EA043816B1 - CRYSTAL FORMS OF PAR4 INHIBITOR - Google Patents

Description

Cross reference to related applications

This application claims priority under 35 U.S.C. §119(e) as per U.S. Provisional Patent Application No. 62/783,223, filed December 21, 2018, the contents of which are incorporated herein by reference in their entirety.

Field of technology

The present invention relates to co-crystals of the protease-activated receptor 4 (PAR4) antagonist 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl )benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide. The present invention also relates to methods of preparation, pharmaceutical compositions and methods of use of the cocrystals of the present invention.

State of the art

Thromboembolic disease remains a leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antithrombotic agents such as aspirin and clopidogrel (PLAVIX®). Current antithrombotic therapies have limitations, including an increased risk of bleeding, as well as partial effectiveness (relative cardiovascular risk reduction ranging from 20 to 30%). Thus, the discovery and development of safe and effective oral or parenteral antithrombotic agents to prevent and treat a wide range of thromboembolic complications remains an important goal.

Alpha-thrombin is the most highly active known activator of platelet aggregation and degranulation. Platelet activation is causally related to atherothrombotic vascular occlusion. Thrombin activates platelets by cleaving G protein-coupled receptors called protease-activated receptors (PARs). PARs have their own cryptic ligand present in the N-terminal extracellular domain, which is unmasked by proteolytic cleavage followed by intramolecular binding to the receptor to induce signal transduction (tethered ligand mechanism); Coughlin, SR, Nature, 407:258 -264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus upon proteolytic activation can induce signaling independent of receptor cleavage. Platelets play a key role in atherothrombotic events. Human platelets express at least two thrombin receptors, usually designated PAR1 and PAR4. PAR1 inhibitors have been extensively studied, and several compounds, including vorapaxar and atopaxar, have entered late-stage clinical trials. Recently, in the phase III TRACER trial in patients with ACS (acute coronary syndrome), vorapaxar did not significantly reduce cardiovascular events but did significantly increase the risk of major bleeding (Tricoci, P. et al., N. Eng. J. Med., 366( 1):20-33 (2012) Thus, there remains a need to discover new antithrombotic agents with increased efficacy and reduced bleeding side effects.

Compound of formula (I), 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6yl)benzofuran-4-yl)oxy) Methyl)thiazol-2-yl)-N,N-dimethylbenzamide (compound (I)) is a PAR4 inhibitor, its synthesis and free form solid preparation and use are described in WO2013/163279.

The essence of the invention

The invention relates to cocrystals containing a compound of formula (I)

(I) and succinic or citric acid, pharmaceutical compositions containing them, and treating or preventing a thromboembolic complication by administering an effective amount of the cocrystal to a patient or mammal in need thereof.

Brief description of graphic materials

In fig. Figure 1 shows the simulated (bottom, calculated from atomic coordinates obtained at room temperature) and experimental (top) PXRD diffraction patterns of a cocrystal of the compound of formula (I) with succinic acid.

In fig. 2 shows the DSC curve of a cocrystal of the compound of formula (I) with succinic acid.

In fig. 3 shows the TGA curve of a cocrystal of the compound of formula (I) with succinic acid.

In fig. 4 shows the FT-Raman spectrum of a cocrystal of the compound of formula (I) with succinic acid.

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In fig. 5 shows the FT-IR spectrum of a cocrystal of the compound of formula (I) with succinic acid.

In fig. 6 shows the simulated (bottom, calculated from atomic coordinates obtained at room temperature) and experimental (top) PXRD diffraction patterns for the N-1 form of a cocrystal of the compound of formula (I) with citric acid.

In fig. 7 shows the DSC curve of Form N-1 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 8 shows the TGA curve of Form N-1 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 9 shows the FT-Raman spectrum of Form N-1 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 10 shows the C-13 CPMAS SSNMR spectrum of Form N-1 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 11 shows the FT-IR spectrum of Form N-1 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 12 shows the simulated (bottom, calculated from atomic coordinates obtained at room temperature) and experimental (top) PXRD patterns of the N-2 form of a cocrystal of the compound of formula (I) with citric acid.

In fig. 13 shows the DSC curve of Form N-2 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 14 shows the TGA curve of Form N-2 of a cocrystal of the compound of formula (I) with citric acid.

In fig. 15 shows the dissolution of cocrystals of the compound of formula (I) with citric acid and succinic acid compared to the dissolution of the free form of the compound of formula (I).

In fig. 16 shows the pharmacokinetic profile (PK) of cocrystals of the compound of formula (I) with citric acid and succinic acid in a dog.

Detailed description

In one embodiment, the present invention provides a cocrystal of a compound of formula (I) and a coformer, where the coformer is citric acid or succinic acid.

(I)

In another embodiment of the present invention, the coformer is succinic acid.

In another embodiment, a cocrystal of a compound of formula (I) and succinic acid is characterized by one or more of the following:

a) a single crystal structure having crystal cell parameters essentially equal to the following:

Crystal system, space group

Unit cell parameters

Volume

Triclinic, P-1 a = 7.5±0.5A alpha =103±1 b = 9.6±0.5 A beta = 92±1° c = 20.1 ±0.5 A gamma = 98±1 1401±30A ³

Number of formula units in unit cell 2

Temperature: room temperature, where the single crystal structure was measured at room temperature;

b) an observed PXRD diffraction pattern substantially as shown in FIG. 1;

c) a PXRD diffraction pattern containing 4 or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2, 16.3±0.2, 17.6± 0.2, 21.4±0.2, 22.4±0.2 and 25.9±0.2 (obtained at room temperature and (CuKa λ= 1.5418 A));

d) infrared spectra, essentially as shown in FIG. 5; and/or

e) FT-Raman spectra essentially as shown in FIG. 6.

In another embodiment, a cocrystal of a compound of formula (I) and succinic acid has a ratio of compound of formula (I) to succinic acid of 1:0.5.

In another embodiment of the present invention, the coformer is citric acid.

In another embodiment, the cocrystal of the compound of formula (I) and citric acid is in the N-1 form and is characterized by one or more of the following:

a) a single crystal structure having crystal cell parameters substantially equal to the following:

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Crystal system, space group

Unit cell parameters

Volume

Triclinic, P-1 a= 10.3±0.5 A b = 12.3±0.5 A c= 13.9±0.5 A 1717±30A ³ alpha = 94±1 beta = 98±1 ° gamma = 98±1°

Number of formula units in a unit cell Temperature

2;

room temperature;

b) a PXRD diffraction pattern substantially as shown in FIG. 6; and/or

c) a powder X-ray diffraction pattern containing 4 or more 2Θ values (CuKa λ= 1.5418 A at room temperature) selected from 6.4±0.2, 12.7±0.2, 14.4±0.2 , 17.1±0.2, 23.9±0.2, 25.0±0.2 and 26.6±0.2.

In another embodiment of the invention, a cocrystal of a compound of formula (I) and citric acid has a ratio of compound of formula (I) to citric acid of 1:1.

In another embodiment of the invention, the cocrystal of the compound of formula (I) and citric acid consists essentially of Form N-1.

In another embodiment of the invention, a cocrystal of a compound of formula (I) and citric acid contains form N-1.

In another embodiment, the cocrystal of the compound of formula (I) and citric acid is in the N-2 form and is characterized by one or more of the following:

a) a single-crystal structure having crystal cell parameters essentially equal to the following:

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 10.4±0.5 A alpha =111±1 °

b=17.8±0.5A beta = 93±1° c = 20.5±0.5A gamma = 102±1°

Volume 3462±30 A ^3;

Temperature: room temperature;

The number of formula units in the unit cell is 4;

b) a PXRD diffraction pattern substantially as shown in FIG. 12; and/or

c) a powder X-ray diffraction pattern containing 4 or more 2Θ values (CuKa λ=1.5418 A at room temperature), selected from 4.6±0.2, 5.5±0.2, 8.4±0.2 , 11.3±0.2, 14.6±0.2, 16.4±0.2, 21.0±0.2, 24.2±0.2 and 25.2±0.2.

In another embodiment of the invention, Form N-1 of the cocrystal has a 1:1 ratio of the compound of formula (I) to citric acid.

In another embodiment of the invention, Form N-2 of the cocrystal has a 1:1 ratio of the compound of formula (I) to citric acid.

In another embodiment of the invention, the cocrystal of the compound of formula (I) and citric acid consists essentially of form N-2.

In another embodiment of the invention, a cocrystal of a compound of formula (I) and citric acid contains form N-2.

In another embodiment, the present invention relates to any of the cocrystals in substantially pure form.

In another embodiment of the invention, a succinic acid cocrystal is characterized by a PXRD containing 4 or more, 5 or more, or 6 or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6±0 ,2, 16.3±0.2, 17.6±0.2, 21.4±0.2, 22.4±0.2 and 25.9±0.2 (CuKa λ=1.5418 A at room temperature).

In another embodiment of the invention, the succinic acid cocrystal is characterized by a PXRD containing at least one or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2,16 ,3±0.2, 17.6±0.2,21.4±0.2, 22.4±0.2 and 25.9±0.2 (CuKa λ=1.5418 A at room temperature) .

In another embodiment of the invention, a succinic acid cocrystal is characterized by a PXRD containing 4 or more, or 5 or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2, 16 .3±0.2, 17.6±0.2 and 25.9±0.2 (CuKa λ=1.5418 A at room temperature).

In another embodiment of the invention, a succinic acid cocrystal is characterized by a PXRD containing 4 or more, or 5 or more, or 6 or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6± 0.2, 16.3±0.2, 17.6±0.2 and 25.9±0.2 (CuKa λ=1.5418 A at room temperature).

In another embodiment of the invention, the succinic acid cocrystal has a single crystal structure with crystal cell parameters substantially equal to the following:

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Temperature room temperature

Crystal system, space group

Unit cell parameters

Volume

Triclinic, P-1 a = 7.5±0.5A alpha = 103±1 b = 9.6±0.5 A beta = 92±G c = 20.1±0.5A gamma = 98±1 1401± 30A ³

The number of formula units in the unit cell is 2.

In another embodiment, the succinic acid cocrystal exhibits an FT-IR spectrum substantially in accordance with FIG. 5. In another embodiment, the succinic acid cocrystal is characterized by an FT-IR spectrum containing peaks at 1627.9, 1704.4 and 3102.1 cm ^-1 (±0.4 cm ^-1 ).

In another embodiment, the succinic acid cocrystal is characterized by an FRaman spectrum substantially in accordance with FIG. 4. In another embodiment, the succinic acid cocrystal is characterized by an FT-Raman spectrum containing peaks at 975.3, 1185.0, 1242.9, 1455.6 and 3104.4 cm ^-1 (±0.3 cm ^-1 ).

In another embodiment, the N-1 form of the citric acid cocrystal is characterized by PXRD substantially in accordance with FIG. 6. In another embodiment, the N-1 form of the citric acid cocrystal is characterized by a PXRD containing 4 or more, or 5 or more, or 6 or more 2θ values selected from 6.4±0.2, 12.7±0.2 , 14.4±0.2, 17.1±0.2, 23.9±0.2, 25.0±0.2 and 26.6±0.2 (CuKa λ=1.5418 A at room temperature). In another embodiment, the N-1 form of the citric acid cocrystal is characterized by a PXRD containing at least one or more 2θ values selected from 6.4±0.2, 12.7±0.2, 14.4±0.2 , 17.1±0.2, 23.9±0.2, 25.0±0.2 and 26.6±0.2 (CuKa λ= 1.5418 A at room temperature). In another embodiment, the N-1 form of the citric acid cocrystal is characterized by PXRD containing 2θ values selected from 6.4±0.2, 12.7±0.2, 14.4±0.2 and 26.6±0. 2 (CuKa λ=1.5418 A at room temperature).

In another embodiment, Form N-1 of the citric acid cocrystal has a single crystal structure with crystal cell parameters substantially equal to the following:

Temperature room temperature

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 10.3±0.5 A alpha = 94±1° b = 12.3±0.5 A beta = 98±1° c=13.9±0.5A gamma = 98±1° Volume 1717±ZOA ³

The number of formula units in the unit cell is 2.

In another embodiment, the N-1 form of the citric acid cocrystal exhibits an FT-IR spectrum substantially in accordance with FIG. 11. In another embodiment, the N-1 form of the citric acid cocrystal is characterized by an FT-IR spectrum containing peaks at 1585.7, 1725.9 and 3150.5 cm ^-1 (±0.4 cm ^-1 ).

In another embodiment, the N-1 form of the citric acid cocrystal is characterized by an FT-Raman spectrum substantially in accordance with FIG. 9. In another embodiment, the N-1 form of the citric acid cocrystal is characterized by an FT-Raman spectrum containing peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6 and 2978.9 cm ^-1 (±0.3 cm ^-1 ).

In another embodiment, the N-2 form of the citric acid cocrystal is characterized by PXRD substantially in accordance with FIG. 12. In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD containing 4 or more, or 5 or more, or 6 or more values of 20 selected from 4.6±0.2, 5.5±0.2 , 8.4±0.2, 11.3±0.2, 14.6±0.2, 16.4+0.2,21.0+0.2, 24.2±0.2 and 25 .2 ±0.2. In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD containing at least one or more values of 20 selected from 4.6±0.2, 5.5±0.2, 8.4±0, 2, 11.3±0.2, 14.6±0.2, 16.4±0.2, 21.0±0.2, 24.2±0.2 and 25.2±0.2. In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD containing 4 or more, or 5 or more 20 values selected from 4.6±0.2, 14.6±0.2, 16.4±0, 2, 21.0±0.2 and 25.2±0.2 (CuKa λ= 1.5418 A at room temperature).

In another embodiment, Form N-2 of the citric acid cocrystal has a single crystal structure with crystal cell parameters substantially equal to the following:

Temperature room temperature

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 10.4±0.5 A alpha =111±1° b = 17.8±0.5 A beta = 93±1° c = 20.5±0.5 A gamma = 102±1 °

Volume 3462±30 A ³

The number of formula units in a unit cell is 4.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one cocrystalline form of a compound of formula (I) and a pharmaceutically acceptable carrier.

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In another embodiment, the present invention provides a method of treating a thromboembolic complication, which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the cocrystalline forms of a compound of formula (1).

In some embodiments, the present invention provides a pharmaceutical composition that further comprises other therapeutic agent(s). In a preferred embodiment, the present invention relates to a pharmaceutical composition wherein the additional therapeutic agent(s) is an antithrombotic agent or a combination thereof. Preferably, the antithrombotic agent(s) are P2Y12 antagonists and/or aspirin. Preferably, the P2Y12 antagonists are clopidogrel, ticagrelor or prasugrel. In another preferred embodiment, the present invention relates to a pharmaceutical composition wherein the additional therapeutic agent(s) is an anticoagulant or a combination thereof. Preferably, the anticoagulant agent(s) are FXa inhibitors or thrombin inhibitors. Preferably, the FXa inhibitors are apixaban or rivaroxaban. Preferably, the thrombin inhibitor is dabigatran.

In some embodiments, the present invention provides a method of treating or preventing a thromboembolic complication, which includes the step of administering to a subject (e.g., a human) in need of such treatment or prevention a therapeutically effective amount of at least one cocrystalline form of a compound of formula (I) disclosed herein, for example, a succinic acid cocrystal, a citric acid cocrystal, a Form N-1 citric acid cocrystal, or a Form N-2 citric acid cocrystal.

In some embodiments, the present invention provides methods for treating a thromboembolic complication or primary or secondary prevention of a thromboembolic complication, which comprise the steps of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystalline forms of a compound of formula (I) disclosed in herein, for example, a succinic acid cocrystal, a citric acid cocrystal, a Form N-1 citric acid cocrystal, or a Form N-2 citric acid cocrystal, wherein the thromboembolic complication is selected from the group consisting of arterial cardiovascular thromboembolic complications, venous cardiovascular thromboembolic complications, cerebrovascular thromboembolic complications and thromboembolic complications in the chambers of the heart or in the peripheral circulation.

In some embodiments, the present invention provides methods for treating a thromboembolic complication or primary or secondary prevention of a thromboembolic complication, which comprise the steps of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystalline forms of a compound of formula (I) disclosed in herein, for example, a succinic acid cocrystal, a citric acid cocrystal, a Form N-1 citric acid cocrystal, or a Form N-2 citric acid cocrystal, wherein the thromboembolic complication is selected from the group consisting of acute coronary syndrome, unstable angina, stable angina, myocardial infarction with ST segment elevation, myocardial infarction without ST segment elevation, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral thrombosis arterial embolism, cerebral embolism, renal vascular embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis resulting from medical implants, devices, and procedures that expose blood to an artificial surface that promotes thrombosis.

In some embodiments, the present invention provides methods for treating a thromboembolic complication or primary or secondary prevention of a thromboembolic complication, which comprise the steps of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystalline forms of a compound of formula (I) disclosed in herein, for example, succinic acid co-crystal, citric acid co-crystal,

Form N-1 citric acid cocrystal or Form N-2 citric acid cocrystal, wherein the thromboembolic complication is selected from the group consisting of acute coronary syndrome, unstable angina, stable angina, myocardial infarction with ST segment elevation, myocardial infarction without ST segment elevation .

In some embodiments, the present invention provides methods for treating a thromboembolic complication or primary or secondary prevention of a thromboembolic complication, which comprise the steps of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystalline forms of a compound of formula (I) disclosed in herein, for example, a succinic acid cocrystal, a citric acid cocrystal, a Form N-1 citric acid cocrystal, or a Form N-2 citric acid cocrystal, wherein

- 5 043816 thromboembolic complication selected from the group consisting of transient ischemic attack and stroke.

In some embodiments, the present invention provides methods for treating a thromboembolic complication or primary or secondary prevention of a thromboembolic complication, which comprise the steps of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystalline forms of a compound of formula (I) disclosed in herein, for example, a succinic acid cocrystal, a citric acid cocrystal, a Form N-1 citric acid cocrystal, or a Form N-2 citric acid cocrystal, wherein the thromboembolic complication is peripheral arterial disease.

In some embodiments, the present invention includes a method as described above, wherein the thromboembolic complication is selected from unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, sudden coronary death, transient ischemic attack, stroke, atherosclerosis, disease peripheral artery thrombosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal vascular embolism, pulmonary embolism and thrombosis resulting from the installation of medical implants, devices or procedures in which the blood is exposed exposure to an artificial surface, which promotes thrombosis.

In some embodiments, the present invention provides a method of inhibiting or preventing platelet aggregation, which includes the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the cocrystal forms of a compound of formula (I) disclosed herein, e.g. a succinic acid cocrystal, a citric acid cocrystal, a form N-1 citric acid cocrystal, or a form N-2 citric acid cocrystal.

In yet another further embodiment, the individual cocrystal forms of compound (I) are substantially pure.

In yet another embodiment, the individual cocrystal forms of compound (I) contain at least about 90 wt%, preferably at least about 95 wt%, and more preferably at least about 99 wt% of the compound (I) by weight of individual cocrystal forms of compound (I).

In another embodiment, a compound of formula (I) may contain a mixture of cocrystals described herein.

The present invention includes the use of cocrystals of a compound of formula (I) for use in therapy.

The present invention is directed to the use of cocrystals of a compound of formula (I) for the preparation of a medicament for the treatment or prevention of a thromboembolic complication.

When preparing a pharmaceutical composition, a form of the active ingredient is required that has a balance of target properties, such as, for example, dissolution rate, solubility, bioavailability and/or shelf stability. For example, a form of the active ingredient is required that has sufficient solubility, bioavailability and storage stability to prevent the conversion of a sufficiently soluble and bioavailable form during storage to another form having an undesirable solubility and/or bioavailability profile.

The present invention relates to at least one co-crystal form of compound (I), which unexpectedly provides a balance of properties required for a pharmaceutical composition. The present invention is also directed to other important aspects.

The present invention also covers all combinations of alternative aspects of the invention noted herein. It should be appreciated that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. In addition, any elements of an embodiment are intended to be combined with any or all other elements from any of the embodiments to describe additional embodiments.

Definitions

The features and advantages of the invention may be better understood by those skilled in the art upon reading the following detailed description. It should be appreciated that certain features of the invention, which are described above and below in the context of individual embodiments for better understanding, may also be combined to form a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be combined to form subcombinations thereof.

The names used herein to characterize a particular form, e.g., N-1, etc., are designations only and are to be interpreted in accordance with the characteristic information provided herein and are not intended to be limiting to the exclusion of any another substance having similar or identical physical and chemical characteristics. The definitions set forth herein supersede the definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.

All numbers expressing quantities of ingredients, weight percentages, temperatures and the like that are preceded by the word about are to be understood as approximations only, so that slight deviations above and below the stated number may be applied to achieve substantially the same results as the stated quantity. Accordingly, unless otherwise indicated, numerical parameters preceded by the word about or substantially in accordance with are approximations that may vary depending on the target properties to be obtained. At the very least, and not as an attempt to limit the application of the theory of equivalents to the scope of the claims, each numerical parameter should, at a minimum, be interpreted in light of the number of significant figures reported and using generally accepted rounding techniques.

All measurements are subject to experimental error and are within the spirit of the invention.

As used herein, the term cocrystal means a crystalline solid that consists of two or more molecules in the same crystal lattice that are in a neutral state, interact through nonionic interactions, and are solids as separate components at room temperature.

As used herein, the term polymorphs refers to crystalline forms that have the same chemical structure but a different spatial arrangement of the molecules and/or ions forming the crystals.

As used herein, the term solvate refers to a crystalline form of a molecule, atom and/or ions, which further contains solvent molecules or solvents included in the crystal lattice structure. When the solvent is water, the form is referred to as a hydrate. The solvent molecules in the solvate can be in a regular and/or disordered arrangement. The solvate may contain either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate with a non-stoichiometric number of solvent molecules may result from partial loss of solvent from the solvate. Solvates may exist as dimers or oligomers containing more than one molecule or cocrystal of the compound of formula (I) in the crystal lattice structure.

As used herein, the term amorphous refers to the solid form of a molecule, atom and/or ions that is not crystalline. An amorphous solid does not show a clear powder diffraction pattern.

As used herein, the expression substantially pure, when applied to a cocrystal form, means a compound having a purity of greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 wt.%, and also including equal to about 100 wt.% of the co-crystal of compound (I) based on the weight of the compound. The remaining substance contains other form(s) of the compound, and/or reaction impurities, and/or process impurities resulting from its preparation. For example, the cocrystalline form of compound (I) may be considered substantially pure in the sense that it is greater than 90 wt.% pure, as measured by means currently known and generally accepted in the art, where less than 10 wt.% remains. wt.% of the substance contains other form(s) of compound (I) and/or reaction impurities and/or process impurities.

When dissolved, the cocrystal forms of the compound of formula (I) lose their crystalline structure and are therefore referred to as a solution of the compound of formula (I). However, all forms of the present invention can be used for the preparation of liquid formulations in which the drug is dissolved or suspended. Additionally, cocrystal forms of the compound of formula (I) may be included in solid formulations.

As used herein, an XRPD (powder X-ray diffraction pattern) or PXRD (powder X-ray diffraction pattern) containing or having a number of peaks selected from a particular group of peaks is intended to include PXRD patterns containing additional peaks that are not included in the specified group of peaks. For example, a PXRD diffraction pattern comprising at least one or more, four or more, five or more, or six or more 2θ values selected from: A, B, C, D, E, F, G, and H is intended to include a PXRD diffraction pattern comprising: (a) at least one or more, four or more, five or more, six or more 2θ values selected from: A, B, C, D, E, F, G and H ; and (b) zero or more peaks that are not one of Peaks A, B, C, D, E, F, G, and H.

In the context of this document, the term DSC refers to differential scanning calorimetry. The term TGA refers to thermogravimetric analysis. The term IR. refers to infrared spectroscopy. The abbreviation FT stands for Fourier transform.

The term room temperature usually means approximately 22°C, but can increase or decrease by up to 7°C.

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When the term substantially consistent is applied to XRPD or PXRD diffraction patterns, it should be understood that the measurement of peak locations for a given crystalline form of the same compound will vary within an error limit. It should also be understood that peak intensities may vary between different PXRD patterns of the same crystalline form of the same compound. The relative intensities of the various peaks are not intended to limit the comparison of different PXRD patterns.

A therapeutically effective amount is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit and/or antagonize PAR4 and/or prevent or treat the disorders listed herein. When applied to a combination, the term refers to combined amounts of active ingredients that result in a prophylactic or therapeutic effect, whether administered in combination, sequentially or simultaneously.

As used herein, the term thrombosis refers to the formation or presence of a thrombus (pl. thrombi) within a blood vessel that can cause ischemia or infarction of the tissue supplied by that vessel. As used herein, the term embolism refers to a sudden blockage of an artery by a clot or foreign material that has been carried to its site by the bloodstream. As used herein, the term thromboembolism refers to the occlusion of a blood vessel by a thrombotic substance carried by the blood stream from the site of formation to occlude another vessel. The term thromboembolic complications includes both thrombotic and embolic disorders (defined above).

As used herein, the term thromboembolic events includes arterial cardiovascular thromboembolic events, venous cardiovascular or cerebrovascular thromboembolic events, and thromboembolic events in the chambers of the heart or in the peripheral circulation. As used herein, the term thromboembolic complications also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, primary or recurrent myocardial infarction, sudden coronary death, transient ischemic attack, stroke, atherosclerosis, peripheral artery disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal vascular embolism, pulmonary embolism and thrombosis resulting from the installation of medical implants, devices or procedures in which blood exposed to the artificial surface, which promotes thrombosis. Medical implants or devices include, but are not limited to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access devices, ventricular assist devices and artificial hearts or cardiac chambers and vascular grafts. These techniques include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term thromboembolic complications includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.

In some embodiments, the therapeutically effective amount of the PAR4 compound is preferably less than about 100 mg/kg, 50 mg/kg, 10 mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In another embodiment, the therapeutically effective amount of the PAR4 compound is less than 5 mg/kg. In another embodiment, the therapeutically effective amount of the PAR4 compound is less than 1 mg/kg. In another embodiment, the dosage is from 8 mg to 48 mg. Effective doses vary, as recognized by those skilled in the art, depending on the route of administration and use of the excipient.

The cocrystalline forms are typically administered in mixtures with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected according to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups and the like and in accordance with standard pharmaceutical practice.

For example, for oral administration in tablet or capsule form, the active drug component may be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like ; for oral administration in liquid form, the components of the oral drug can be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and colorants may also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc.

- 8 043816 similar. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The cocrystals of the present invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The cocrystals of the present invention can also be associated with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide polylysine substituted with palmitoyl moieties. In addition, the compounds of the present invention may be associated with a class of biodegradable polymers useful for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, polylactic-polyglycolic acid copolymers, polypsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates and cross-linked or amphipathic block copolymers of hydrogels.

Dosage dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 100 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.5-95% by weight of the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the drug over several hours. Compressed tablets may be coated with sugar or film to mask any unpleasant taste and protect the tablet from the atmosphere, or may have an enteric coating for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain colors and flavors to enhance patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering agents. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, the standard reference in the art.

Exemplary suitable pharmaceutical dosage forms for administering the compounds of the present invention may be illustrated as follows:

Capsules.

Large quantities of standard capsules can be prepared by filling standard bivalve hard gelatin capsules, each containing 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules.

A mixture of the active ingredient in a digestible oil, such as soybean oil, cottonseed oil or olive oil, can be prepared and introduced by a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. Capsules must be washed and dried.

Pills.

Tablets can be prepared by conventional methods such that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to enhance palatability or delay absorption.

Dispersion.

The spray-dried dispersion can be prepared for oral administration by methods known to one skilled in the art.

- 9 043816

Dosage form for injection.

A parenteral composition suitable for administration by injection can be prepared by mixing 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. The solution must be made isosmotic with sodium chloride and sterilized.

Suspension.

The aqueous suspension may be prepared for oral administration such that each 5 ml contains 100 mg of finely divided active ingredient, 200 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution, U.S.P., and 0.025 ml vanillin.

When two or more of the above second therapeutic agents are administered with a cocrystal of a compound of Formula I, generally, the amount of each component in a typical daily dose and typical dosage form may be reduced compared to the typical dosage of the agent when administered alone, due to the additive or synergistic effect of the therapeutic agents. agents when administered in combination.

In particular, when provided in unit dosage form, there is the possibility of chemical interaction between the combined active ingredients. For this reason, when cocrystal forms of compound (I) and the second therapeutic agent are combined in a unit dosage form, they are formulated in such a way that, although the active ingredients are combined in a unit dosage form, physical contact between the active ingredients is minimized (that is, yes, reduced). For example, one active ingredient may be enteric coated. By enteric coating of one of the active ingredients, it is not only possible to minimize contact between the combined active ingredients, but it is also possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach, but rather is released in the gastrointestinal tract. intestinal tract. One of the active ingredients may also be coated with a substance that provides sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In addition, the sustained release component may be further coated with an enteric coating such that release of the component occurs only in the intestinal tract. Another approach may involve formulating a combination product in which one component is coated with a sustained and/or enteric release polymer and the other component is also coated with a polymer such as low viscosity hydroxypropyl methcellulose (HPMC) or other suitable materials known in the art to further separation of the active components. The polymer coating serves as an additional barrier to interaction with another component.

These, as well as other methods for minimizing contact between the components of the combination products of the present invention, administered either in a single dosage form or administered in separate forms, but at the same time in the same way, will be obvious to those skilled in the art armed with real disclosure.

As discussed above, the compounds of the present invention, including cocrystal forms of the compound of Formula I, can be administered orally, intravenously, or both.

Examples

Cocrystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet atomization. Methods for crystallizing or recrystallizing cocrystalline forms from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding the crystal in a supersaturated solvent mixture of the molecule and/or salt, freeze-drying the solvent mixture, and adding antisolvents to the solvent mixture.

For crystallization processes that employ a solvent, the choice of solvent or solvents generally depends on one or more factors such as the solubility of the compound, the crystallization method, and the vapor pressure of the solvent. Combinations of solvents may be used, for example, the compound may be dissolved in a first solvent to form a solution, followed by the addition of an antisolvent to reduce the solubility of the compound in the solution and form crystals. An antisolvent is a solvent in which a compound has low solubility.

In one method of preparing crystals, the compound is suspended and/or stirred in a suitable solvent to form a suspension, which can be heated to promote dissolution. As used herein, the term suspension means a saturated solution of a compound, which may also contain an additional amount of compound to obtain a heterogeneous mixture of compound and solvent at a given temperature.

Seed crystals can be added to any crystallization mixture to accelerate crystallization. Priming can be used to control the growth of a specific polymorph or

- 10 043816 for monitoring the granulometric composition of the crystalline product. Accordingly, the calculation of the required amount of seed depends on the size of the available seed and the target size of the average particle of the substance, as described, for example, in Programmed Cooling of Batch Crystallizers, J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Typically, small seeds are needed to effectively control crystal growth in a batch. A small seed crystal can be obtained by sifting, grinding or fine grinding of large crystals or microcrystallization of solutions. Care should be taken to ensure that grinding or fine grinding of the crystals does not result in any change in the crystallinity of the target crystalline form (ie, change to an amorphous or other polymorphic form).

The cooled crystallization mixture can be filtered under vacuum and the isolated solids can be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a stream of nitrogen to obtain the desired crystalline form. The isolated solids can be analyzed using a suitable spectroscopic or analytical technique, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, powder X-ray diffractometry, and the like, to ensure formation of the preferred crystalline form of the product. The resulting crystalline form is typically obtained in an amount greater than about 70% by weight of the actual yield, preferably greater than 90% by weight of the actual yield, based on the weight of the compound initially used in the crystallization process. If necessary, the product can be co-ground or passed through a sieve to separate the product.

The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD), Raman or PC spectroscopy, or solid state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks when comparing an experimentally measured PXRD diffraction pattern with a simulated PXRD diffraction pattern may indicate the presence of more than one polymorph in the sample. A simulated PXRD diffraction pattern can be calculated from single crystal X-ray data. See Smith, D.K., A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns; Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

Cocrystalline forms of the compound of formula (I) of the invention can be characterized using various techniques, the effects of which are well known to those skilled in the art. forms can be characterized and isolated using single crystal X-ray diffraction, which is based on measurements of the unit cell of a single crystal of the form at a fixed analytical temperature. A detailed description of unit cells is presented in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), chapter 3, which is incorporated herein by reference. Alternatively, the spatial arrangement of atoms within a crystal lattice can be characterized according to the observed fractional atomic coordinates. Another means of characterizing crystal structure is analysis using X-ray powder diffraction, in which the diffraction profile is compared to a simulated profile representing the pure powdered substance, where both are performed at the same analytical temperature and measurements of the form of interest are characterized as a series of 2θ values (usually four or more) .

Other shape characterization tools may be used, such as solid state nuclear magnetic resonance (SS-NMR), differential scanning calorimetry, thermogravimetric analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the shape of an object. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined using other suitable analytical techniques.

Example 1. Co-crystal of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy) methyl)thiazol-2-yl)-N,N-dimethylbenzamide:succinic acid (1:0.5).

To a 250 ml glass reactor was added the compound of formula (I) in free form (2 g, 3.561 mmol), dichloromethane (100 ml) and methanol (20 ml). The reaction mass was heated to 39°C until complete dissolution. Succinic acid (0.45 g, 3.8 mmol) was then added in one portion. After 3 days, 50 ml of the solution mass was distilled off until a suspension was formed. Ethyl acetate (70 ml) was added. Volatile components were removed to dryness, ethyl acetate (100 ml) was added to the reaction mixture, and the reaction mixture was stirred for 12 hours. The resulting suspension was then filtered and the resulting solid was washed with ethyl acetate (10 ml). The solid was dried in a vacuum oven for 24 hours (30 mmHg, 50°C) to obtain a cocrystal of the compound of formula (I) with succinic acid. The product was obtained as a white solid (1.8 g, 41% yield) with a purity of 99.4% by HPLC. 1H NMR (400 MHz, DMSO-d6) d 8.37 (s, 2H), 8.03 (s, 2H), 8.01 (s, 2H), 7.94 (s, 2H), 7.54 (d, J=7 ,8 Hz, 4H), 7.03 (s, 2H), 6.85 (dd, J=1.8, 0.8 Hz, 2H), 6.65 (d, J=1.8 Hz, 2H), 5, 39 (s, 4H), 4.20 (s, 6H), 3.90 - 3.77 (m, 6H), 3.31 (s, 5H), 3.00 (br s, 6H), 2.94 (br s, 6H ), 2.43 - 2.41 (m, 4H).

- 11 043816

The succinic acid cocrystal had a stoichiometry of one molecule of compound of formula (I) per

0.5 molecule of succinic acid or hemisuccinate of the compound of formula (I).

The cocrystal of the compound of formula (I) with succinic acid was characterized by a diffraction pattern

PXRD shown in FIG. 1, the differential scanning calorimetry (DSC) curve shown in FIG. 2 and the thermogravimetric analysis (TGA) curve shown in FIG. 3.

PXRD of a cocrystal of the compound of formula (I) with succinic acid showed 2Θ peaks at 4.5, 9.5, 14.6, 16.3, 17.6, 21.4, 22.4 and 25.9 (all peaks in degrees 20±O.2). PXRD was obtained at room temperature and diffraction peak positions (in degrees 2θ±0.2) based on a ground truth diffraction pattern obtained using a diffractometer (CiKa) with a 20 spin capillary calibrated with NIST or other suitable standard.

The succinic acid cocrystal was also characterized by PXRD containing at least one or more, or 4 or more, 20 values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2 , 16.3±0.2, 17.6±0.2, 21.4±0.2, 22.4±0.2 and 25.9±0.2.

The succinic acid cocrystal was also characterized by PXRD containing 4 or more 20 values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2, 16.3±0.2, 17. 6±0.2 and 25.9±0.2. A single crystal X-ray diffraction pattern of a cocrystal of the compound of formula (I) with succinic acid was obtained with the following results: Temperature: room temperature

Wavelength 1.54178 A

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 7.5209(7) A alpha = 103.201(4) ° b = 9.6255(6) A beta = 91.833(5) ° c = 20.089(1) A gamma = 97.501(6) ° Volume 1400.8(2) A ³

Calculated density value 1.471 g/cm ³

Number of formula units in unit cell 2

The atomic coordinates of the single-crystal X-ray diffraction pattern of the succinic acid cocrystal are shown in Table. 1.

Table 1

Atomic coordinates of a succinic acid cocrystal

Atom X ⁷ 1 ^z Atom 1 * Y Z S1 1.3819 1.0196 0.3789 S24 0.2564 0.1992 0.9920 S2 0.7569 0.4869 0.6965 S25 0.2529 -0.0588 0.9814 N1 1.2580 1.0724 0.5123 S26 1.1240 1.5674 0.9257 N2 1.4110 1.2469 0.4731 S27 1.6643 1.3165 0.3026 N3 1.5027 1.2961 0.4223 C1A 0.9198 0.2959 0.4847 N4 0.7484 0.6470 0.8167 C2A 0.9469 0.4532 0.5200 N5 0.3134 0.0672 0.9555 O1A 0.8302 0.2168 0.5217 01 1.2217 1.3320 0.6754 O2A 0.9747 0.2484 0.4300 02 0.9340 0.9577 0.7554 H2 1.4037 1.4072 0.5620 OZ 1.0570 1.4185 0.9115 H8 1.0862 0.9976 0.6269 04 1.5673 1.1838 0.3121 H9 1.1903 1.4944 0.8017 05 0.4178 -0.0757 0.8652 NI 0.9418 1.1606 0.8709 C1 1.2781 1.2022 0.5618 H13A 0.7596 0.9324 0.8240 C2 1.3725 1.3113 0.5387 Н13В 0.9547 0.9076 0.8446 NW 1.3401 1.1067 0.4604 H15 0.8764 0.7121 0.6758 C4 1.4962 1.1865 0.3716 H18 0.5560 0.2468 0.7232 C5 1.2023 1.2016 0.6267 H19 0.4316 0.0645 0.7711 C6 1.1440 1.3005 0.7326 H21 0.5601 0.3188 0.9581 C7 1.0753 1.1557 0.7190 H22 0.6856 0.5006 0.9107 C8 1.1150 1.0935 0.6504 H24A 0.3231 0.2325 1.0355 C9 1.1432 1.3976 0.7948 H24V 0.1305 0.1822 0.9990 SJ 1.0669 1.3400 0.8459 H24S 0.2776 0.2708 0.9658 JV 0.9935 1.1945 0.8352 H25A 0.1387 -0.1048 0.9589 C12 0.9972 1.1015 0.7722 Н25В 0.2408 -0.0299 1.0299 C13 0.8653 0.8919 0.8068 H25S 0.3390 -0.1251 0.9726 C14 0.8180 0.7344 0.7755 H26A 1.2475 1.5798 0.9149 C15 0.8322 0.6670 0.7094 H26V 1.1148 1.6097 0.9734 C16 0.7090 0.5131 0.7815 H26S 1.0548 1.6137 0.8985 C17 0.6313 0.3948 0.8115 H27A 1.5917 1.3924 0.3147 C18 0.5558 0.2622 0.7706 Н27В 1.6922 1.3050 0.2556 C19 0.4807 0.1528 0.7993 H27S 1.7737 1.3406 0.3313 S20 0.4775 0.1732 0.8699 H2A1 1.0025 0.4686 0.5651 S21 0.5576 0.3044 0.9107 H1A1 0.8341 0.4795 0.5272 S22 0.6330 0.4135 0.8823 H1A 0.8025 0.1272 0.4991 S23 0.3986 0.0463 0.8965

DSC of the succinic acid cocrystal showed a variable endotherm at about 182°C, which represented a melt with decomposition. TGA of the succinic acid cocrystal showed negligible mass loss up to 150 °C.

FT-IR and FT-Raman are shown in Figs. 4 and 5, respectively, and showed characteristic peaks in the range from 1700 to 3500 cm' ¹ .

- 12043816

The FT-Raman spectrum for the succinic acid cocrystal contained characteristic peaks at 975.3,

1185.0, 1242.9, 1455.6 and 3104.4 cm-1 (±0.3 cm ^-1 ).

The FT-IR spectrum of the succinic acid cocrystal contained characteristic peaks at 1627.9, 1704.4 and 3102.1 cm ^- 1 (±0.4 cm ^-1 ).

Example 2. Co-crystal of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy) methyl)thiazol-2-yl)-N,N-dimethylbenzamide:citric acid (1:1), form N-1.

Mixture of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazole -2-yl)-N,N-dimethylbenzamide (6.1 g, 11 mmol, 1.0 eq.) and citric acid (3.3 g, 18 mmol, 1.6 eq.) in ethyl acetate (210 ml) heated to 76°C for 10 hours, then slowly cooled to room temperature and left to stir for 16 hours. The suspension was filtered and washed with EtOAc (80 ml) followed by drying the precipitate under vacuum in an oven at 55°C for 1 day to obtain 8.0 g (98% yield) of citric acid cocrystal Form N-1 as a white solid.

Alternative way.

EtOAc (17 L) was added to citric acid (222.5 g, 1.16 mol, 1.3 eq) and heated to 55°C for 2 hours to obtain a clear solution. 4-(4-(((6-methoxy-2-(2methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2 was added -yl)-N,N-dimethylbenzamide (500.00 g, 0.89 mol, 1.0 eq.) followed by EtOAc (1 L). The mixture was heated to 76°C for 1 hour. Cocrystal of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6yl)benzofuran-4-yl)oxy)methyl)thiazol-2 -yl)-N,N-dimethylbenzamide with citric acid (1.0 g, 0.2 wt%) in EtOAc (15 ml) was added as a seed. The mixture was heated for an additional 30 minutes, then slowly cooled to room temperature over 2 hours and left to stir for 5 hours. The suspension was filtered and washed twice with EtOAc (3 L) followed by drying the precipitate under vacuum in an oven at 50°C for 3 days to obtain 663.7 g (99% yield) of citric acid cocrystal form N-1 with a purity of 99.8 AP in as a white solid.

Form N-1 of the cocrystal of the compound of formula (I) with citric acid had a stoichiometry of 1 molecule of the compound of formula (I) for each molecule of citric acid (1:1).

Form N-1 of the cocrystal of the compound of formula (I) with citric acid was characterized by the PXRD diffraction pattern shown in FIG. 6, the DSC curve shown in FIG. 7 and the TGA curve shown in FIG. 8.

PXRD of Form N-1 of a cocrystal of the compound of formula (I) with citric acid showed 2Θ peaks at 6.4, 12.7, 14.4, 17.1, 23.9, 25.0 and 26.6 (all peaks at degrees 2θ±0.2). PXRD was obtained at room temperature and diffraction peak positions (in degrees 2θ±0.2) based on the ground truth diffraction pattern obtained using a diffractometer (CuKa) with a 2θ spinning capillary calibrated with NIST or other suitable standard.

PXRD of Form N-1 of a cocrystal of the compound of formula (I) with citric acid showed 2θ peaks at 6.4, 12.7, 14.4 and 26.6 (all peaks in degrees 2θ±0.2). PXRD was obtained at room temperature and diffraction peak positions (in degrees 2θ±0.2) based on the ground truth diffraction pattern obtained using a diffractometer (CuKa) with a 2θ spinning capillary calibrated with NIST or other suitable standard.

The N-1 form of the citric acid cocrystal was also characterized by PXRD containing one or more, or 4 or more, 2θ values selected from 6.4±0.2, 12.7±0.2, 14.4±0.2, 17.1±0.2, 23.9±0.2,

25.0±0.2 and 26.6±0.2.

The N-1 form of the citric acid cocrystal was also characterized by PXRD to contain 4 or more 2θ values selected from 6.4±0.2, 12.7±0.2, 14.4±0.2 and 26.6±0 ,2.

A single crystal X-ray diffraction pattern of the N-1 form of a cocrystal of the compound of formula (I) with citric acid was obtained with the following results:

Temperature room temperature

Wavelength 1.54178 A

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 10.293(1) A alpha = 94.005(7) ^c b = 12.270(2) A beta = 98.188(7) ° c = 13.937(2) A gamma = 98.166(8)

Volume 1717.1(4) A ³

Calculated density value 1.458 g/cm ³

Number of formula units in unit cell 2

The atomic coordinates of the single crystal X-ray diffraction pattern of the N-1 form of the citric acid cocrystal are shown in Table. 3.

- 13 043816

Table 3

Atomic coordinates of the N-1 form of the citric acid cocrystal

Atom X G A Atom X G A S1 0.4512 0.2863 0.0346 O4A 0.1933 0.5023 0.1043 S2 -0.1441 0.8204 0.2062 O5A 0.2960 0.3715 0.1681 01 0.2395 0.6123 -0.2546 O6A 0.2312 0.8560 0.3198 02 -0.0047 0.8097 -0.0771 O7A 0.3254 0.7611 0.4332 OZ 0.0104 0.8900 -0.4059 C1A 0.2109 0.5546 0.3320 04 0.6135 0.1678 -0.0342 C2A 0.1252 0.5423 0.4139 05 -0.6703 1.0474 0.4089 SZA 0.2224 0.4387 0.1736 N1 0.3138 0.4519 -0.0458 C4A 0.1510 0.4546 0.2594 N2 0.4482 0.3695 -0.1267 C5A 0.2605 0.7644 0.3553 N3 0.5346 0.2939 -0.1355 C6A 0.2014 0.6641 0.2873 N4 -0.2186 0.9346 0.0679 H1 0.4173 0.4544 -0.2496 N5 -0.5866 1.2223 0.3927 H6 0.1554 0.6310 -0.0458 C1 0.3986 0.4421 -0.1876 H9 0.1647 0.7329 -0.4003 C2 0.3948 0.3784 -0.0436 NI -0.0537 0.9041 -0.2414 nw 0.3156 0.4921 -0.1366 H13A 0.6484 0.1157 -0.1636 C4 0.5418 0.2462 -0.0559 Н13В 0.7482 0.0848 -0.0777 C5 0.2397 0.5788 -0.1613 H13S 0.7614 0.2064 -0.1072 C6 0.1695 0.6386 -0.1096 H14A 0.1468 0.8857 -0.4910 C7 0.1205 0.7163 -0.1722 Н14В 0.0116 0.9120 -0.5442 C8 0.1643 0.6967 -0.2600 H14S 0.0252 0.7910 -0.5197 C9 0.1331 0.7493 -0.3426 NIA -0.1850 0.8463 -0.1133 SJ 0.0506 0.8285 -0.3329 NIV -0.0760 0.9508 -0.0793 SI 0.0021 0.8511 -0.2453 H17 -0.0259 0.7544 0.0869 C12 0.0364 0.7957 -0.1658 H20 -0.2839 0.8978 0.3374 C13 0.7000 0.1415 -0.1012 H21 -0.4284 0.9766 0.4215 C14 0.0519 0.8679 -0.4977 H23 -0.5284 1.1471 0.1961 C15 -0.1056 0.8751 -0.0674 H24 -0.3877 1.0645 0.1097 C16 -0.1332 0.8696 0.0352 H26A -0.4142 1.2742 0.3470 C17 -0.0843 0.8031 0.0993 H26V -0.4545 1.3616 0.4203 C18 -0.2338 0.9175 0.1577 H26S -0.5262 1.3431 0.3121 C19 -0.3212 0.9714 0.2133 H27A -0.7613 1.2107 0.4406 S20 -0.3341 0.9473 0.3081 Н27В -0.6959 1.3331 0.4355 S21 -0.4196 0.9953 0.3589 H27S -0.6419 1.2655 0.5198 S22 -0.4923 1.0709 0.3180 H1A 0.3765 0.5958 0.4066 S23 -0.4797 1.0963 0.2246 NZA 0.1166 0.4960 0.5267 S24 -0.3949 1.0467 0.1727 H4A 0.2349 0.4901 0.0597 S25 -0.5889 1.1146 0.3758 H6A 0.2650 0.9091 0.3587 S26 -0.4867 1.3077 0.3657 H4A1 0.1492 0.3885 0.2939 S27 -0.6794 1.2612 0.4522 H4A2 0.0597 0.4618 0.2352 O1A 0.3438 0.5445 0.3654 H6A1 0.2461 0.6648 0.2306 O2A 0.0121 0.5695 0.3989 N6A2 0.1086 0.6683 0.2655 OZA 0.1700 0.4982 0.4882

DSC of the N-1 form of the citric acid cocrystal showed a variable endotherm at about 185-190°C, which was a melt with decomposition. TGA of the N-1 form of the citric acid cocrystal showed negligible mass loss up to 150 °C.

C-13 Solid State NMR Spectroscopy (C-13 SSNMR) of the citric acid cocrystal showed peaks as shown in Table. 4. C-13 SSNMR was consistent with Z’=2.

Table 4

Chemical shifts of the C-13 form of the N-1 cocrystal of citric acid

(m.d.) (m.d.) 182 126.3 175.5 122.9 172.3 113 171.1 109.2 167 99 160.1 94.9 156 86.7 154.1 74.7 151.4 65.5 148.2 60.4 141.3 55.8 135.9 42.9 133.7 40.9 131.2 40 35.2

IR. and Raman spectroscopy of the N-1 form of the citric acid cocrystal revealed peaks as shown in FIG. 9 and 11. The spectra show characteristic peaks in the range from 1700 to 3500 cm' ¹ .

The FT-Raman spectrum for the N-1 form of the citric acid cocrystal contained characteristic peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6 and 2978.9 cm ^-1 (±0. 3 cm ^-1 ).

The FT-IR spectrum of the N-1 form of the citric acid cocrystal contained characteristic peaks at 1585.7, 1725.9 and 3150.5 cm-1 (±0.4 cm ^-1 ).

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Example 3. Co-crystal of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6yl)benzofuran-4-yl)oxy)methyl) thiazol-2-yl)-N,Ndimethylbenzamide:citric acid (1:1), form N-2.

Mixture of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazole -2-yl)-N,N-dimethylbenzamide (5.00 g, 8.9 mmol, 1 eq.) and citric acid (2.50 g,

13.4 mmol, 1.5 eq) in 200 ml EtOAc was heated to 74°C for 18 h.

The mixture was slowly cooled to room temperature and left to stir for 3 hours. The suspension was filtered and washed twice with EtOAc (20 ml) followed by drying the precipitate under vacuum in an oven at 55°C for 1 day to obtain 6.5 g (97% yield) of citric acid cocrystal Form N-2 as a needle-like white solid. .

Form N-2 of the cocrystal of the compound of formula (I) with citric acid contains 1 molecule of the compound of formula (I) for each molecule of citric acid (1:1).

Form N-2 of the cocrystal of the compound of formula (I) with citric acid was characterized by the PXRD diffraction pattern shown in FIG. 12, the DSC curve shown in FIG. 13 and the TGA curve shown in FIG. 14.

PXRD of Form N-2 of a cocrystal of the compound of formula (I) with citric acid showed 2Θ peaks at 4.6, 14.6, 16.4, 21.0 and 25.2 (all peaks in degrees 20 ± 0.2). PXRD was obtained at room temperature and diffraction peak positions (in degrees 20 ± 0.2) based on the ground truth diffraction pattern obtained using a diffractometer (CuKa) with a 2θ spinning capillary calibrated using an appropriate NIST standard.

PXRD of Form N-2 of a cocrystal of the compound of formula (I) with citric acid showed 2θ peaks at 4.6, 5.5, 8.4, 11.3, 14.6, 16.4, 21.0, 24.2 and 25.2 (all peaks in degrees 2θ±0.2). PXRD was obtained at room temperature and diffraction peak positions (in degrees 2θ±0.2) based on the ground truth diffraction pattern obtained using a diffractometer (CuKa) with a 2θ spinning capillary calibrated using an appropriate NIST standard.

The N-2 form of the citric acid cocrystal was also characterized by PXRD containing one or more, or 4 or more, 2θ values selected from 4.6±0.2, 5.5±0.2, 8.4±0.2, 11.3±0.2, 14.6±0.2, 16.4±0.2, 21.0±0.2, 24.2±0.2 and 25.2±0.2.

The N-2 form of the citric acid cocrystal was also characterized by PXRD containing 4 or more 2θ values selected from 4.6±0.2, 14.6±0.2, 16.4±0.2, 21.0±0, 2 and 25.2 ±0.2.

A single crystal X-ray diffraction pattern of the N-2 form of a cocrystal of the compound of formula (I) with citric acid was obtained with the following results: Temperature: room temperature

Wavelength 1.54178 A

Crystal system, space group Triclinic, R-1

Unit cell parameters a = 10.4364(4) A alpha = 111.270(2) b = 17.8418(8) A beta = 92.635(3)° c = 20.5491(9) A gamma = 101.641(3)

Volume 3462.4(3) A ³

Estimated density value 1.446 g/cm ³

Number of molecules in unit cell 4

The atomic coordinates for the single crystal X-ray diffraction pattern of the N-2 form of the citric acid cocrystal are shown in Table. 5.

Table 5

Atom X Υ Ζ Atom X Υ Ζ S1A 1.3310 0.7354 0.5021 S17A 0.5743 0.8576 0.6817 S2A 0.4560 0.7843 0.6928 S18A 0.3450 0.8447 0.6976 O1A 1.1165 1.0559 0.5766 S19A 0.2074 0.8178 0.7076 O2A 0.7224 0.9856 0.6550 S20A 0.1562 0.7380 0.7022 OZA 0.8398 1.2529 0.6454 S21A 0.0304 0.7147 0.7157

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O4A 1.5651 0.7506 0.4617 S22A -0.0485 0.7716 0.7351 O5A -0.2774 0.7204 0.7003 S23A 0.0000 0.8505 0.7380 N1A 1.3618 0.8842 0.5136 S24A 0.1266 0.8733 0.7242 N2A 1.1688 0.8494 0.5467 S25A -0.1862 0.7457 0.7489 N3A 1.4787 0.8671 0.4896 S26A -0.3437 0.7303 0.8269 N4A 0.3948 0.9154 0.6924 S27A -0.1039 0.7825 0.8731 N5A -0.2089 0.7523 0.8134 H2A 0.9429 0.9077 0.6056 C1A 0.9221 1.0276 0.6170 H5A 1.0531 1.2020 0.5996 C2A 0.9786 0.9572 0.6007 H7A 0.7037 1.1350 0.6649 SZA 1.0931 0.9768 0.5770 NIA 1.3508 1.0045 0.5305 C4A 1.0087 1.0859 0.6016 H13A 1.0143 1.3283 0.6699 C5A 0.9913 1.1636 0.6097 Н13В 0.9021 1.3656 0.6495 C6A 0.8738 1.1794 0.6341 H13S 0.9558 1.2995 0.5907 C7A 0.7816 1.1219 0.6492 H14A 1.6625 0.8097 0.4087 C8A 0.8043 1.0462 0.6412 Н14В 1.7455 0.7617 0.4375 C9A 1.1929 0.9309 0.5519 H14C 1.7180 0.8448 0.4888 S10A 1.2734 0.8247 0.5236 NIA 0.5496 1.0093 0.6392 SNA 1.3118 0.9534 0.5317 NIV 0.6098 1.0457 0.7191 S12A 1.4725 0.7921 0.4827 H17A 0.6609 0.8537 0.6757 C13A 0.9356 1.3167 0.6383 H20A 0.2079 0.6995 0.6892 S14A 1.6822 0.7953 0.4481 H21A -0.0027 0.6607 0.7119 S15A 0.5982 0.9985 0.6749 H23A -0.0528 0.8885 0.7493 S16A 0.5248 0.9223 0.6829 H24A 0.1586 0.9267 0.7260 H26A -0.3902 0.7701 0.8231 С23В 1.4293 0.8360 0.9069 H26V -0.3436 0.7299 0.8735 С24В 1.3255 0.7665 0.8778 H26S -0.3865 0.6764 0.7931 С25В 1.6190 0.9253 0.9936 H27A -0.0209 0.7996 0.8582 S26V 1.6008 0.9733 1.1221 Н27В -0.0998 0.7389 0.8895 S27V 1.8027 1.0251 1.0738 H27S -0.1222 0.8286 0.9104 H4B 0.7471 0.4913 1.0036 S1B 0.5594 0.5998 1.2742 H6B 0.7120 0.2888 0.7500 S2B 1.1726 0.5790 0.7956 Н8В 0.3909 0.2354 0.8380 N1B 0.4242 0.4780 1.1705 NIV 0.3459 0.3823 1.0729 N2B 0.6072 0.5252 1.1322 H13D 0.3750 0.1134 0.7475 N3B 0.3447 0.4793 1.2218 H13E 0.3553 0.0961 0.6668 N4B 1.0939 0.6095 0.9156 H13F 0.3107 0.1710 0.7209 N5B 1.6697 0.9689 1.0605 H14D 0.1733 0.5046 1.3077 O1B 0.4772 0.3577 0.9610 H14E 0.2115 0.5318 1.3890 02B 0.8449 0.4158 0.8440 H14F 0.2531 0.4548 1.3361 03B 0.5007 0.1896 0.7202 NIS 0.9411 0.4809 0.9385 04B 0.3617 0.5617 1.3404 H15D 0.8430 0.5248 0.9140 05B 1.6767 0.9384 0.9467 Н17В 1.0003 0.4608 0.7686 S1B 0.6566 0.3891 0.9088 Н20В 1.3144 0.7121 1.0103 C2B 0.5337 0.3352 0.9001 Н21В 1.4937 0.8245 1.0554 SZV 0.5687 0.4260 1.0083 Н23В 1.4558 0.8681 0.8807 С4В 0.6747 0.4474 0.9810 H24V 1.2837 0.7526 0.8326 S5V 0.7250 0.3723 0.8487 H26D 1.5086 0.9682 1.1100 С6В 0.6660 0.3025 0.7888 H26E 1.6371 1.0254 1.1600 S7V 0.5460 0.2540 0.7840 H26F 1.6115 0.9291 1.1364 С8В 0.4736 0.2684 0.8405 H27D 1.8461 1.0083 1.0325 S9V 0.5265 0.4576 1.0792 H27E 1.8540 1.0224 1.1126 S10V 0.5405 0.5346 1.1860 H27F 1.7939 1.0807 1.0850 SIV 0.4143 0.4270 1.0997 O1S 0.7831 0.6012 0.4018 С12В 0.4074 0.5408 1.2783 O2C 0.9404 0.7581 0.5441 С13В 0.3756 0.1385 0.7133 OZS 1.0462 0.6593 0.5261 С14В 0.2397 0.5088 1.3436 O4S 0.4498 0.4070 0.3877 С15В 0.9062 0.4910 0.8986 O5S 0.6139 0.4260 0.3268 С16В 1.0154 0.5341 0.8712 O6S 0.9247 0.4868 0.3879 S17V 1.0446 0.5097 0.8050 O7S 0.8368 0.4575 0.4756 С18В 1.1810 0.6399 0.8832 O8S 0.8560 0.8242 1.1341 S19V 1.2840 0.7181 0.9153 O9S 0.8059 0.6897 1.2373 S20V 1.3445 0.7419 0.9829 O10C 0.8179 0.6314 1.1240 S21V 1.4508 0.8107 1.0105 ois 1.0582 0.8819 1.0424 С22В 1.4933 0.8583 0.9726 O12C 1.2146 0.9688 1.1232 013C 0.8728 0.7087 1.0120 H2S 1.0152 0.7857 0.5473 014C 1.0666 0.6951 1.0509 NZS1 0.7469 0.6602 0.5362 S1S 0.7690 0.5603 0.4498 NZS2 0.8145 0.6003 0.5580 С2С 0.9446 0.6828 0.5318 H4S 0.4185 0.3675 0.3509 SZS 0.8120 0.6271 0.5246 N5S1 0.6173 0.4999 0.4859 С4С 0.5652 0.4460 0.3801 N5S2 0.5726 0.5594 0.4542 S5S 0.6246 0.5184 0.4470 H7S 0.8829 0.4237 0.4665 С6С 0.8530 0.4979 0.4332 H8S 0.7896 0.7867 1.1250 С7С 0.9685 0.7917 1.1316 N9S1 1.0507 0.7320 1.1849 С8С 0.8570 0.6898 1.1866 N9S2 0.9867 0.8001 1.2339 S9S 0.9736 0.7551 1.1883 H10S 0.7536 0.5974 1.1257 С10С 1.1140 0.9052 1.0993 NIS 1.0887 0.9043 1.1959 THX 1.0928 0.8630 1.1502 H11D 1.1693 0.8413 1.1548 С12С 0.9629 0.7271 1.0581 H12S 1.2238 0.9912 1.0946 H1S 0.7373 0.6351 0.4107 H14G 1.0601 0.6609 1.0106

DSC of the N-2 form of the citric acid cocrystal showed a variable endotherm around 180°C, which represents melting with decomposition. TGA of the succinic acid cocrystal showed negligible mass loss up to 150 °C. Analytical data for each of the cocrystals described here were obtained using the following techniques.

- 16 043816

Single crystal data.

For the citric acid cocrystals described here, a Bruker X8 APEX II CCD diffractometer equipped with a MICROSTAR-H microfocus monochromatic Cu Ka X-ray generator (λ= 1.54178 A) with a rotating anode was used to collect diffraction data at room temperature. For the cocrystalline form of succinic acid, a Bruker X8 Prospector Ultra diffractometer equipped with a microfocus X-ray source IμS monochromatic CuKa radiation (λ = 1.54178 A) and an APEX II detector was used to collect diffraction data at room temperature. Indexing and processing of intensity measurement data was carried out using the APEX2 software package (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the complete data set. The structures were solved by direct methods and refined using the least squares technique in the full matrix approximation using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). Refinements to the structure involved minimizing the function given by Σw(|F _o |-|F _c |) ² where w is the appropriate weighting factor based on errors in the observed intensities, Fo is the structure factor based on measured reflections, and Fc represents a structural factor based on calculated reflections. The agreement between the refined crystal structure model and experimental X-ray diffraction data was assessed using residual factors R=Σ||Fo|-|Fc||/Σ|Fo| and wR= [Σw(|Fo|-|Fc|) ² /Σ|Fo|] ^1/2 - Fourier difference maps were studied at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were generally calculated using an idealized geometry, refined isotropically, and included in structure factor calculations with fixed parameters. There were a few exceptions where hydrogen atoms were localized using Fourier difference maps and refined isotropically, such as the acidic hydrogen atoms of succinic acid in a cocrystal structure.

PXRD.

PXRD data were acquired using a Bruker C2 GADDS (General Area Detector Diffraction System). The radiation was CuKa (40 kV, 40 mA). The sample-detector distance was 15 cm. The samples were placed in sealed glass capillaries with a diameter of <1 mm. The capillary was rotated during data collection. The transmitted data is collected in an angle region of approximately 2<2θ<32° with a sample exposure time of at least 1000 seconds. The resulting 2D diffraction lines were combined to create a conventional 1D PXRD diffraction pattern with a step size of 0.05 degrees 2θ over an approximate range of 2 to 32 degrees 2θ.

DSC.

TA INSTRUMENT® Model Q2000, Q1000, or 2920 were used to obtain DSC data. Measurements were performed using standard TA Instruments sealed crucibles. The measurement was carried out at a heating rate of 10 ^o C/min at a temperature from room to 300°C in a nitrogen environment with a sample size of about 2-10 mg. The DSC curve was plotted with endothermic peaks pointing downward.

TGA.

TGA data were obtained using TA INSTRUMENT® Model Q5000, Q500 or 2950. Measurements were performed using standard TA Instruments Platinum crucibles. The measurement was carried out at a heating rate of 10 ^o C/min at a temperature from room to 300°C in a nitrogen environment with a sample size of about 10-30 mg.

Solid State Nuclear Magnetic Resonance (SSNMR).

All solid-state C-13 NMR measurements were performed on a Bruker DSX-400, 400 MHz NMR spectrometer. High-resolution spectra were obtained using full proton decoupling and a TPPM and rising amplitude cross-polarization (RAMP-CP) pulse sequence with magic angle spinning (MAS) at approximately 12 kHz (A.E. Bennett et al., J. Chem. Phys. ., 1995, 103, 6951), (G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A., 1994, 110, 219-227). Approximately 70 mg of sample, packaged in a zirconia rotor container design, was used for each experiment. Chemical shifts (5) were applied to external adamantane with a high frequency resonance set at 38.56 ppm (W.L. Earl and D.L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).

Raman spectroscopy.

Raman spectra were acquired at 4 cm ^-1 resolution with an accumulation of 64 scans using an IS50 FT-Raman spectrophotometer. The laser excitation wavelength was 1064 nm. A CaF ₂ beam splitter and a highly sensitive InGaAs detector were used.

Infrared spectroscopy (IR).

Infrared spectra were obtained with a resolution of 4 cm ^-1 with an accumulation of 64 scans using an IS50 FT-IR spectrophotometer, including a KBr beam splitter and a DTGS detector. Sample preparation was performed using the attenuated total internal reflection (ATR) technique using a single reflection ATR accessory with a sampling diamond. The ATR correction stage was included to correct the optical path length.

- 17 043816

Dissolution data.

The dissolution of cocrystals of the compound of formula (I) form N-1 with citric acid and with succinic acid was tested in comparison with the dissolution of the free form of the compound of formula (I). Solubility parameters, rate, extent and peak solubility were tested in FaSSIF (fasting simulated intestinal fluid).

This experiment was performed using the pION Microdissolution Profiler™, an API-retaining, low-volume concentration instrument with UV fiber optic (UVFO) probes to measure dissolution profiles in biorelevant media in real time. The experiment was carried out under the following conditions:

device: pIon Microdissolution Profiler, media: FaSSIF, pH 6.5, volume: 15 ml at 37°C, mixing: 150 rpm with small stirrer, dose: API powder at 0.2 mg/ml or 3 mg/vial, duration studies: 180 min, time points: several time points to record the initial dissolution rate and after 180 min (typical time for absorption).

The results were analyzed using UVFO analysis: standard curve range 0-3 μg/ml; probe windows with an optical path length of 10 mm; detection wavelength 315 nm; slope ~17 μg/ml/AU; R ² =0.99.

The results are shown in Fig. 15 and in table. 5 below.

The dissolution of cocrystals of both succinic and citric acids in FaSSIF was better than the free form. The citric acid cocrystal had 3-4 times higher dissolution rate, AUC (extent of dissolution) and peak solubility compared to the succinic acid cocrystal.

Clinical characteristics.

To demonstrate the ability of the cocrystal to be absorbed, a pharmacokinetic study was performed in a canine model. The cocrystals were tested using the following compositions:

1. Succinic acid cocrystal capsule (dose 5 mg) - fasting dogs pre-treated with pentagastrin.

2. Citric acid cocrystal capsule (5 mg dose) - fasting dogs pre-treated with pentagastrin.

The study design was as follows:

Crossover study on 4 fasting male dogs (~10 kg); dose 5 mg/dog; washing with 50 ml of water; 2-week washout period between treatments; 8 blood sampling points for each procedure.

The results are presented in table. 7 and fig. 16.

Citric acid cocrystals and succinic acid cocrystals demonstrated measurable systemic absorption in a canine model at appropriate doses. Bioavailability varied from 32 to 55% relative to the well-absorbed comparator drug.

The PK variability (%CV) of both cocrystal capsules was high, mainly due to one dog showing very low/undetectable blood levels.

In view of the above idea, many modifications and variations of the present invention are possible. Accordingly, it is intended that within the scope of the appended claims, the invention may be practiced in a manner other than that specifically described herein.

Table 6

Dissolution of cocrystals of the compound of formula (I) and the free form. Average values

* All free-form values were below the detection limit, i.e. there was no signal.

AUC - area under the curve (calculated using the trapezoidal formula).

SD - standard deviation.

CV - coefficient of variability.

Form N-1 of citric acid cocrystal.

-

Claims (6)

Table 7 Pharmacokinetic parameters_________ Dose (mg) Stach (ng/ml) Ttah (h) AUCo-24 (ng-h/ml) VA (%) CV (%) Value Standard Deviation Value Standard Deviation Value Standard Deviation Succinic acid cocrystal capsule 5 12.22 9.52 1.5 93.97 66.64 31.94 22.65 70.92 Citric acid cocrystal capsule 5 29.28 20.51 2.0 161.61 107.98 54.93 36.70 66.82 Cmax is the maximum concentration in plasma during the period of action. AUC - area under the curve over time 0-24 hours. BA is the bioavailability of a relatively well absorbed comparator drug. CV - coefficient of variability. Form N-1 of citric acid cocrystal. CLAIM 1. Cocrystal of the compound of formula (1) and a coformer, where the coformer is succinic acid or citric acid. 2. Cocrystal according to claim 1, where the coformer is succinic acid. 3. Cocrystal of the compound of formula (1) and a coformer, where the coformer is succinic acid; and wherein the cocrystal is characterized by one or more of the following: a) a single-crystal structure having crystal cell parameters essentially equal to the following: crystal system, space group: triclinic, P-1, unit cell parameters: a=7.5±0.5 A, alpha=103±1°, b=9.6±0.5 A, beta=92±1°, c=20.1±0.5 A, gamma=98 ±1°, volume 1401±30 A ³ , number of formula units in a unit cell: 2, where the single crystal structure was measured at room temperature; b) an observed PXRD diffraction pattern substantially as shown in FIG. 1; c) a PXRD diffraction pattern containing 4 or more 2θ values selected from 4.5±0.2, 9.5±0.2, 14.6±0.2, 16.3±0.2, 17.6± 0.2, 21.4±0.2, 22.4±0.2 and 25.9±0.2 (obtained at room temperature and (CuKa λ = 1.5418 A)); d) infrared spectra, essentially as shown in FIG. 5; and/or e) FT-Raman spectra essentially as shown in FIG. 6. 4. Cocrystal according to claims 1-3, where the ratio of the compound of formula (I) to succinic acid is 1:0.5. 5. Cocrystal according to claim 1, wherein the coformer is citric acid. 6. Cocrystal of the compound of formula (1) and a coformer, where the coformer is citric acid; and wherein the cocrystal is in the N-1 form and is characterized by one or more of the following: a) a single crystal structure having crystal cell parameters substantially equal to the following: Crystal system, space group: triclinic, P-1, Unit cell parameters: a=10.3±0.5 A, alpha=94±1°, b=12.3±0.5 A, beta=98±1°, c=13.9±0.5 A, gamma=98 ±1°, -