Bulk density: 0.178g / ml; - Compressibility index: 30.7; - Hausner ratio: 1.44.

[0112] Example 4 (Comparative): Preparation of DF2755A Monohydrate by Crystallization in the Presence of Water (Failure) The preparation of Example 2A was repeated on a 100 g scale in the presence of water in order to obtain the monohydrate polymorph directly.

[0113] Specifically, during the salification step, the solution was cooled to 20° C., then toluene and 6% water were added. After 1 hour, the product began to precipitate, and the resulting solid was stirred at 5° C. for an additional 12 hours.

[0114] However, after filtration and drying under vacuum at 40° C. for about 24 hours, the product obtained was anhydrous DF2755A. 1 Confirmation was achieved by H-NMR, HPLC, Karl Fischer and XRPD analyses.

[0115] Example 5 (Comparative): Preparation of Stable Stoichiometric Hydrate DF2755A by Controlled Hydration (Failure) A sample of anhydrous DF2755A prepared according to Example 2A was placed in a climate chamber under the following conditions:

[0116] Ex.5A: 24 hours, 25℃, 50%RH Ex.5B: 24 hours, 25℃, 60%RH Ex.5C 72 hours, 25℃, 60%RH At the end of the hydration experiment, 1 Samples analyzed by H-NMR, HPLC, Karl Fischer and XRPD were all found to be non-stoichiometric hydrates and not DF2755A monohydrate.

Claims

1. Crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, characterized by an X-ray diffraction pattern (XRPD) with peaks at 7.9°, 18.3°, 19.8°, 23.8°, and 25.5° 2θ ± 0.2° 2θ.

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

3. 3. The crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate of claim 1 or 2, characterized by an X-ray diffraction pattern (XRPD) having additional peaks at 9.3°, 15.5°, 22.1°, 22.3°, 23.0°, and 24.6° 2θ±0.2° 2θ.

4. One or more of the following powder properties: - particle size distribution of D(0.1) = 2-2.5 μm, D(0.5) = 6.5-8.5 μm, D(0.9) = 20-30 μm, measured by a Malvern Mastersizer 3000 using the Aero S accessory; a bulk density of 0.17 to 0.20 g / ml, measured according to Ph. Eur. 2.9.34; 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 less than 1.50 The crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate according to any one of claims 1 to 3, characterized in that

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

6. 6. The composition of claim 5, having a content of (2S)-2-(4-{[4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl]amino}phenyl)propanoic acid of less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1%, as determined by the HPLC method described herein.

7. 1. A process for preparing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate, comprising the steps of: i) providing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; ii) exposing the material to an atmosphere having a relative humidity (R.H.) of greater than 60% and less than 80% by weight at a temperature of 25° C. to 40° C. and atmospheric pressure, preferably for 12 to 72 hours, thereby providing crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate; A method comprising:

8. 8. The method of claim 7, wherein the R.H. of the atmosphere is 65% to 75% by weight.

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

10. 13. The method of 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 of claim 11 or 12.

11. 1. A process for preparing anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate, comprising the steps of: - preparing 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 said acid in said solution is between 0.08 and 0.12 Kg / l; - adding a sodium base to said solution in a molar ratio to said acid of 0.9:1 to 0.95:1, thus resulting in a mixture; - adding an anti-solvent selected from toluene, m-xylene, p-xylene and mixtures thereof to the mixture in a volume ratio of 0.4:1 to 0.6:1 relative to the solvent, thereby precipitating anhydrous sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate; A method comprising:

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

13. A pharmaceutical composition comprising a therapeutically effective amount of crystalline 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. Crystalline sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate monohydrate according to any one of claims 1 to 4 for use as a pharmaceutical.

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

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