WO2018138272A1 - Eluxadoline crystalline form and process for the preparation thereof - Google Patents

Eluxadoline crystalline form and process for the preparation thereof Download PDF

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Publication number
WO2018138272A1
WO2018138272A1 PCT/EP2018/051973 EP2018051973W WO2018138272A1 WO 2018138272 A1 WO2018138272 A1 WO 2018138272A1 EP 2018051973 W EP2018051973 W EP 2018051973W WO 2018138272 A1 WO2018138272 A1 WO 2018138272A1
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eluxadoline
crystalline form
step
dispersion
according
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PCT/EP2018/051973
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French (fr)
Inventor
Giuseppe Barreca
Giampiero Ventimiglia
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Quimica Sintetica, S. A.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles

Abstract

It is described a novel crystalline form of Eluxadoline, having the formula (I). It is also described a process for the preparation of said crystalline form.

Description

ELUXADOLINE CRYSTALLINE FORM AND PROCESS FOR THE PREPARATION

THEREOF

Field of the invention

The present invention relates to a new crystalline form of Eluxadoline, as well as to a process for preparation thereof.

State of the art

Eluxadoline is the INN denomination assigned to the compound having lUPAC name 5-({[(2S)- 2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 /-/-imidazol-2- yl)ethyl]amino}methyl)-2-methox benzoic acid and the formula reported below:

Figure imgf000002_0001

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system. The drug, administered orally, is active locally in the intestine and is able to control gastrointestinal function (Gl) and at the same time to reduce the pain and mitigate the effect of constipation. Its use has been approved for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).

The family of compounds to which Eluxadoline belongs is disclosed in patent application WO 2005/090315 A1 , while patent application WO 2006/099060 A2 is directed to processes for the preparation of these compounds.

As it is well known, any active principle generally may exist under amorphous or different crystalline forms (polymorphs), either as pure compound or in forms in which in the structure of the crystal are present molecules of water (hydrates) or of another solvent (solvates); besides, in case of hydrates and solvates, the ratio between the number of molecules of active principle and molecules of water or solvent may vary, giving rise to different solid forms of the compound.

This form diversity has very important implications for the pharmaceutical industry, because each different polymorph, solvate, hydrate or amorphous form generally has different properties such as stability, solubility, and hygroscopicity; these differences in physical and chemical behaviors in turn may affect the preparation of the formulations in which the active principle is included, their shelf-life, the possible need of protecting them from external agents (e.g., temperature, humidity or light), and the bioavailability of the active principle once the formulation is administered to a patient.

Additionally, salt selection is a strategy that is commonly employed to modulate and improve the physicochemical properties of pharmaceutical compounds. Crystalline salts can also confer useful attributes such as different aqueous solubility, chemical stability and bioavailability relative to those of the free acid of base of the active compound. Besides, salts of active compounds can make possible the efficient removal of impurities, resulting in a suitable manufacturing process of high-purity drug substance from regulatory point of view. For these reasons, chemical compounds useful in the pharmaceutical field are systematically screened looking for the physical form(s) that present the best set of production, storage and handling properties, and that are thus best suited for administration to the patients.

Patent application WO 2009/009480 A2 discloses three polymorphic forms of eluxadoline, referred to in the document respectively as zwitterion, Form a and Form β. According to this patent application, Form a is characterized by a powder X-ray diffraction pattern having the main peaks at about 10.2°, 1 1 .3°, 1 1.8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ, while Form β is characterized by a powder X-ray diffraction pattern having the main peaks at about 1 1 .0°, 12.4°, 14.9°, 15.2°, 22.1 °, 25.6°, 27.4°, and 30.4° 2Θ. Although Forms a and β are characterized by X-ray powders diffraction (XRPD), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA), no information is provided in the document about any useful properties from the standpoint of the pharmaceutical industry, neither regarding ease of handling of the forms in the production of formulations or storage stability, nor regarding the bioavailability of eluxadoline when prepared in one of these crystalline forms. Further it's worth mentioning that no data are provided in respect of the zwitterion of eluxadoline.

Additionally, patent application WO 2006/099060 A2 describes the isolation of eluxadoline as di-hydrochloride adduct. Anyway, no information is provided in the document about any useful properties from the standpoint of the pharmaceutical industry once again.

IPCOM000245543D and IPCOM0002451 14D describe the isolation of the di-hydrochloride salt of methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-/V-((S)-1 -(4-phenyl-1 /-/- imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate, i.e. the methyl ester derivative of eluxadoline.

It is thus still open in the field the need of providing new salts of eluxadoline which has physical stability and desirable physical properties.

Summary of the invention These objectives are achieved with the present invention that, in a first aspect thereof, relates to a new crystalline form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 H-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoic acid (eluxadoline) of formula (I).

Figure imgf000004_0001

(I)

The novel crystalline form of eluxadoline (referred to in the following as form delta, δ) is characterized by an X-ray powder diffraction pattern comprising peaks at 8.58°, 10.94°, 17.24°, 20.10° and 26.62° ± 0.20° 2Θ obtained using Ka radiation of copper (λ = 1 .5408 A).

Preferably said crystalline form of eluxadoline has a melting point from about 190 to about 195°C and/or contains an amount of chloride, as determined by argentometric titration, lower than 10% by weight, preferably from 0.2% to 8% by weight, more preferably from 0.3% to 7% by weight, even more preferably from 0.4% to 6% by weight.

In a second aspect thereof, the invention relates to a process for producing the crystalline form of eluxadoline object of the first aspect of the present the invention.

In a third aspect thereof, the invention relates to a pharmaceutical formulation that includes the crystalline form of eluxadoline according to the first aspect of the present invention together with at least one pharmaceutically acceptable excipient and/or vehicle.

The present invention also relates to said crystalline form of eluxadoline or a pharmaceutical composition comprising it for use in therapy, preferably for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D). According to a further aspect, the invention provides a process for the preparation of a crystalline form of eluxadoline characterized by a powder X-ray diffraction pattern having the main peaks at about 10.2°, 1 1 .3°, 1 1 .8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ (in the following referred to as form a), by means of the novel crystalline form of eluxadoline, in the following referred to as form δ.

Brief description of the drawings

Figure 1 represents the XRD powders diffractogram of the crystalline form of eluxadoline of the invention. Figure 2 reproduces the graph obtained in a DSC test carried out on the crystalline form of eluxadoline of the invention, wherein the data corresponding to the four areas are included below: (1 ): Integral -226.44 mJ, normalized -49.55 Jg"1, Onset 79.43 °C, Peak 103.86 °C, Left Limit 48.89 °C, Right Limit 124.59 °C; (2) Integral -38.50 mJ, normalized -8.42 Jg"1, Onset 127.53 °C, Peak 137.17 °C, Left Limit 126.01 °C, Right Limit 146.04 °C; (3) Integral -84.67 mJ, normalized -18.53 Jg"1, Onset 149.17 °C, Peak 158.47 °C, Left Limit 148.02 °C, Right Limit 163.65 °C; (4) Integral -194.97 mJ, normalized -42.66 Jg"1, Onset 178.16 °C, Peak 200.21 °C, Left Limit 166.19 °C, Right Limit 224.79 °C.

Figure 3 reproduces the graph obtained in a TGA test carried out on eluxadoline crystalline form of the invention.

Detailed description of the invention

All terms used in this application, unless otherwise specified, are to be understood in their ordinary meaning as known in the technical field. Other more specific definitions of certain terms used in this application are listed below and are intended to be applied uniformly to the entire application, unless indicated otherwise.

The term "about includes the range of experimental errors, which can normally occur performing a measurement.

The term "excipienf means any substance contained in the final pharmaceutical form other than the active ingredient and which generally may not be therapeutically effective by itself. Excipients are essential for the administration of the active substance, as they allow to deliver the drug to the target site. Excipients are commonly referred to as raw materials entering into the composition of a pharmaceutical preparation with the aim of giving a shape, to facilitate administration and preserve the active ingredient. Furthermore, they contribute to characterize the pharmaceutical preparation from the point of view of appearance, stability, biopharmaceutical profile and acceptability by the patient.

It has been found that the crystalline forms of eluxadoline prepared according to the present invention are crystalline as determined by means of XRPD, and show complex DSC profile. Such crystalline forms undergo thermal transitions involving desolvation/dehydration processes and subsequent melting of desolved/dehydrated forms characterized by their DSC melting peak temperatures. Further thermal transitions may follow when e.g. degradation occurs. It will be understood that the onset and/or peak temperature values of the DSC may vary slightly from one machine to another, one method to another or from one sample to another, and so the values quoted are not to be construed as absolute. In fact, observed temperatures will depend on the rate of temperature change as well as sample preparation technique and the particular instrument employed. It will be estimated and taken into account that the temperature values obtained applying such different conditions may have a ±4 °C accuracy.

In its first aspect, the invention regards a new crystalline form of eluxadoline of formula (I) (referred to in the following as form delta, δ). This novel crystalline form δ is characterized by a XRPD trace with main peaks at 8.58°, 10.94°, 17.24°, 20.10° and 26.62° ± 0.20° 2Θ in a diffractogram collected with the copper KC1 radiation (λ = 1.5408 A). A more complete listing of peaks in the diffractogram comprises peaks at angles 8.58°, 10.06°, 10.94°, 13.24°, 17.24°, 20.10°, 21 .54°, 23.52° and 26.62° ± 0.20° 2Θ.

In a preferred embodiment of this aspect of the invention, the crystalline form δ of eluxadoline shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (λ = 1.5408 A), is characterized by at least 5 peaks (± 0.2° 2Θ) selected from Table 1 A or 1 B:

Figure imgf000006_0001
Figure imgf000006_0002

In a more preferred embodiment of this aspect of the invention, the crystalline form δ of eluxadoline shows an XRPD trace as substantially depicted in Figure 1 .

Even more preferably said crystalline form δ of eluxadoline has a melting point from about 190 to about 195 °C and/or contains an amount of chloride, as determined, e.g., by argentometric titration, lower than 10% by weight, preferably from 0.2% to 8% by weight, more preferably from 0.3% to 7% by weight, even more preferably from 0.4% to 6% by weight.

According to a further more preferred embodiment of this aspect of the invention, the crystalline form δ of eluxadoline is a monohydrochloride salt of eluxadoline, thus having a chloride content from 4.0% to 6.5% by weight.

While not intending to be bound by any theory, it is believed that, the crystalline form δ of eluxadoline retains a XRPD profile as substantially depicted in Figure 1 irrespective of the amount of chloride present in the crystalline structure, provided that its content, as determined, e.g., by argentometric titration, is within the prescribed range.

The crystalline form δ of eluxadoline can be further characterized by a DSC thermogram showing a feature between 48.9 °C and 124.6 °C (with a maximum at 103.9 °C), an event between 126.0 °C and 146.0 °C (with a maximum at 137.7 °C), a feature between 148.0 °C and 163.6 °C (with a maximum at 158.5 °C), and an event between 166.2 °C and 224.8 °C (with a maximum at 200.2 °C).

More preferably the crystalline form δ of eluxadoline is characterized by DSC TGA thermograms, as substantially depicted in Figures 2 and 3, respectively.

In a second aspect thereof, the invention refers to a process for the preparation of the crystalline form δ of eluxadoline described above, said process comprising the steps of:

a) dispersing eluxadoline di-hydrochloride salt in at least one organic solvent or in a mixture comprising at least one organic solvent and water;

b) mixing the dispersion resulting from step a) with at least one weak base or with a dispersion comprising at least one weak base and at least one solvent; and c) maintaining the mixture under stirring so as to cause the conversion into crystalline form δ of eluxadoline.

Preferably step of a) comprises dispersing, more preferably suspending, the di-hydrochloride adduct resulting from the synthetic process described in WO 2006/099060 A2 (e.g. from steps A to D of example 5, which are incorporated herein by reference) in at least one organic solvent (preferably an organic solvent immiscible with water, more preferably an acetate, even more preferably ethyl acetate) or in a mixture comprising at least one organic solvent (preferably an organic solvent immiscible with water, more preferably an acetate, even more preferably ethyl acetate) and water. This step is conveniently carried out at a temperature from 10 °C to 30 °C, preferably from 15 °C to 25 °C, even more preferably from 20 °C to 22 °C, e.g. at room temperature.

The following step b) includes mixing the dispersion (preferably the suspension) resulting from step a) with at least one weak base or with a dispersion comprising at least one weak base and at least one solvent (preferably an aqueous dispersion of a weak base) at a temperature normally from 10 °C to 30 °C, preferably from 15 °C to 25 °C, even more preferably from 20 °C to 22 °C, e.g. at room temperature. Preferably step b) is carried out by mixing the dispersion resulting from step a) with a dispersion comprising at least one weak base and a solvent (preferably water) or a solvents mixture comprising water. More preferably step b) is carried out by mixing the dispersion resulting from step a) with an aqueous solution of the at least one weak base.

Weak bases useful for the aim are conveniently selected from those having a pKa from 4.0 to 6.0. Preferably the weak base is selected from the group comprising, or preferably consisting of, bicarbonates (hydrogen carbonates) and acetates. More preferably the weak base is selected from the group comprising, or preferably consisting of, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, sodium acetate, potassium acetate, lithium acetate, and calcium acetate.

In the case when the at least one weak base used in step b) is a bicarbonate, the amount of said weak base or of the dispersion thereof is normally from 1 .0 to 3.0 equivalents, preferably from 1.1 to 2.0 equivalents compared to the molar quantity of starting solid form of eluxadoline used.

In the case when the at least one base used in step b) is an acetate, the amount of said base or of the dispersion thereof is conveniently from 1 to 50 equivalents, preferably from 2 to 20 equivalents, more preferably from 5 to 10 equivalents compared to the molar quantity of starting solid form of eluxadoline used.

Step b) can be carried out either by adding the weak base (or the dispersion thereof, preferably an aqueous dispersion thereof) to the dispersion (preferably the suspension) of the di- hydrochloride salt of eluxadoline prepared in step a) or, conversely, by adding the dispersion (preferably the suspension) of the di-hydrochloride salt of eluxadoline prepared in step a) to the weak base (or to the dispersion thereof, preferably an aqueous dispersion thereof). In either case, the addition can be carried out in a single step (i.e. a single addition of the entire quantity to be added) or, preferably, in multiple additions (i.e. by dosing the amount to be added).

According to the following step c), the mixture resulting from step b) is maintained under stirring so as to cause the conversion into crystalline form δ of eluxadoline, e.g. for at least 10 minutes, preferably for a period from 20 minutes to 50 hours, more preferably from 30 minutes to 20 hours, even more preferably from 1 to 16 hours.

The final operation of the process comprises filtering the suspension for recovering the crystalline form δ of the invention and drying it, at a temperature from 30 to 60 °C, preferably from 35 to 55 °C, more preferably from 40 to 45 °C, and optionally under reduced pressure. An optional further operation comprises washing the filtered solid with the solvent or solvent mixture used in step a) before drying it.

According to a further aspect of the invention, a process for the preparation of a crystalline form of eluxadoline having a powder X-ray diffraction pattern with main peaks at about 10.2°, 1 1.3°, 1 1 .8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ, referred to simply as form a, is provided, said process comprising:

d) dispersing the crystalline form δ of eluxadoline in at least one solvent;

e) maintaining the dispersion to a temperature from 40 °C to the reflux temperature of the at least one solvent used in step c) for at least 30 minutes; f) cooling the mixture to a temperature from 20 to 35 °C; and

g) recovering the resulting solid and, drying it.

Step d) comprises dispersing the crystalline form δ of eluxadoline in at least one solvent, preferably an acetate, more preferably ethyl acetate. This step is normally carried out at a temperature from 10 °C to 30 °C, preferably from 15 °C to 25 °C, even more preferably from 20 °C to 22 °C. The amount of solvent can vary in a very wide range; preferably, the overall volume of ketone may vary from 5 mL to 50 mL per gram of eluxadoline; more preferably, the volume is from 7 to 25 mL per gram of eluxadoline; even more preferably from 10 to 15 mL. According to the following step e), the dispersion resulting from step d) is maintained at a temperature from 40 °C to the reflux temperature of the at least one solvent used in step d), preferably under reflux conditions, for at least 30 minutes, preferably for a period from 60 minutes to 50 hours, more preferably from 2 hours to 20 hours, even more preferably from 4 to 10 hours.

Step f) includes cooling the mixture to a temperature from 20 to 35 °C, preferably from 15 °C to 25 °C, even more preferably from 20 °C to 22 °C.

The resulting solid, is recoverd in step g) using known techniques such as filtration or centrifugation and dried, e.g. according to the any of the procedures known in the field, preferably by treating the recovered solid at a temperature from 30 to 60 °C, preferably from 35 to 55 °C, more preferably from 40 to 45 °C, and optionally under reduced pressure.

The invention will be further illustrated by the following examples.

The instruments and methods used to characterize the obtained solid form are as follows: XRPD: Analyses were performed on an EasyX600 TNX bench-top diffractometer at 25 °C, using a Cu Ka tube (30 kV, 20 mA, λ = 1.5408 A) as the X-ray source, equipped with a scintillation detector. Data collection was made in coupled mode and in theta-theta configuration, with 2Θ range increment of 0.04°. Samples were accurately grinded and placed in the hollow of a spinning aluminum sampler. The instrument was previously calibrated by means of zinc oxide, then allowing collection and elaboration of data by means of DFP acquisition software. RH (relative humidity) in the cabin: 28-30%.

DSC: DSC tests were conducted by use of a Mettler-Toledo DSC1 Star6 System. Indium was used for calibration. Accurately weighed samples (3-7 mg) were placed in open aluminum pans and heated at a rate of 10 °C/min under a 70 ml/min nitrogen purge. Range from 30 °C up to 300 °C was investigated.

Melting point: Tests performed by means of a M-560 Buchi instrument. Set point: 180 °C; scan: 0.5 °C/min.

TGA: TGA-DTG analyses were performed by means of a Perkin-Elmer Pyris 1 TGA instrument endowed with an EGA oven and a platinum sampler. The samples (approximately 6-7 mg) were heated with a scan rate of 10 °C/min under a 90 mL/min nitrogen purge from 25 to 800 °C. The instrument was calibrated with calcium oxalate di-hydrate.

NMR: 1H NMR solution spectra were performed on a Jeol Eclipse 300 at 298 K, using DMSO- d6 as solvent. Chemical shifts are measured in δ ppm relative to tetramethylsilane. Accurately weighted amounts of sample were dissolved in a suitable test NMR tube and analyzed with 10 seconds delay.

Karl Fisher titration: Water content was determined by means of Karl-Fischer titration with a Mettler-Toledo V20 Compact equipment.

Argentometric titration: Chloride content was determined using a Series DL67 titrator (Mettler Toledo) equipped with Glass electrode DM141 -SC (KNO3 in water 1 M). To a solution of an accurately weighed amount of the sample to be tested (40 ± 2 mg) dissolved in MeOH (20 mL) and water (40 mL), 1 mL of Nitric acid 70% was added. Then titrate with 0.1 N silver nitrate. Before each analysis, perform a blank determination.

Dissolution test: Dissolution tests were performed by means of Sotax AT7 Smart equipped with 6X800mL volume vessels and using a 50 mM phosphate buffer pH=7.4, previously heated to 37 °C. 20 mg of the sample to be tested were placed in each vessel, and stirred (with paddles) at 1 10 rpm for 60 minutes at 37 ± 0.2 °C. Aliquots were taken at 5, 10, 20, 30, 45 and 60 min, filtered through 0.45 μηη Chromafil Xtra RC 45/25 syringe filter and analysed by UV/VIS spectrometer Perkin Elmer Lambda 35, 1 cm quartz cell (absorbance at 203 nm). pH was determined using a Mettler Toledo pH Meter FE20 equipped with a lnLab®420 electrode.

Example 1

Preparation of crystalline form δ of eluxadoline

Eluxadoline di-hydrochloride used as starting compound in this example was prepared according to the process described in patent application WO 2006/099060 A2.

28.6 g of Eluxadoline di-hydrochloride were suspended at 20-25 °C in 286 mL of ethyl acetate and 28.6 mL of water under stirring in a glass flask. 150 g of a 5% w/w sodium bicarbonate aqueous solution were added thereto over a period of 10 minutes, and the resulting suspension was kept under stirring for one additional hour. The suspension was finally filtered through a Buckner funnel, the flask rinsed with 85 mL of ethyl acetate and 28 mL of water and the obtained solid washed with 56 mL of ethyl acetate thus affording, after drying at 45 °C under reduced pressure, 23.5 grams of Eluxadoline (sodium content as per elemental analysis: < 0.05% w/w and chloride content - as per argentometric titration - 4.56% w/w).

The obtained product was analysed by XRPD, obtaining the diffractogram shown in Figure 1. The product was also subjected to DSC and TGA analyses, which gave as results the graphs shown in Figures 2 and 3, respectively. The DSC profile is mainly characterized by multiple complex broad endothermic events with onset at 79 °C, 127 °C, 149 °C and 178 °C, related to the loss of water and melting of the solid. The same complex loss is evidenced by TGA screening between 25 °C and 250 °C. A 1H NMR analysis of a portion of the product was carried out for estimating the possible presence of residual solvents, giving as a result that no detectable amount of solvent is trapped in the crystal structure of the novel salt.

Finally, portions of the sample were used for carrying out a measure of melting point and a

Karl Fisher assay: the observed melting point was 193 °C, while the resulting water content was 8.57% by weight. Melting took place with no degradation, namely, no browning or other colour change, nor phenomena linked to the evolution of gases, were observed.

A portion of the product was subjected to a dissolution test in 50 mM phosphate buffer at pH=7.4 giving the results summarised below:

Figure imgf000011_0001

Example 2

Preparation of crystalline form δ of eluxadoline

10.0 g of eluxadoline di-hydrochloride salt, prepared according to WO 2006/099060 A2, were suspended at 20-25 °C in 100 mL of ethyl acetate. 57.2 g of 5% w/w sodium acetate aqueous solution was added to the mixture over a period of 10 minutes, and the resulting suspension was maintained under stirring for one additional hour. The suspension was finally filtered through a Buckner funnel, the flask rinsed with 30 mL of ethyl acetate and 10 mL of water and the obtained solid washed with 10 mL of ethyl acetate thus affording, after drying at 45 °C under reduced pressure, 8.47 grams of Eluxadoline (chloride content - as per argentometric titration -7.10% w/w).

The product is characterized by XRPD, DSC, and TGA spectra corresponding to those obtained in example 1 .

Example 3

Preparation of crystalline form δ of eluxadoline

6.0 g of eluxadoline di-hydrochloride salt, prepared according to WO 2006/099060 A2, were added under stirring to a dispersion of 8.9 g of sodium acetate in 30 mL of ethyl acetate and 30 mL of water at 25 °C: The resulting suspension was maintained under stirring for additional 16 hours, then it was filtered through a Buckner funnel. The resulting solid was washed with 5 mL of ethyl acetate and 5 mL of water thus affording, after drying at 45 °C under reduced pressure, 4.91 g of Eluxadoline (chloride content - as per argentometric titration -1.10% w/w). The product is characterized by XRPD, DSC, and TGA spectra corresponding to those obtained in example 1 .

Example 4

Preparation of crystalline form a starting from the crystalline form δ of eluxadoline

4.91 g of crystalline form δ of eluxadoline, prepared according to Example 3, were suspended in dispersion of 8.9 g of sodium acetate in 32.5 mL of ethyl acetate and 32.5 mL of water at 25 °C: The resulting suspension was heated to reflux (70-72 °C) and maintained in these conditions for four hours. The suspension was then cooled to 20-25 °C and filtered. The attained solid was dried at 40 °C under reduced pressure, thus affording the eluxadoline (3.91 g) in its polymorphic form alfa as defined in WO 2009/009480 A2 (chloride content - as per argentometric titration -lower than 0.03 % w/w)

Claims

Crystalline form of 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 H-imidazol-2-yl)ethyl]amino}methyl)-2- methox benzoic acid (eluxadoline):
Figure imgf000013_0001
having an X-ray powder diffraction pattern comprising peaks at 8.58°, 10.94°, 17.24°, 20.10° and 26.62° ± 0.20° 2Θ obtained using Ka radiation of copper (λ = 1 .5408 A). Crystalline form of eluxadoline according to claim 1 , showing an X-ray powder diffraction pattern that, when collected with Ka radiation of copper (λ = 1.5408 A), is characterized by at least the following main peaks at 8.58°, 10.06°, 10.94°, 13,24°, 17.24°, 20.10°, 21.54°, 23.52° and 26.62° ± 0.20° 2Θ.
Crystalline form of eluxadoline according to any one of claims 1 and 2 containing an amount of chloride, as determined by argentometric titration, lower than 10% by weight. Crystalline form of eluxadoline according to any one of claims 1 to 3 containing an amount of chloride, as determined by argentometric titration, from 0.2% to 8% by weight.
Crystalline form of eluxadoline according to any one of claims 1 to 4 containing an amount of chloride, as determined by argentometric titration, from 0.3% to 7% by weight.
Crystalline form of eluxadoline according to any one of claims 1 to 5 containing an amount of chloride, as determined by argentometric titration, from 0.4% to 6% by weight.
Crystalline form of eluxadoline according to any one of claims 1 to 6 having a melting point from 190 to 195 °C.
Process for the preparation of the crystalline form of eluxadoline as defined in any one of claims 1 to 7, comprising the steps of:
a) dispersing eluxadoline di-hydrochloride salt in at least one organic solvent or in a mixture comprising at least one organic solvent and water;
b) mixing the dispersion resulting from step a) with at least one weak base or with a dispersion comprising at least one weak base and at least one solvent; and c) maintaining the mixture under stirring so as to cause the conversion into the crystalline form of eluxadoline defined in any one of claims 1 to 7.
9. Process according to claim 8, wherein the weak base used in step b) has a pKa from 4.0 to 6.0.
10. Process according to any one of claims 8 and 9 wherein in step b) a dispersion of the at least one weak base in water or in a solvents mixture comprising water is used.
1 1 . Process according to any one of claims 8 to 10, wherein the base used in step b) is selected from the group consisting of bicarbonates and acetates.
12. Process according to any one of claims 8 to 1 1 , wherein the base used in step b) is selected from the group consisting of sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, calcium hydrogen carbonate, sodium acetate, potassium acetate, lithium acetate, and calcium acetate.
13. Process according to any one of claims 8 to 12, wherein, in step b), the weak base or a dispersion of said weak base in a solvent is added to the dispersion of the di- hydrochloride salt of eluxadoline prepared in step a).
14. Process according to any one of claims 8 to 13, wherein, when the weak base used in step b) is an acetate, its amount is from 1 to 50 equivalents compared to the molar quantity of dihydrochloride salt of eluxadoline used.
15. Process according to any one of claims 8 to 14, further comprising filtering the suspension so as to recover the crystalline form of eluxadoline defined in any one of claims 1 to 7.
16. Process according to claim 15, further comprising the steps of washing the filtered crystalline form of eluxadoline, and drying it.
17. Process for the preparation of a crystalline form of eluxadoline having a powder X-ray diffraction pattern that, when collected with Ka radiation of copper (λ = 1.5418 A), is characterized by at least the following main peaks at 10.2°, 1 1 .3°, 1 1 .8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ, comprising the steps of:
d) dispersing the crystalline form of eluxadoline as defined in any one of claims 1 to 7 in at least one solvent;
e) maintaining the dispersion to a temperature from 40 °C to the reflux temperature of the at least one solvent used in step d) for at least 30 minutes;
f) cooling the mixture to a temperature from 20 to 35 °C; and
g) recovering the resulting solid and, drying it.
18. Use of a crystalline form of eluxadoline as defined in any one of claims 1 to 7 for preparing a pharmaceutical composition comprising eluxadoline.
19. Pharmaceutical composition comprising, as active ingredient, an effective amount of the crystalline form of eluxadoline as defined in any one of claims 1 to 7 and a pharmaceutically acceptable excipient.
20. Crystalline form of eluxadoline as defined in any one of claims 1 to 7 for use in therapy.
21 . Pharmaceutical composition as defined in claim 18 for use in therapy.
22. Crystalline form of eluxadoline according to claim 20 for use in the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).
23. Pharmaceutical composition according to claim 19 for use in the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).
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