Crystalline Forms of PAR4 Inhibitors

Abstract

The present invention relates to co-crystals of compounds of formula (I), methods for preparing the co-crystals, pharmaceutical compositions thereof, and methods of using the co-crystals for treating or preventing thromboembolic disorders, wherein the co-former molecule in the co-crystals is succinic acid or citric acid.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application No. 62 / 783,223, filed on December 21, 2018, the entire disclosure of which is incorporated herein by reference. Technical field

[0003] The present invention relates to a co - crystal 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 manufacture, pharmaceutical compositions, and methods of using the co - crystals of the present invention. Background art

[0004] Although anticoagulants such as warfarin heparin, low - molecular - weight heparin (LMWH), synthetic pentasaccharides, and anti - platelet agents such as aspirin and clopidogrel are available, thromboembolic diseases remain a major cause of death in developed countries.

[0005] Current anti - platelet therapies have limitations, including an increased risk of bleeding and partial efficacy (a relative cardiovascular risk reduction in the range of 20% to 30%). Thus, the discovery and development of safe and effective oral or parenteral antithrombotic drugs for the prevention and treatment of a wide range of thromboembolic disorders remains an important goal.

[0006] α-Thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally related to atherothrombotic vascular occlusion. Thrombin activates platelets by cleaving G protein-coupled receptors (termed protease-activated receptors (PARs)). PARs present their own cryptic ligands in the N-terminal extracellular domain, which become unmasked by proteolytic cleavage and subsequently bind intramolecularly to the receptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus after proteolytic activation can induce signaling independent of receptor cleavage. Platelets are key participants in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors of PAR1 have been extensively studied and several compounds, including vorapaxar and atopaxar, have entered late-stage clinical trial phases. Recently, in the TRACER phase III trial in ACS patients, vorapaxar did not significantly reduce cardiovascular events but significantly increased the risk of major bleeding (Tricoci, P. et al., N. Engl. J. Med., 366(1):20-33 (2012)). Thus, there remains a need to discover new antiplatelet agents with increased efficacy and reduced bleeding side effects.

[0007] The compound of formula (I), 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 (Compound (I)), is a PAR4 inhibitor and its synthesis, preparation as a free-form solid material, and uses are described in WO 2013 / 163279.

[0008] SUMMARY OF THE INVENTION

[0009] The present invention relates to a cocrystal comprising a compound of formula (I),

[0010]

[0011] and succinic acid or citric acid, a pharmaceutical composition comprising the same, and treating or preventing a thromboembolic disorder by administering an effective amount of the cocrystal to a patient or mammal in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows the simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns for the succinic acid cocrystal of the compound of formula (I).

[0013] Figure 2 shows the DSC of the succinic acid cocrystal of the compound of formula (I).

[0014] Figure 3 shows the TGA of the succinic acid cocrystal of the compound of formula (I).

[0015] Figure 4 shows the FT-Raman spectrum of the succinic acid cocrystal of the compound of formula (I).

[0016] Figure 5 shows the FT-IR spectrum of the succinic acid cocrystal of the compound of formula (I).

[0017] Figure 6 shows the simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns for the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0018] Figure 7 shows the DSC of the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0019] Figure 8 shows the TGA of the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0020] Figure 9 shows the FT-Raman of the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0021] Figure 10 shows the C-13 CPMAS SSNMR of the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0022] Figure 11 shows the FT-IR of the N-1 form of the citric acid cocrystal of the compound of formula (I).

[0023] Figure 12 shows the simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns for the N-2 form of the citric acid cocrystal of the compound of formula (I).

[0024] Figure 13 shows the DSC of the N-2 form of the citric acid cocrystal of the compound of formula (I).

[0025] Figure 14 shows the TGA of the N-2 form of the citric acid cocrystal of the compound of formula (I).

[0026] Figure 15 shows the dissolution of the citric acid cocrystal and succinic acid cocrystal of the compound of formula (I) and the dissolution of the free form of the compound of formula (I).

[0027] Figure 16 shows the pharmacokinetic (PK) profiles of the citric acid cocrystal and succinic acid cocrystal of the compound of formula (I) in dogs. Detailed implementation mode

[0028] In one embodiment of the present invention, it is a eutectic of a compound of formula (I) and a coformer, wherein the coformer is citric acid or succinic acid

[0029]

[0030] In another embodiment of the present invention, the coformer is succinic acid.

[0031] In another embodiment, the eutectic of the compound of formula (I) and succinic acid is characterized by one or more of the following:

[0032] a) A single crystal structure having unit cell parameters substantially equal to the following:

[0033]

[0034] wherein the measurement of the single crystal structure is at room temperature;

[0035] b) The observed PXRD pattern is substantially as shown in Figure 1;

[0036] c) A PXRD pattern comprising 4 or more 2θ values selected from the following: 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

[0037] d) An infrared spectrum substantially as shown in Figure 5; and / or

[0038] e) An FT-Raman spectrum substantially as shown in Figure 6.

[0039] In another embodiment, the eutectic of the compound of formula (I) and succinic acid has a ratio of the compound of formula (I) to succinic acid of 1:0.5.

[0040] In another embodiment of the present invention, the coformer is citric acid.

[0041] In another embodiment, the eutectic 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:

[0042] a) A single crystal structure having unit cell parameters substantially equal to the following:

[0043]

[0044] b) A PXRD pattern substantially as shown in Figure 6; and / or

[0045] c) an X-ray powder diffraction pattern having four or more 2θ values selected from the following (at room temperature) ): 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.

[0046] In another embodiment of the present invention, the cocrystal of the compound of formula (I) and citric acid has a ratio of 1:1.

[0047] In another embodiment of the present invention, the cocrystal of the compound of formula (I) and citric acid consists essentially of Form N-1.

[0048] In another embodiment of the present invention, the cocrystal of the compound of formula (I) and citric acid contains Form N-1.

[0049] In another embodiment, the cocrystal of the compound of formula (I) and citric acid is in Form N-2 and is characterized by one or more of the following:

[0050] a) a single crystal structure having unit cell parameters substantially equal to the following:

[0051]

[0052] b) a PXRD pattern substantially as shown in Figure 12; and / or

[0053] c) an X-ray powder diffraction pattern having four or more 2θ values selected from the following (at room temperature) ): 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.

[0054] In another embodiment of the present invention, the Form N-1 of the cocrystal of the compound of formula (I) and citric acid has a ratio of 1:1.

[0055] In another embodiment of the present invention, the Form N-2 of the cocrystal of the compound of formula (I) and citric acid has a ratio of 1:1.

[0056] In another embodiment of the present invention, the cocrystal of the compound of formula (I) and citric acid consists essentially of Form N-2.

[0057] In another embodiment of the present invention, the cocrystal of the compound of formula (I) and citric acid contains Form N-2.

[0058] In another embodiment of the present invention, the present invention relates to any eutectic in substantially pure form.

[0059] In another embodiment of the present invention, the succinic acid eutectic is characterized by having a PXRD with 4 or more, 5 or more, or 6 or more 2θ values selected from the following: 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 (at room temperature ).

[0060] In another embodiment of the present invention, the succinic acid eutectic is characterized by having a PXRD with at least one or more 2θ values selected from the following: 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 (at room temperature ).

[0061] In another embodiment of the present invention, the succinic acid eutectic is characterized by having a PXRD with 4 or more, or 5 or more 2θ values selected from the following: 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 (at room temperature ).

[0062] In another embodiment of the present invention, the succinic acid eutectic is characterized by having a PXRD with 4 or more, or 5 or more, or 6 or more 2θ values selected from the following: 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 (at room temperature ).

[0063] In another embodiment of the present invention, the succinic acid eutectic has a single crystal structure, and the single crystal structure has unit cell parameters substantially equal to the following:

[0064]

[0065] In another embodiment, the succinic acid eutectic is characterized by substantially conforming to the FT-IR of Figure 5. In another embodiment, the succinic acid eutectic is characterized by having an FT-IR spectrum with peaks at 1627.9, 1704.4, and 3102.1 cm -1 (±0.4 cm -1 ).

[0066] In another embodiment, the succinic acid co-crystal is characterized by an FT-Raman substantially conforming to Figure 4. In another embodiment, the succinic acid co-crystal is characterized by an FT-Raman spectrum having peaks at 975.3, 1185.0, 1242.9, 1455.6, and 3104.4 cm -1 (±0.3 cm -1 ).

[0067] In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD substantially conforming to Figure 6. In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD having 4 or more, or 5 or more, or 6 or more 2θ values selected from the following: 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 (at room temperature ). In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD having at least one or more 2θ values selected from the following: 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 (at room temperature ). In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD comprising 2θ values selected from the following: 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, and 26.6 ± 0.2 (at room temperature ).

[0068] In another embodiment, the N-1 form of the citric acid co-crystal has a single crystal structure having unit cell parameters substantially equal to those of a single crystal structure having unit cell parameters substantially equal to the following:

[0069]

[0070] In another embodiment, the N-1 form of the citric acid co-crystal is characterized by an FT-IR substantially conforming to Figure 11. In another embodiment, the N-1 form of the citric acid co-crystal is characterized by an FT-IR spectrum having peaks at 1585.7, 1725.9, and 3150.5 cm -1 (±0.4 cm -1 ).

[0071] In another embodiment, the N-1 form of the citric acid cocrystal is characterized by an FT-Raman substantially conforming to FIG. 9. In another embodiment, the N-1 form of the citric acid cocrystal is characterized by an FT-Raman spectrum having peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6, and 2978.9 cm -1 (±0.3 cm -1 ).

[0072] In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD substantially conforming to FIG. 12. In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD having 4 or more, or 5 or more, or 6 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. In another embodiment, the N-2 form of the citric acid cocrystal is characterized by a PXRD having at least one 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. In another embodiment, the N-1 form of the citric acid cocrystal is characterized by a PXRD comprising 2θ values selected from 4 or more, or 5 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. (at room temperature ).

[0073] In another embodiment, the N-2 form of the citric acid cocrystal has a single crystal structure having unit cell parameters substantially equal to the following:

[0074]

[0075] In another embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal form of at least one compound of formula (I) and a pharmaceutically acceptable carrier.

[0076] In another embodiment, the present invention describes a method for treating a thromboembolic disorder, the method comprising administering to a host in need of such treatment a therapeutically effective amount of a cocrystal form of at least one compound of formula (1).

[0077] In some embodiments, the present invention provides a pharmaceutical composition, which further comprises another therapeutic agent or agents. In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent or agents is an antiplatelet agent or a combination thereof. Preferably, the one or more antiplatelet agents are P2Y12 antagonists and / or aspirin. Preferably, the P2Y12 antagonist is clopidogrel, ticagrelor, or prasugrel. In another preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent or agents is an anticoagulant or a combination thereof. Preferably, the one or more anticoagulants are FXa inhibitors or thrombin inhibitors. Preferably, the FXa inhibitor is apixaban or rivaroxaban. Preferably, the thrombin inhibitor is dabigatran.

[0078] In some embodiments, the present invention provides a method for treating or preventing a thromboembolic disorder, the method comprising administering to a subject (e.g., a human) in need of such treatment or prevention a therapeutically effective amount of a cocrystal form of at least one compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2).

[0079] In some embodiments, the present invention provides a method for treating a thromboembolic disorder or for primary or secondary prevention of a thromboembolic disorder, the method comprising administering to a patient in need thereof (e.g., a human) a therapeutically effective amount of a cocrystal form of a compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2), wherein the thromboembolic disorder is selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or in the peripheral circulation.

[0080] In some embodiments, the present invention provides methods for treating a thromboembolic disorder or for primary or secondary prevention of a thromboembolic disorder, the methods comprising the step of administering to a patient in need thereof (e.g., a human) a therapeutically effective amount of a cocrystal form of a compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2), wherein the thromboembolic disorder is selected from acute coronary syndrome, unstable angina, stable angina, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral artery disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis caused by medical implants, devices, and surgeries (wherein blood is exposed to artificial surfaces that promote thrombosis).

[0081] In some embodiments, the present invention provides methods for treating a thromboembolic disorder or for primary or secondary prevention of a thromboembolic disorder, the methods comprising the step of administering to a patient in need thereof (e.g., a human) a therapeutically effective amount of a cocrystal form of a compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2), wherein the thromboembolic disease is selected from acute coronary syndrome, unstable angina, stable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction.

[0082] In some embodiments, the present invention provides methods for treating a thromboembolic disorder or for primary or secondary prevention of a thromboembolic disorder, the methods comprising the step of administering to a patient in need thereof (e.g., a human) a therapeutically effective amount of a cocrystal form of a compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2), wherein the thromboembolic disorder is selected from transient ischemic attack and stroke.

[0083] In some embodiments, the present invention provides methods for treating a thromboembolic disorder or for primary or secondary prevention of a thromboembolic disorder, the methods comprising the step of administering to a patient in need thereof (e.g., a human) a therapeutically effective amount of a cocrystal form of a compound of formula (I) disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2), wherein the thromboembolic disorder is peripheral artery disease.

[0084] In another embodiment, the invention includes the method as described above, wherein the thromboembolic disorder is selected from unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device, or surgery where blood is exposed to an artificial surface that promotes thrombosis.

[0085] In some embodiments, the invention includes a method of inhibiting or preventing platelet aggregation, the method comprising administering to a subject in need thereof, such as a human, a therapeutically effective amount of a cocrystal form of a compound of formula (I) as disclosed herein (e.g., succinic acid cocrystal, citric acid cocrystal, citric acid cocrystal N-1, or citric acid cocrystal N-2).

[0086] In still yet even further embodiments, the respective cocrystal forms of compound (I) are substantially pure.

[0087] In still yet another embodiment, based on the weight of the respective cocrystal forms of compound (I), the respective 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 compound (I).

[0088] In another embodiment, the compound of formula (I) can have a mixture of cocrystals as described herein.

[0089] The invention includes the use of a cocrystal of a compound of formula (I) in therapy.

[0090] The invention relates to the use of a cocrystal of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of a thromboembolic disorder.

[0091] In preparing a pharmaceutical composition, a form of the active ingredient that seeks to have a balance of desired properties such as, for example, dissolution rate, solubility, bioavailability, and / or storage stability is sought. For example, a form of the active ingredient that has sufficient solubility, bioavailability, and storage stability is sought to prevent the form that is sufficiently soluble and bioavailable from converting during storage to another form having undesirable solubility and / or bioavailability characteristics.

[0092] The invention provides at least one cocrystal form of compound (I) which unexpectedly provides a balance of the properties sought in a pharmaceutical composition. The invention also relates to other important aspects.

[0093] The present invention also encompasses all combinations of alternative aspects of the invention mentioned herein. It should be understood that any and all embodiments of the present invention can be used in combination with any other embodiment to describe additional embodiments of the present invention. In addition, any element of an embodiment is intended to be combined with any and all other elements in any embodiment to describe additional embodiments.

[0094] Definitions

[0095] After reading the following detailed description, those of ordinary skill in the art can more easily understand the features and advantages of the present invention. It should be understood that, for the sake of clarity, certain features of the present invention described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for the sake of brevity, the various features of the present invention described in the context of a single embodiment may also be combined to form sub-combinations thereof.

[0096] Names used herein to characterize particular forms, such as "N-1", etc., are merely identifiers interpreted in accordance with the characterization information provided herein and should not be restricted to exclude any other substances having similar or identical physical and chemical characteristics.

[0097] The definitions set forth herein prevail over any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0098] All numbers representing amounts of ingredients, weight percentages, temperatures, etc. that are preceded by the word "about" should be understood to be approximate only, such that minor variations above and below the stated numbers can be used to achieve substantially the same result as the stated numbers. Accordingly, unless indicated to the contrary, the numerical parameters before the words "about" or "substantially conforming" are approximations that can vary according to the desired properties sought to be obtained. At the very least and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in accordance with the number of significant digits reported and by application of ordinary rounding techniques.

[0099] All measurements are subject to experimental error and are within the spirit of the present invention.

[0100] As used herein, "eutectic" means a crystalline material in the solid state, which is composed of two or more kinds of molecules in the same crystal lattice, the molecules being in a neutral state, interacting via non-ionic interactions, and being a solid as a single component at room temperature.

[0101] As used herein, "polymorph" refers to a crystal form having the same chemical structure but a different spatial arrangement of the molecules and / or ions that form the crystal.

[0102] As used herein, "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further contains molecules of one or more solvents incorporated into the lattice structure. When the solvent is water, the form is called a "hydrate". The solvent molecules in a solvate can be present in a regular arrangement and / or a disordered arrangement. A solvate can contain a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may result from partial loss of the solvent from the solvate. A solvate can exist in the form of a dimer or oligomer that contains more than one molecule or eutectic of the compound of formula (I) in the lattice structure.

[0103] As used herein, "amorphous" refers to a non-crystalline molecular, atomic, and / or ionic solid form. An amorphous solid does not exhibit a definite X-ray diffraction pattern.

[0104] As used herein, "substantially pure", when used in reference to a eutectic form, means a compound having the following purity: greater than 90% by weight, including greater than 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, and 99% by weight, and also including approximately 100% by weight of the eutectic of compound (I). The remaining material includes one or more other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, the eutectic form of compound (I) can be considered substantially pure because it has a purity greater than 90% by weight, as measured by means known and generally accepted in the art at the time, where the remaining less than 10% by weight of the material contains one or more other forms of compound (I) and / or reaction impurities and / or processing impurities.

[0105] When dissolved, the eutectic form of the compound of formula (I) loses its crystal structure and is thus called a solution of the compound of formula (I). However, all forms of the invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, the eutectic form of the compound of formula (I) can be incorporated into solid formulations.

[0106] As used herein, an XRPD (X-ray powder diffraction) or PXRD (powder X-ray diffraction) pattern that “comprises” or has multiple peaks selected from a specified set of peaks is intended to include a PXRD pattern that has additional peaks not included in the specified set of peaks. For example, a PXRD pattern that comprises 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 pattern that has: (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 any of the A, B, C, D, E, F, G, and H peaks.

[0107] As used herein, 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.

[0108] The term “room temperature” generally means about 22 °C, but can vary up or down by 7 °C.

[0109] When the term “substantially conforms” is used with respect to an XRPD or PXRD pattern, it should be understood that measurements of the peak positions for a given crystalline form of the same compound will vary within the error range. It should also be understood that the intensities of the peaks can vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of the different peaks are not intended to limit the comparison of different PXRD scans.

[0110] 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 to prevent or treat the disorders listed herein. When applied to a combination, the term refers to the combined amount of the active ingredients that produces a prophylactic or therapeutic effect whether administered in the combination, continuously, or simultaneously.

[0111] As used herein, the term “thrombosis” refers to the formation or presence of a thrombus within a blood vessel that can cause local ischemia or infarction of the tissue supplied by the vessel. As used herein, the term “embolism” refers to the sudden obstruction of an artery by a clot or foreign material that is carried by the bloodstream to its site of deposition. As used herein, the term “thromboembolism” refers to the obstruction of a blood vessel by thromboembolic material that is carried by the bloodstream from its original site to block another blood vessel. The term “thromboembolic disorder” includes both “thrombotic” disorders and “embolic” disorders (as defined above).

[0112] As used herein, the term "thromboembolic disorder" includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or in the peripheral circulation. As used herein, the term "thromboembolic disorder" also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries where blood is exposed to artificial surfaces that promote thrombosis. Medical implants or devices include, but are not limited to: artificial valves, prosthetic valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices, and artificial hearts or heart chambers, as well as vascular grafts. Surgeries include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term "thromboembolic disorder" includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.

[0113] In some embodiments, a therapeutically effective amount of the PAR4 compound is preferably about less than 100 mg / kg, 50 mg / kg, 10 mg / kg, 5 mg / kg, 1 mg / kg, or less than 1 mg / kg. In another embodiment, a therapeutically effective amount of the PAR4 compound is less than 5 mg / kg. In another embodiment, a therapeutically effective amount of the PAR4 compound is less than 1 mg / kg. In another embodiment, the dose is 8 mg to 48 mg. As will be appreciated by those skilled in the art, the effective dose varies depending on the route of administration and the excipient used.

[0114] Typically, the eutectic form is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected for the intended form of administration (oral tablets, capsules, elixirs, syrups, etc.) and consistent with conventional pharmaceutical practice.

[0115] For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with an orally non-toxic pharmaceutically acceptable inert carrier (such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, mannitol, sorbitol, etc.); for oral administration in liquid form, the oral pharmaceutical ingredient can be combined with any orally non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). In addition, when desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth) or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0116] The cocrystals of the present invention can also be administered in the form of liposome delivery systems (such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles). Liposomes can be formed from various phospholipids (such as cholesterol, stearamide, or phosphatidylcholine).

[0117] The cocrystals of the present invention can also be conjugated with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, poly(hydroxypropyl methacrylamide)-phenol, poly(hydroxyethyl asparagine)phenol, or poly(ethylene oxide)-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be conjugated with a class of biodegradable polymers that can be used to achieve controlled drug release, such biodegradable polymers are, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic hydrogel block copolymers.

[0118] Each dosage unit of the dosage form (pharmaceutical composition) suitable for administration can contain from about 1 milligram to about 100 milligrams of the active ingredient. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.5% - 95% by weight based on the total weight of the composition.

[0119] Gelatin capsules can contain the active ingredient and a powdery carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be made into sustained-release products to provide continuous release of the drug over a period of several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablets from air, or enteric-coated to selectively disintegrate in the gastrointestinal tract.

[0120] Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

[0121] Typically, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration may contain water-soluble salts of the active ingredient, suitable stabilizers, and buffering substances (if required). Antioxidants (such as sodium bisulfite, sodium sulfite, or ascorbic acid), alone or in combination, are suitable stabilizers. Citric acid and its salts, as well as sodium EDTA, are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol.

[0122] Suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, which is a standard reference in the field.

[0123] Representative and useful pharmaceutical dosage forms for administering the compounds of the present invention may be illustrated as follows:

[0124] Capsules

[0125] Large numbers of unit capsules may be prepared by filling standard two-piece 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.

[0126] Soft gelatin capsules

[0127] A mixture of the active ingredient in a digestible oil (such as soybean oil, cottonseed oil, or olive oil) may be prepared and the mixture may be injected into gelatin by a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should be washed and dried.

[0128] Tablets

[0129] Tablets may be prepared by conventional procedures 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. Suitable coatings may be applied to increase palatability or delay absorption.

[0130] Dispersions

[0131] Spray-dried dispersions for oral administration may be prepared by methods known to those skilled in the art.

[0132] Injections

[0133] A parenteral composition suitable for injection administration can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

[0134] Suspension

[0135] An aqueous suspension can be prepared for oral administration such that each 5 mL contains 100 mg of the subdivided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (U.S.P.), and 0.025 mL of vanillin.

[0136] When two or more of the aforementioned second therapeutic agents are administered together with the cocrystal of the compound of formula I, generally, in view of the additive or synergistic effects of the therapeutic agents when administered in combination, the amount of each component in the typical daily dose and typical dosage form can be reduced relative to the usual dose of the agent when administered alone.

[0137] Especially when provided as a single dosage unit, there is a possibility of chemical interaction between the combined active ingredients. For this reason, when the cocrystal form of compound (I) and the second therapeutic agent are combined in a single dosage unit, they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, one of the active ingredients can be enteric-coated. By enteric-coating one of the active ingredients, not only can the contact between the combined active ingredients be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled such that one of these components is not released in the stomach but in the intestine. One of the active ingredients can also be coated with a material that achieves sustained release throughout the gastrointestinal tract and is also used to minimize the physical contact between the combined active ingredients. In addition, the sustained-release component can be additionally enteric-coated such that the release of this component occurs only in the intestine. Yet another method involves formulating a combined product in which one component is coated with a sustained-release and / or enteric-release polymer, and the other component is also coated with a polymer (such as low-viscosity grade hydroxypropyl methylcellulose (HPMC)) or other suitable materials known in the art to further separate the active components. The polymer coating is used to form an additional barrier against interaction with other components.

[0138] Once incorporated into the present disclosure, these and other ways of minimizing the contact between the components of the inventive combined product, whether administered in a single dosage form or in separate forms (but administered simultaneously in the same manner), will be readily apparent to those skilled in the art.

[0139] As discussed above, the compounds of the present invention (including the cocrystal form of the compound of formula I) can be administered orally, intravenously, or both.

[0140] Example

[0141] Eutectic 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 spray spraying. Techniques for crystallizing or recrystallizing eutectic forms from solvent mixtures include, for example, evaporating the solvent, reducing 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 an antisolvent (antisolvent) to the solvent mixture.

[0142] For crystallization techniques using solvents, the choice of one or more solvents generally depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used. For example, a compound can be dissolved in a first solvent to provide a solution, and then an antisolvent is added to reduce the solubility of the compound in the solution and provide the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

[0143] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which can be heated to facilitate dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain an additional amount of the compound to provide a non-uniform mixture of the compound and the solvent at a given temperature.

[0144] Seeds can be added to any crystallization mixture to facilitate crystallization. Seeds can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystallization product. Therefore, the calculation of the amount of seeds required depends on the available seeds and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are required to effectively control the growth of crystals in a batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. It should be noted that grinding or micronizing of the crystals does not result in any change in the form of crystallinity compared to the desired crystal form (i.e., becoming amorphous or another polymorph).

[0145] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as the cold recrystallization solvent) and dried under a nitrogen purge to provide the desired crystalline form. The separated solid can be analyzed by suitable spectroscopic or analytical techniques (such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc.) to ensure the formation of the preferred crystalline form of the product. Based on the weight of the compound initially used in the crystallization procedure, the resulting crystalline form is typically produced in an isolated yield of greater than about 70% by weight, preferably greater than 90% by weight. If desired, the product can be co-ground or passed through a sieve to deblock the product.

[0146] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or by solid-state nuclear magnetic resonance spectroscopy using Raman or IR spectroscopy. For example, when comparing an experimentally measured PXRD pattern with a simulated PXRD pattern, the presence of additional peaks may indicate the presence of more than one polymorph in the sample. Simulated PXRD 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).

[0147] The eutectic forms of the compounds of formula (I) according to the present invention can be characterized using a variety of techniques, the operation of which is well known to those of ordinary skill in the art. Single-crystal X-ray diffraction can be used to characterize and distinguish the forms, which is based on the unit cell measurements of single crystals of the forms at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout and Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the unique arrangement of atoms in the spatial relationships within the lattice can be characterized based on the observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder X-ray diffraction analysis (where the diffraction spectrum is compared with a simulated spectrum representative of the pure powder material, both run at the same analysis temperature) and measurement of the subject form (characterized as a series of 2θ values (usually four or more)).

[0148] Other means of characterizing the form can be used, such as solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermal analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the subject form. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined by other suitable analytical methods.

[0149] Example 1

[0150] 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 cocrystal (1:0.5)

[0151] 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 mixture was heated to 39 °C until completely dissolved. Then succinic acid (0.45 g, 3.8 mmol) was added in one portion. After 3 days, 50 mL of the solution was distilled off until a slurry form. Ethyl acetate (70 mL) was added. The volatiles were removed to dryness and ethyl acetate (100 mL) was charged to the reaction mixture and the reaction mixture was stirred for 12 h. Then the resulting slurry was filtered and the resulting solid was washed with ethyl acetate (10 mL). The solid was dried in a vacuum oven for 24 h (30 mmHg, 50 °C) to obtain the succinic acid cocrystal of the compound of formula (I). The product was obtained as a white solid (1.8 g, 41% yield) with a purity of 99.4% by HPLC. 1 1H NMR (400 MHz, DMSO-d6) δ 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).

[0152] The succinic acid cocrystal has a stoichiometry of one molecule of the compound of formula (I) with 0.5 molecule of succinic acid or a hemisuccinate ester of the compound of formula (I).

[0153] The succinic acid cocrystal of the compound of formula (I) gave the PXRD pattern shown in Figure 1, the differential scanning calorimetry (DSC) shown in Figure 2, and the thermogravimetric analysis (TGA) shown in Figure 3.

[0154] The PXRD of the succinic acid cocrystal of the compound of formula (I) has selected 2θ peaks at 4.5, 9.5, 14.6, 16.3, 17.6, 21.4, 22.4, and 25.9 (all peaks are at 2θ ± 0.2 degrees). The PXRD was obtained at room temperature, and the diffraction peak positions (2θ ± 0.2 degrees) are based on high-quality patterns collected with a diffractometer (CuKα) with a rotating capillary, where 2θ was calibrated with other suitable NIST standards.

[0155] The succinic acid cocrystal is further characterized by a PXRD having at least one or more, or 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.

[0156] The succinic acid cocrystal is further characterized by a PXRD having 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, and 25.9 ± 0.2.

[0157] Single crystal X-rays of the succinic acid cocrystal of the compound of formula (I) were obtained and gave the following results:

[0158]

[0159] The atomic coordinates for the single crystal X-rays of the succinic acid cocrystal are shown in Table 1.

[0160] Table 1. Atomic Coordinates of the Succinic Acid Cocrystal

[0161]

[0162]

[0163]

[0164] The DSC of the succinic acid cocrystal showed a variable endotherm at about 182 °C, indicating that the melt has decomposition. The TGA of the succinic acid cocrystal showed negligible weight loss up to 150 °C.

[0165] FT-IR and FT-Raman are shown in Figures 4 and 5, respectively, and show characteristic peaks in the range of 1700 to 3500 cm -1 range.

[0166] The FT-Raman spectrum for the succinic acid co-crystal has characteristic peaks at 975.3, 1185.0, 1242.9, 1455.6, and 3104.4 cm -1 (±0.3 cm -1 ).

[0167] The FT-IR spectrum for the succinic acid co-crystal has characteristic peaks at 1627.9, 1704.4, and 3102.1 cm -1 (±0.4 cm -1 ).

[0168] Example 2

[0169] 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 co-crystal (1:1), Form N-1.

[0170] A mixture 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 (6.1 g, 11 mmol, 1.0 equiv) and citric acid (3.3 g, 18 mmol, 1.6 equiv) in ethyl acetate (210 mL) was heated to 76 °C for 10 h and then slowly cooled to room temperature and allowed to stir for 16 h. The slurry was filtered and washed with EtOAc (80 mL), and then the filter cake was dried in vacuo in an oven at 55 °C for 1 day to afford 8.0 g (98% yield) of the N-1 form of the citric acid co-crystal as a white solid.

[0171] Alternative procedure

[0172] Ethyl acetate (17 L) was added to citric acid (222.5 g, 1.16 mol, 1.3 eq) and heated to 55 °C for 2 h to obtain a clear solution. 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 (500.00 g, 0.89 mol, 1.0 eq) was added, and then ethyl acetate (1 L) was added. The mixture was heated to 76 °C over 1 h. 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 citrate cocrystal (1.0 g, 0.2% wt) in ethyl acetate (15 mL) was added as a seed. The mixture was heated for an additional 30 min and then slowly cooled to room temperature over 2 h and allowed to stir for 5 h. The slurry was filtered and washed twice with ethyl acetate (3 L), and then the filter cake was dried in vacuo in an oven at 50 °C for 3 days to obtain 663.7 g (99% yield) of the N-1 form of the citrate cocrystal of 99.8 AP purity as a white solid.

[0173] The N-1 form of the citrate cocrystal of the compound of formula (I) has a stoichiometry of 1 molecule of the compound of formula (I) per molecule of citric acid (1:1).

[0174] The N-1 form of the citrate cocrystal of the compound of formula (I) gives the PXRD pattern shown in Figure 6, the DSC shown in Figure 7, and the TGA shown in Figure 8.

[0175] The N-1 form of the citrate cocrystal of the compound of formula (I) has a PXRD with selected 2θ peaks at 6.4, 12.7, 14.4, 17.1, 23.9, 25.0, and 26.6 (all peaks at 2θ ± 0.2 degrees). The PXRD was obtained at room temperature, and the diffraction peak positions (2θ ± 0.2 degrees) are based on a high-quality pattern collected with a diffractometer (CuKα) with a spinning capillary, where 2θ was calibrated with NIST or other suitable standards.

[0176] The N-1 form of the citrate cocrystal of the compound of formula (I) has a PXRD with selected 2θ peaks at 6.4, 12.7, 14.4, and 26.6 (all peaks at 2θ ± 0.2 degrees). The PXRD was obtained at room temperature, and the diffraction peak positions (2θ ± 0.2 degrees) are based on a high-quality pattern collected with a diffractometer (CuKα) with a spinning capillary, where 2θ was calibrated with NIST or other suitable standards.

[0177] The N-1 form of the citric acid cocrystal is further characterized by having a PXRD with one or more, or 4 or more 2θ values selected from the following: 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.

[0178] The N-1 form of the citric acid cocrystal is further characterized by having a PXRD with 4 or more 2θ values selected from the following: 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, and 26.6 ± 0.2.

[0179] Obtaining a single crystal X-ray of the N-1 form of the citric acid cocrystal of the compound of formula (I) and producing the following results:

[0180]

[0181]

[0182] The atomic coordinates for the single crystal X-ray of the N-1 form of the citric acid cocrystal are shown in Table 3.

[0183] Table 3

[0184]

[0185]

[0186] The DSC of the N-1 form of the citric acid cocrystal shows a variable endotherm at about 185 °C - 190 °C, indicating that the melt has decomposition. The TGA of the N-1 form of the citric acid cocrystal shows a negligible weight loss up to 150 °C.

[0187] The C-13 solid state NMR (C-13 SSNMR) of the N-1 form of the citric acid cocrystal exhibits the peaks shown in Table 4. The C-13 SSNMR is consistent with Z’ = 2.

[0188] Table 4: C-13 Chemical Shifts of the N-1 Citric Acid Cocrystal

[0189]

[0190]

[0191] The IR and Raman spectroscopy of the N-1 form of the citric acid cocrystal exhibit the peaks shown in Figures 9 and 11. The spectra exhibit the characteristic peaks shown in the range from 1700 to 3500 cm-1.

[0192] The FT-Raman spectrum of the N-1 citric acid cocrystal has characteristic peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6, and 2978.9 cm -1 (±0.3 cm -1 ).

[0193] The FT-IR spectrum of the N-1 citric acid cocrystal has characteristic peaks at 1585.7, 1725.9, and 3150.5 cm -1 (±0.4 cm -1 ).

[0194] Example 3

[0195] 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 cocrystal (1:1), Form N-2.

[0196] A mixture 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 (5.00 g, 8.9 mmol, 1 equivalent) and citric acid (2.50 g, 13.4 mmol, 1.5 equivalents) in 200 mL of EtOAc was heated to 74 °C for 18 h. The mixture was slowly cooled to room temperature and allowed to stir for 3 h. The slurry was filtered and washed twice with EtOAc (20 mL), and then the filter cake was dried in vacuo in an oven at 55 °C for 1 day to give 6.5 g (97% yield) of Form N-2 of the citric acid cocrystal as a white solid in needles.

[0197] The N-2 form of the citric acid cocrystal of the compound of formula (I) contains 1 molecule of the compound of formula (I) per molecule of citric acid (1:1).

[0198] The N-2 form of the citric acid cocrystal of the compound of formula (I) gave the PXRD pattern shown in Figure 12, the DSC shown in Figure 13, and the TGA shown in Figure 14.

[0199] The N-2 form of the citric acid cocrystal of the compound of formula (I) has a PXRD with selected 2θ at 4.6, 14.6, 16.4, 21.0, and 25.2 (all peaks at 2θ ± 0.2 degrees). The PXRD was obtained at room temperature, and the diffraction peak positions (2θ ± 0.2 degrees) are based on high-quality patterns collected with a diffractometer (CuKα) with a spinning capillary, where 2θ was calibrated with a NIST appropriate standard.

[0200] The N-2 form of the citrate cocrystal of the compound of formula (I) has a PXRD having selected 2θ at 4.6, 5.5, 8.4, 11.3, 14.6, 16.4, 21.0, 24.2, and 25.2 (all peaks at 2θ ± 0.2 degrees). The PXRD was obtained at room temperature, and the diffraction peak positions (2θ ± 0.2 degrees) are based on a high-quality pattern collected with a diffractometer (CuKα) with a rotating capillary, where 2θ was calibrated with a NIST appropriate standard.

[0201] The N-2 form of the citrate cocrystal is further characterized by a PXRD having 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.

[0202] The N-2 form of the citrate cocrystal is further characterized by a PXRD having 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.

[0203] Single crystal X-rays of the N-2 form of the citrate cocrystal of the compound of formula (I) were obtained and yielded the following results:

[0204]

[0205] The atomic coordinates for the single crystal X-rays of the N-2 form of the citrate cocrystal are shown in Table 5.

[0206] Table 5

[0207]

[0208]

[0209]

[0210]

[0211] The DSC of the N-2 form of the citrate cocrystal showed a variable endotherm at about 180 °C, indicating that the variable melt has decomposition. The TGA of the succinate cocrystal showed negligible weight loss up to 150 °C.

[0212] The analytical data for each of the cocrystals described herein was obtained using the following procedures.

[0213] Single crystal data

[0214] For the citric acid cocrystal form disclosed herein, diffraction data at room temperature were collected using a Bruker X8 APEX II CCD diffractometer equipped with a MICROSTAR-H microfocus rotating anode X-ray generator with monochromatic Cu Kα radiation For the succinic acid cocrystal form, diffraction data at room temperature were collected using a Bruker X8 ProspectorUltra diffractometer equipped with an IμS microfocus X-ray source and an APEX II detector with monochromatic Cu Kα radiation The measured intensity data were indexed and processed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, Wisconsin 53711 USA). The final unit cell parameters were determined using the complete data set. The structure was solved by direct methods and refined by full-matrix least-squares methods using the SHELXTL software package (G. M. Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, Wisconsin, USA). Structure refinement involved minimizing the function defined by ∑w(|F o |-|F c |) 2 where w is an appropriate weighting factor based on the observed intensity errors, F o is the structure factor based on the measured reflections, and F c is the structure factor based on the calculated reflections. The agreement between the refined crystal structure model and the experimental X-ray diffraction data was evaluated using the residual factors R = ∑||F o |-|F c || / ∑|F o | and wR = [∑w(|F o |-|F c |) 2 / ∑w|F o |] 1 / 2 Difference Fourier maps were examined at all stages of the refinement. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were generally calculated using idealized geometries, refined isotropically, and included in the structure factor calculations with fixed parameters. There were a few exceptions where hydrogen atoms were located from difference Fourier maps and refined isotropically, such as the acidic hydrogen atoms of succinic acid in the cocrystal structure.

[0215] PXRD

[0216] PXRD data was obtained using a Bruker C2 GADDS (General Area Detector Diffraction System). The radiation was CuKα (40 KV, 40 mA). The sample-detector distance was 15 cm. The sample was placed in a sealed glass capillary with a diameter ≤ 1 mm. The capillary was rotated during data collection. Transmission data was collected for approximately 2 ≤ 2θ ≤ 32°, where the sample exposure time was at least 1000 seconds. The resulting two-dimensional diffraction arcs were integrated to create a conventional 1-D PXRD pattern with a step size of 0.05 degrees 2θ in the approximate range of 2 to 32 degrees 2θ.

[0217] DSC

[0218] DSC data was generated using a TA model Q2000, Q1000, or 2920. Measurements were made using a standard TA Instruments hermetic pan. Measurements were carried out from room temperature to 300 °C at a heating rate of 10 °C / min in a nitrogen atmosphere, with a sample amount of approximately 2 - 10 mg. The DSC plot was drawn with endothermic peaks pointing downwards.

[0219] TGA

[0220] TGA data was generated using a TA model Q5000, Q500, or 2950. Measurements were made using a standard TA Instruments platinum pan. Measurements were carried out from room temperature to 300 °C at a heating rate of 10 °C / min in a nitrogen atmosphere, with a sample amount of approximately 10 - 30 mg.

[0221] Solid-state nuclear magnetic resonance (SSNMR)

[0222] All solid-state C-13 NMR measurements were performed using a Bruker DSX-400, 400 MHz NMR spectrometer. High-resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramped amplitude cross polarization (RAMP-CP) 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 the sample loaded into a zirconia rotor designed for the can was used for each experiment. The chemical shift (δ) reference high-frequency resonance was set to an external adamantane at 38.56 ppm (W.L. Earl and D.L. VanderHart, J. Magn. Reson., 1982, 48, 35 - 54).

[0223] Raman spectroscopy

[0224] using an IS50 FT-Raman spectrometer, at 4 cm-1 The Raman spectra were obtained with a resolution of 64 co-added scans. The wavelength of laser excitation was 1064 nm. A CaF2 beam splitter and a high-sensitivity InGaS detector were used.

[0225] IR spectroscopy

[0226] The IR spectra were obtained with a resolution of 4 cm -1 using an IS50 FT-IR spectrophotometer, in combination with a KBr beam splitter and a DTGS detector, with 64 co-added scans. Sample preparation was carried out by attenuated total reflection (ATR) using a single bounce diamond ATR sampling accessory. An ATR correction step was included to correct the path length.

[0227] Dissolution data:

[0228] Dissolution tests were performed on the free form of the compound of formula (I), the N-1 form of the citric acid cocrystal of the compound of formula (I), and the dissolution of the succinic acid cocrystal of the compound of formula (I). Dissolution characteristics, rates, and extents; and peak solubility were tested in FaSSIF (fasted state simulated intestinal fluid).

[0229] This experiment was carried out on a pION Microdissolution Profiler TM The pION Microdissolution Profiler TM is an API-sparing low-volume dissolution instrument with a UV fiber optic (UVFO) probe (to measure real-time dissolution profiles in biorelevant media). The experiment was run under the following conditions:

[0230] Instrument: pIon Microdissolution Analyzer

[0231] Medium: FaSSIF, pH 6.5

[0232] Volume: 15 mL at 37 °C

[0233] Stirring: 150 rpm, with a small stir bar

[0234] Dose: API powder, at 0.2 mg / mL or 3 mg / vial

[0235] Study duration: 180 min

[0236] Time points: Capture the initial dissolution rate and several time points throughout 180 min (a typical time for absorption)

[0237] The results were analyzed using UVFO Analysis: standard curve range 0 - 3 μg / mL; 10 mm path length probe window; detection wavelength 315 nm; slope approximately 17 μg / mL / AU; R2 = 0.99.

[0238] The results are shown in Figure 15 and Table 6 below.

[0239] The succinic acid cocrystal and the citric acid cocrystal both dissolve better in FaSSIF than the free form. The dissolution rate, AUC (extent of dissolution), and peak solubility of the citric acid cocrystal are 3 - 4 times those of the succinic acid cocrystal.

[0240] In vivo performance:

[0241] To demonstrate the ability of the cocrystals to be absorbed, a pharmacokinetic study was conducted in a canine model. The cocrystals were tested using the following formulations:

[0242] 1. Succinic acid cocrystal capsules (5 mg dose) - fasted dogs pretreated with pentagastrin

[0243] 2. Citric acid cocrystal capsules (5 mg dose) - fasted dogs pretreated with pentagastrin The study design was as follows:

[0244] A crossover was performed in 4 fasted male dogs (approximately 10 kg); dose 5 mg / dog; flushed with 50 mL of water; a 2 - week washout between treatments; 8 blood sampling points for each treatment.

[0245] The results are shown in Table 7 and Figure 16.

[0246] The citric acid cocrystal and the succinic acid cocrystal showed measurable systemic absorption in the canine model at relevant doses. The bioavailability was in the range of 32% - 55% relative to a well - absorbed reference formulation.

[0247] The PK variability (%CV) of both cocrystal capsules was high, mainly due to one dog showing very low / undetectable blood levels.

[0248] In view of the above teachings, many modifications and variations to the present invention are possible. Accordingly, it is to be understood that within the scope of the appended claims, the invention may be practiced in a manner different from that specifically described herein.

[0249] 。

Claims

1. A eutectic of a compound of formula (I) and a co-former, wherein the co-former is citric acid, wherein the ratio of the compound of formula (I) to citric acid is 1:1, and wherein the eutectic is in the N-1 form and is characterized by one or more of the following: a) a single crystal structure having unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P-1 Cell scale α = 94 ± 1° β＝98±1° γ = 98 ± 1° Volume Formula units / cell 2; b) a PXRD pattern substantially as shown in Figure 6; and / or c) Comprising at room temperature and A PXRD pattern having four or more 2θ values selected from the following: 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, obtained 2. The eutectic according to claim 1, wherein the eutectic is characterized by a single crystal structure having unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P-1 Cell scale α = 94 ± 1° β＝98±1° γ = 98 ± 1° Volume Formula units / cell 2.

3. The eutectic according to claim 1, wherein the eutectic is characterized by a PXRD pattern substantially as shown in Figure 6.

4. The eutectic according to claim 1, wherein the eutectic is characterized by comprising a PXRD pattern having four or more 2θ values selected from the following obtained at room temperature and 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.

2.

5. The eutectic according to claim 1, wherein the eutectic is characterized by comprising a PXRD pattern having five or more 2θ values selected from the following obtained at room temperature and 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.

6. The eutectic according to claim 1, wherein the eutectic is characterized by comprising a PXRD pattern having six or more 2θ values selected from the following obtained at room temperature and 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.

7. The eutectic according to claim 1, wherein the eutectic is characterized by an FT-IR spectrum having peaks at 1585.7, 1725.9, and 3150.5 cm -1 (±0.4 cm -1 ).

8. The eutectic according to claim 1, wherein the eutectic is characterized by an FT-IR spectrum substantially as shown in Figure 11.

9. The eutectic according to claim 1, wherein the eutectic is characterized by an FT-Raman spectrum having peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6, and 2978.9 cm -1 (±0.3 cm -1 ).

10. The eutectic according to claim 1, wherein the eutectic is characterized by an FT-Raman spectrum substantially as shown in Figure 9.

11. The eutectic according to any one of claims 1-10, which is in a substantially pure form.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the eutectic according to any one of claims 1-10, alone or in combination with another therapeutic agent.

13. The pharmaceutical composition according to claim 12, wherein the eutectic is in a substantially pure form.

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