Highly soluble salts

Abstract

The present invention relates to a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), (I). The present invention also concerns certain formulations comprising the compound.

Description

[0001] TITLE

[0002] Highly soluble salts

[0003] TECHNICAL FIELD

[0004] The present invention relates to novel salts and crystalline forms of a compound of formula (I). Furthermore, the present invention concerns the compound of formula (I) in solution or as a solid for use in pharmaceutical compositions for treating a mammal, such as a human subject, suffering from or diagnosed with, for instance, atrial fibrillation.

[0005] BACKGROUND ART

[0006] The heart is a muscle, which pumps the blood in the circulation by contracting 1-3 times per second. The heartbeat is caused by simultaneous contraction of the individual cardiac muscle cells (cardiac myocytes). The synchronization of the cellular contraction is governed by the electrical cardiac impulse (the cardiac action potential), which is generated in the pacemaker cells of the sine node and spreads rapidly over the heart through a specific conduction system.

[0007] Disturbances in the generation of the impulse and the conduction of impulse may occur either as a consequence of a disease, a drug treatment, or electrolyte imbalances. Such disturbances in the impulse are called arrhythmia or dysrythmia and they may lead to unease, emboli, syncope or sudden death. In its simplest form, an arrhythmia covers everything different from a normal cardiac sinus rhythm. Disturbances can cover anything from simple palpitations to devastating ventricular fibrillation including bradycardia and tachycardia.

[0008] At a molecular level a group of proteins called ion channels underlie the electrical events in the heart since they are able to conduct electrical currents across the cell membrane. Different types of ion channels are thus instrumental in the generation and conduction of the cardiac action potential, in the regulation of the heart rate by the autonomic nervous system, and in the contractile process in the individual heart cells. The different types of ion channels are therefore evident targets for anti -arrhythmic cardiac drugs, and many anti-arrhythmic drugs on the market do exert their effect by interacting with ion channels.

[0009] Anti -arrhythmic drugs are usually divided into four main classes according to the so-called Singh Vaughan Williams classification: Class I compounds all inhibit the cardiac voltage-dependent sodium channel. Some Class I compounds do have additional effects influencing the cardiac action potential being the basis for a further subdivision into three subclasses: Class IA compounds are sodium channel inhibitors such as Quinidine, Procainamide or Disopyramid, which prolong the action potential;

[0010] Class IB compounds are sodium channel inhibitors such as Lidocaine, Mexiletine, Tocainide or Phenytoine, which shorten the action potential; and

[0011] Class IC compounds are sodium channel inhibitors such as Flecainide, Moricizine or Propafenone, which do not change the action potential duration.

[0012] Class II compounds are P-adrenoceptor inhibitors and include drugs like Atenolol, Metoprolol, Timolol or Propranolol. P-adrenoceptor inhibitors can be selective for cardiac pi- receptors or have affinity for pi - as well as p2-receptors.

[0013] Class III compounds are potassium channel inhibitors such as Amiodarone, Dronedarone, Sotalol, Ibutilide and Dofetilide, which prolong the action potential.

[0014] Class IV compounds are inhibitors of L-type calcium channels such as Verapamil. Small-conductance calcium-activated potassium (SK) channels belongs to the family of Ca2+- activated K+channels. Three SK channel subtypes have been cloned: SKI, SK2 and SK3 (corresponding to KCNN1-3 using the genomic nomenclature). The activity of these channels is determined by the concentration of free intracellular calcium ([Ca2+]i) via calmodulin that is constitutively bound to the channels. SK channels are widely expressed in the central nervous system (CNS) and in peripheral tissue, including the heart.

[0015] An SK channel inhibitor is a pharmaceutical agent that impairs the conduction of potassium ions (K+) through Ca2+-activated small conductance K+channels. A review of SK channels and SK channel modulators may be found in Wulff H et al.: "Modulators of Small- and Intermediate- Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications", Currrent Medicinal Chemistry 2007 14 1437-1457; and in Liegeois J-F et al.: ’’Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry”, Current Medicinal Chemistry 2003 10 625-647.

[0016] Based on the important role of SK channels in linking [Ca2+]i and membrane potential, SK channels are interesting targets for developing novel therapeutic agents, and the potential of inhibitors of SK channels for use in anti-arrhythmic treatment has been established, see e.g. Nattel S; J. Physiol. 2009 587 1385-1386; Diness JG, Sorensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS; Circ. Arrhythm. Electrophysiol. 2010 3 380-90; and Diness et al; Hypertension 2011 57 1129-1135. In International patent application with publication number WO2017 / 144183 are described inhibitors or negative modulators of the small-conductance calcium activated potassium (SK) channel. Some of these compounds also have physicochemical properties suitable for a drug substance and important for making pharmaceutical formulations. Further, some of these compounds have pharmacokinetic properties making them suitable for using as pharmaceutical drugs. A particular useful compound is described in example 56 of WO2017 / 144183 that is the compound of formula (I)

[0017] (I).

[0018] SUMMARY OF THE DISCLOSURE

[0019] The present invention relates to a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I)

[0020] (I).

[0021] The salts are very soluble in water and / or in a water and lactic acid mixture. In particular, the lactate salt, the hydrochloride salt, the succinate salt, the citrate salt and the maleate salt all have a solubility in water at room temperature of at least 1 mg / mL (milligram per milliliter) and some of them even have a solubility in water at room temperature of at least 4 mg / mL. The free base of the compound of formula (I) has a relative low solubility in water at room temperature of less than 0.5 mg / mL, however, when lactic acid is added, either alone or as the lactic acid salt of the compound of formula (I) the solubility increases dramatically. The solubility of the hydrochloride salt, tartrate salt, succinate salt, citrate salt and / or maleate salt of the compound of formula (I) in water at room temperature increases when lactic acid is added, either alone or as the lactic acid salt of the compound of formula (I), and in some instances increases the solubility more than 50%.

[0022] In an embodiment the compound is a solid form, such as amorphous, semi -amorphous, semi -crystalline or crystalline form. In a further embodiment the compound is a crystalline form.

[0023] In a still further embodiment, the compound is selected from the group consisting of salts obtainable by reaction of the compound of formula (I) with an acid selected from lactic acid, HC1, tartaric acid, succinic acid, citric acid and maleic acid.

[0024] In a further embodiment the compound is selected from the group consisting of a lactic acid salt, hydrochloride salt, a hemi-tartrate salt, a hemi-succinate salt, a hemi -citrate salt and a hemi-maleate salt.

[0025] In a still further embodiment, the compound is a lactic acid salt that is in a solid form, preferably a crystalline form that is characterized by the following XRPD peaks: 3.2200 Pos. [°2Th.], 5.6248 Pos. [°2Th.], 19.2321 Pos. [°2Th.] and 25.3221 Pos. [°2Th.].

[0026] In a further embodiment the compound is a HC1 salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks: 5.5121 Pos. [°2Th.], 6.3516 Pos. [°2Th.], 7.1200 Pos. [°2Th.], 7.6005 Pos. [°2Th.], 8.9006 Pos. [°2Th.], 9.5707 Pos. [°2Th.], 10.8783 Pos. [°2Th.], 12.6826 Pos. [°2Th.], 13.5397 Pos. [°2Th.], 14.7076 Pos. [°2Th.], 15.3655 Pos. [°2Th.], 15.6498 Pos. [°2Th.], 16.1771 Pos. [°2Th.], 16.3977 Pos. [°2Th.], 16.7038 Pos. [°2Th.], 17.7137 Pos. [°2Th.], 17.9872 Pos. [°2Th.], 18.4715 Pos. [°2Th.], 19.1970 Pos. [°2Th.], 19.3342 Pos. [°2Th.], 19.8371 Pos. [°2Th.], 20.1291 Pos. [°2Th.], 20.6847 Pos. [°2Th.], 21.5920 Pos. [°2Th.], 22.1415 Pos. [°2Th.], 22.9190 Pos. [°2Th.], 24.3724 Pos. [°2Th.], 25.0984 Pos. [°2Th.], 25.4518 Pos. [°2Th.], 26.0917 Pos. [°2Th.], 26.4768 Pos. [°2Th.], 27.0813 Pos. [°2Th.], 27.3489 Pos. [°2Th.], 28.3910 Pos. [°2Th.], 30.0421 Pos. [°2Th.], 31.3214 Pos. [°2Th.], 31.9249 Pos. [°2Th.], 33.1039 Pos. [°2Th.].

[0027] In a still further embodiment the compound is a hemi-tartrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks: 5.4038 Pos. [°2Th.], 6.1493 Pos. [°2Th.], 7.3131 Pos. [°2Th.], 9.1195 Pos. [°2Th.], 10.0257 Pos. [°2Th.], 11.1230 Pos. [°2Th.], 12.7984 Pos. [°2Th.], 13.8675 Pos. [°2Th.], 14.6409 Pos. [°2Th.], 15.4125 Pos. [°2Th.], 16.1065 Pos. [°2Th.], 17.3943 Pos. [°2Th.], 18.3377 Pos. [°2Th.], 18.6233 Pos. [°2Th.], 19.1123 Pos. [°2Th.], 19.3903 Pos. [°2Th.], 19.6856 Pos. [°2Th.], 20.1147 Pos. [°2Th.], 20.5016 Pos. [°2Th.], 20.8607 Pos. [°2Th.], 21.8794 Pos. [°2Th.], 22.4461 Pos. [°2Th.], 23.9178 Pos. [°2Th.], 24.3693 Pos. [°2Th.], 24.9312 Pos. [°2Th.], 25.5910 Pos. [°2Th.], 26.7010 Pos. [°2Th.], 28.0426 Pos. [°2Th.], 29.3745 Pos. [°2Th.], 29.7308 Pos. [°2Th.], 30.7073 Pos. [°2Th.], 31.2874 Pos. [°2Th.], 32.6855 Pos. [°2Th.], 33.6562 Pos. [°2Th.], 34.2587 Pos. [°2Th.].

[0028] In a further embodiment the compound is a hemi-succinate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks: 5.6580 Pos. [°2Th.], 7.3357 Pos. [°2Th.], 8.1986 Pos. [°2Th.], 10.7259 Pos. [°2Th.], 11.6171 Pos. [°2Th.], 12.2091 Pos. [°2Th.], 12.4728 Pos. [°2Th.], 12.9965 Pos. [°2Th.], 13.7663 Pos. [°2Th.], 14.7434 Pos. [°2Th.], 15.8677 Pos. [°2Th.], 16.4811 Pos. [°2Th.], 17.0683 Pos. [°2Th.], 18.0981 Pos. [°2Th.], 18.4433 Pos. [°2Th.], 18.8245 Pos. [°2Th.], 19.0046 Pos. [°2Th.], 19.9192 Pos. [°2Th.], 21.0571 Pos. [°2Th.], 21.4078 Pos. [°2Th.], 22.3724 Pos. [°2Th.], 22.9593 Pos. [°2Th.], 23.8409 Pos. [°2Th.], 24.1665 Pos. [°2Th.], 24.5771 Pos. [°2Th.], 24.8406 Pos. [°2Th.], 25.1205 Pos. [°2Th.], 25.5645 Pos. [°2Th.], 25.8133 Pos. [°2Th.], 26.2217 Pos. [°2Th.], 26.4674 Pos. [°2Th.], 26.5978 Pos. [°2Th.], 27.7801 Pos. [°2Th.], 27.9340 Pos. [°2Th.], 29.7462 Pos. [°2Th.], 30.3368 Pos. [°2Th.], 30.9059 Pos. [°2Th.], 31.1610 Pos. [°2Th.], 32.0284 Pos. [°2Th.], 32.4917 Pos. [°2Th.], 33.0368 Pos. [°2Th.], 34.7039 Pos. [°2Th.].

[0029] In a still further embodiment the compound is a hemi -citrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks: 5.5866 Pos. [°2Th.], 7.1866 Pos. [°2Th.], 8.6152 Pos. [°2Th.], 9.5965 Pos. [°2Th.], 11.0629 Pos. [°2Th.], 14.4306 Pos. [°2Th.], 16.0686 Pos. [°2Th.], 16.6580 Pos. [°2Th.], 17.7791 Pos. [°2Th.], 18.3213 Pos. [°2Th.], 19.4935 Pos. [°2Th.], 20.3765 Pos. [°2Th.], 21.0489 Pos. [°2Th.], 21.7831 Pos. [°2Th.], 23.9648 Pos. [°2Th.], 26.3998 Pos. [°2Th.], 26.6610 Pos. [°2Th.], 27.1403 Pos. [°2Th.], 28.0543 Pos. [°2Th.].

[0030] In a further embodiment the compound is a hemi-maleate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks: 5.6099 Pos. [°2Th.], 6.7751 Pos. [°2Th.], 8.2693 Pos. [°2Th.], 14.0558 Pos. [°2Th.], 17.7186 Pos. [°2Th.], 18.9592 Pos. [°2Th.], 20.2532 Pos. [°2Th.], 22.6761 Pos. [°2Th.], 24.4336 Pos. [°2Th.], 24.9746 Pos. [°2Th.], 26.2849 Pos. [°2Th.], 28.0237 Pos. [°2Th.], 29.7648 Pos. [°2Th.]. In a still further embodiment, the compound is a salt that is obtainable by a process comprising: a) adding lactic acid, HC1, tartaric acid, succinic acid, citric acid or maleic acid as a solution or as a suspension, to the compound in formula (I) as a free base or a salt thereof, such as a solid, as a solution or as a suspension, to provide a solution or a suspension of the corresponding salt; b) obtaining the salt as a solid by precipitation or crystallization, such as by cooling, evaporation of solvent, addition of an antisolvent or addition to an antisolvent, or by addition of a co-crystallizing agent, followed by filtration or centrifugation and optionally purifying the salt.

[0031] In a further embodiment the compound is a salt that is obtainable by the process as described in the experimental section herein.

[0032] In a still further embodiment, the compound has a solubility in a solution mixture of water and lactic acid at room temperature of at least 5 mg / mL, such as from 5-20 mg / mL.

[0033] In a further aspect the present invention relates to a compound of formula (I) selected from a crystalline Form B that is characterized by the following XRPD peaks: 5.4583 Pos. [°2Th.], 8.6494 Pos. [°2Th.], 9.4935 Pos. [°2Th.], 9.9758 Pos. [°2Th.], 11.0201 Pos. [°2Th.], 11.6273 Pos. [°2Th.], 12.2790 Pos. [°2Th.], 13.2330 Pos. [°2Th.],

[0034] 14.5131 Pos. [°2Th.], 14.6913 Pos. [°2Th.], 16.0913 Pos. [°2Th.], 16.6654 Pos. [°2Th.],

[0035] 17.3892 Pos. [°2Th.], 17.8785 Pos. [°2Th.], 20.0832 Pos. [°2Th.], 20.7572 Pos. [°2Th.],

[0036] 21.1411 Pos. [°2Th.], 21.8912 Pos. [°2Th.], 22.9346 Pos. [°2Th.], 23.3471 Pos. [°2Th.],

[0037] 23.7332 Pos. [°2Th.], 24.4525 Pos. [°2Th.], 25.4370 Pos. [°2Th.], 25.6615 Pos. [°2Th.],

[0038] 26.7014 Pos. [°2Th.], 27.3638 Pos. [°2Th.], 27.8805 Pos. [°2Th.], 30.2132 Pos. [°2Th.]. In a further aspect the present invention concerns a pharmaceutical composition comprising the compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiments of the compound of the present invention and optionally a pharmaceutically acceptable additive, such as carrier or excipient.

[0039] In a further embodiment the pharmaceutical composition is a solid oral form, such as a tablet. In some embodiments the solid oral composition is a tablet comprising from 10 mg to 100 mg of the compound of formula (I) or any one of the salts described herein, such as from 20-80 mg, preferably from 30-70 mg, such as 50 mg of the compound of formula (I).

[0040] In another embodiment the pharmaceutical composition is a liquid solution, such as an Intravenous (IV) solution.

[0041] In a further aspect the present invention concerns a liquid composition, such as an Intravenous (IV) solution, comprising a compound of formula (I) and lactic acid, and optionally an acid selected from HC1, tartaric acid, succinic acid, citric acid and maleic acid, and optionally a water-soluble PEG, such as PEG400. In an embodiment the composition is an IV solution for infusion comprising from 1 mg / mL to 10 mg / mL of the compound of formula (I), such as from 2-8 mg / mL, preferably 5-8 mg / mL, more preferred 8-10 mg / mL.

[0042] In another embodiment the composition is a liquid concentrate for the solution for infusion comprising from 10 mg / mL to 200 mg / mL of the compound of formula (I), such as from 10-50 mg / mL, preferably 50-100 mg / mL, more preferred 100-200 mg / mL.

[0043] In a further aspect the present invention concerns a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiments of the compound of the present invention, for use in a method for treating a cardiac disease, disorder or condition in a mammal, such as a human.

[0044] In a still further aspect the present invention concerns a composition comprising the compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiment of the composition of the present invention, for use in a method for treating a cardiac disease, disorder or condition in a mammal, such as a human.

[0045] In a further aspect the present invention concerns a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiment of the compound of the present invention, for use in a method for treating the cardiac disease, disorder or condition wherein the disease, disorder or condition is associated with an abnormal rhythm of the heart.

[0046] In a still further aspect the present invention concerns a composition comprising the compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiment of the composition of the present invention, for use in a method for treating the cardiac disease, disorder or condition wherein the disease, disorder or condition is associated with an abnormal rhythm of the heart.

[0047] In a further aspect the present invention concerns a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiment of the compound of the present invention, for use in a method for treating the cardiac disease, disorder or condition selected from the group consisting of cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmias, and an abnormal rhythm arising after cardiac surgery or a cardiac ablation procedure.

[0048] In a still further aspect the present invention concerns a composition comprising the compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I), as well as any one of the above embodiment of the composition of the present invention, for use in a method for treating the cardiac disease, disorder or condition selected from the group consisting of cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmias, and an abnormal rhythm arising after cardiac surgery or a cardiac ablation procedure.

[0049] DETAILED DESCRIPTION

[0050] The present invention relates to a compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I)

[0051] (i); as well as a stable polymorph of the compound of formula (I) free base named Form B. Form B and the salts are very soluble in water and / or in a water and lactic acid mixture, which provides unique formulation options as described herein.

[0052] In a still further embodiment, the compound is a lactic acid salt that is in a solid form, preferably a crystalline form that is characterized by the following XRPD peaks:

[0053] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0054] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0055] 3.2200 38.79 0.6140 27.43966 14.38 0.7368

[0056] 5.6248 269.66 0.6140 15.71220 100.00 0.7368

[0057] 19.2321 75.52 0.2558 4.61515 28.01 0.3070

[0058] 25.3221 35.36 0.6140 3.51732 13.11 0.7368

[0059] The above XRPD details identifies the specified salt, however, as described herein the salt was not only crystalline but rather had an amorphous composition as well. In a further embodiment the compound is a HC1 salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks:

[0060] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0061] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0062] 5.5121 1 6 ()33 1 251.82 o .1842

[0063] 6.3516 67.21 0.1535 13.91582 5.14 0.1842

[0064] 7.1200 203.28 0.0768 12.41566 15.56 0.0921

[0065] 7.6005 1306.47 0.1023 11.63186 100.00 0.1228

[0066] 8.9006 297.19 0.1023 9.93550 22.75 0.1228

[0067] 9.5707 364.72 0.1279 9.24131 27.92 0.1535

[0068] 10.8783 300.89 0.0768 8.13320 23.03 0.0921

[0069] 12.6826 374.19 0.1023 6.97993 28.64 0.1228

[0070] 13.5397 253.78 0.1023 6.53995 19.42 0.1228

[0071] 14.7076 87.76 0.2047 6.02312 6.72 0.2456

[0072] 15.3655 104.48 0.1535 5.76671 8.00 0.1842

[0073] 15.6498 100.67 0.0768 5.66259 7.71 0.0921

[0074] 16.1771 324.25 0.1023 5.47915 24.82 0.1228

[0075] 16.3977 177.77 0.0768 5.40596 13.61 0.0921

[0076] 16.7038 92.48 0.2047 5.30757 7.08 0.2456

[0077] 17.7137 427.34 0.0768 5.00719 32.71 0.0921

[0078] 17.9872 370.34 0.1023 4.93166 28.35 0.1228

[0079] 18.4715 101.63 0.1535 4.80344 7.78 0.1842

[0080] 19.1970 686.01 0.1023 4.62350 52.51 0.1228

[0081] 19.3342 816.48 0.1023 4.59100 62.50 0.1228

[0082] 19.8371 356.89 0.1023 4.47574 27.32 0.1228

[0083] 20.1291 221.49 0.0768 4.41146 16.95 0.0921

[0084] 20.6847 467.79 0.2047 4.29421 35.81 0.2456

[0085] 21.5920 181.23 0.3070 4.11578 13.87 0.3684

[0086] 22.1415 425.94 0.1023 4.01486 32.60 0.1228 22.9190 139.58 0.1535 3.88039 10.68 0.1842

[0087] 24.3724 147.95 0.1535 3.65219 11.32 0.1842

[0088] 25.0984 186.36 0.1535 3.54816 14.26 0.1842

[0089] 25.4518 742.87 0.1535 3.49969 56.86 0.1842

[0090] 26.0917 636.37 0.1279 3.41530 48.71 0.1535

[0091] 26.4768 620.18 0.1279 3.36649 47.47 0.1535

[0092] 27.0813 465.80 0.1535 3.29270 35.65 0.1842

[0093] 27.3489 268.39 0.1279 3.26108 20.54 0.1535

[0094] 28.3910 247.19 0.1023 3.14371 18.92 0.1228

[0095] 30.0421 54.01 0.4093 2.97459 4.13 0.4912

[0096] 31.3214 26.70 0.1791 2.85595 2.04 0.2149

[0097] 31.9249 73.30 0.2047 2.80333 5.61 0.2456

[0098] 33.1039 67.94 0.2047 2.70614 5.20 0.2456

[0099] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %).

[0100] In a still further embodiment, the compound is a hemi-tartrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks

[0101] Pos. Height FWHM d-spacing Ret Int. Tip width

[0102] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0103] 5.4038 191.80 0.3070 16.35439 5.67 0.3684

[0104] 6.1493 1235.64 0.1279 14.37320 36.51 0.1535

[0105] 7.3131 1083.74 0.1023 12.08821 32.02 0.1228

[0106] 9.1195 447.76 0.1279 9.69750 13.23 0.1535

[0107] 10.0257 375.12 0.1279 8.82292 11.08 0.1535

[0108] 11.1230 170.69 0.1023 7.95487 5.04 0.1228

[0109] 12.7984 696.38 0.1535 6.91703 20.58 0.1842

[0110] 13.8675 78.73 0.2558 6.38608 2.33 0.3070

[0111] 14.6409 258.60 0.2558 6.05043 7.64 0.3070 15.4125 276.38 0.1023 5.74922 8.17 0.1228

[0112] 16.1065 3384.44 0.1279 5.50303 100.00 0.1535

[0113] 17.3943 93.44 0.2047 5.09841 2.76 0.2456

[0114] 18.3377 671.23 0.1279 4.83818 19.83 0.1535

[0115] 18.6233 567.29 0.1279 4.76463 16.76 0.1535

[0116] 19.1123 538.19 0.1535 4.64380 15.90 0.1842

[0117] 19.3903 1326.32 0.1279 4.57786 39.19 0.1535

[0118] 19.6856 561.19 0.1023 4.50984 16.58 0.1228

[0119] 20.1147 460.63 0.1279 4.41460 13.61 0.1535

[0120] 20.5016 1125.27 0.1791 4.33215 33.25 0.2149

[0121] 20.8607 508.57 0.1279 4.25837 15.03 0.1535

[0122] 21.8794 356.20 0.1535 4.06236 10.52 0.1842

[0123] 22.4461 270.59 0.1023 3.96106 8.00 0.1228

[0124] 23.9178 476.34 0.1535 3.72056 14.07 0.1842

[0125] 24.3693 147.66 0.1535 3.65265 4.36 0.1842

[0126] 24.9312 90.91 0.1535 3.57157 2.69 0.1842

[0127] 25.5910 1975.84 0.1535 3.48097 58.38 0.1842

[0128] 26.7010 996.70 0.1535 3.33873 29.45 0.1842

[0129] 28.0426 536.54 0.1535 3.18198 15.85 0.1842

[0130] 29.3745 254.73 0.2558 3.04066 7.53 0.3070

[0131] 29.7308 405.56 0.1791 3.00502 11.98 0.2149

[0132] 30.7073 176.48 0.2047 2.91166 5.21 0.2456

[0133] 31.2874 34.02 0.2558 2.85898 1.01 0.3070

[0134] 32.6855 59.04 0.1535 2.73982 1.74 0.1842

[0135] 33.6562 69.06 0.2558 2.66298 2.04 0.3070

[0136] 34.2587 194.50 0.1535 2.61752 5.75 0.1842

[0137] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %). In a further embodiment the compound is a hemi-succinate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks:

[0138] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0139] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0140] 5.6580248.27 0.460 15.620135 370.5526

[0141] 7.3357 1278.59 0.0768 12.05103 27.66 0.0921

[0142] 8.1986 930.75 0.0768 10.78462 20.13 0.0921

[0143] 10.7259 390.31 0.1023 8.24844 8.44 0.1228

[0144] 11.6171 318.54 0.1023 7.61756 6.89 0.1228

[0145] 12.2091 1195.65 0.1023 7.24951 25.86 0.1228

[0146] 12.4728 111.63 0.0768 7.09687 2.41 0.0921

[0147] 12.9965 510.82 0.1023 6.81205 11.05 0.1228

[0148] 13.7663 257.44 0.0768 6.43278 5.57 0.0921

[0149] 14.7434 992.59 0.1023 6.00859 21.47 0.1228

[0150] 15.8677 2375.25 0.0768 5.58528 51.38 0.0921

[0151] 16.4811 1275.02 0.1023 5.37878 27.58 0.1228

[0152] 17.0683 34.29 0.1535 5.19503 0.74 0.1842

[0153] 18.0981 729.46 0.1279 4.90169 15.78 0.1535

[0154] 18.4433 454.89 0.1023 4.81071 9.84 0.1228

[0155] 18.8245 949.93 0.0768 4.71415 20.55 0.0921

[0156] 19.0046 1855.28 0.0768 4.66989 40.13 0.0921

[0157] 19.9192 765.19 0.0768 4.45748 16.55 0.0921

[0158] 21.0571 630.18 0.1023 4.21911 13.63 0.1228

[0159] 21.4078 2257.27 0.1023 4.15076 48.82 0.1228

[0160] 22.3724 1920.38 0.1023 3.97394 41.54 0.1228

[0161] 22.9593 4623.33 0.1279 3.87366 100.00 0.1535

[0162] 23.8409 130.20 0.1023 3.73239 2.82 0.1228

[0163] 24.1665 535.22 0.1023 3.68283 11.58 0.1228

[0164] 24.5771 425.12 0.1023 3.62223 9.20 0.1228 24.8406 587.21 0.1023 3.58440 12.70 0.1228

[0165] 25.1205 282.27 0.1023 3.54509 6.11 0.1228

[0166] 25.5645 164.90 0.0768 3.48452 3.57 0.0921

[0167] 25.8133 439.49 0.1023 3.45150 9.51 0.1228

[0168] 26.2217 137.32 0.0768 3.39866 2.97 0.0921

[0169] 26.4674 398.04 0.0936 3.36487 8.61 0.1123

[0170] 26.5978 443.89 0.1023 3.35145 9.60 0.1228

[0171] 27.7801 213.22 0.0768 3.21144 4.61 0.0921

[0172] 27.9340 229.09 0.1279 3.19409 4.96 0.1535

[0173] 29.7462 477.10 0.1279 3.00351 10.32 0.1535

[0174] 30.3368 227.34 0.1535 2.94637 4.92 0.1842

[0175] 30.9059 153.68 0.1023 2.89340 3.32 0.1228

[0176] 31.1610 187.73 0.1023 2.87029 4.06 0.1228

[0177] 32.0284 180.95 0.1279 2.79451 3.91 0.1535

[0178] 32.4917 52.39 0.1535 2.75571 1.13 0.1842

[0179] 33.0368 126.15 0.1535 2.71148 2.73 0.1842

[0180] 34.7039 290.78 0.1535 2.58495 6.29 0.1842

[0181] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %).

[0182] In a still further embodiment, the compound is a hemi-citrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks:

[0183] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0184] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0185] 5.5866 308.12 0.8187 15.81957 56.66 0.9824

[0186] 7.1866 543.81 0.0768 12.30078 100.00 0.0921

[0187] 8.6152 76.87 0.1535 10.26401 14.14 0.1842

[0188] 9.5965 119.79 0.1535 9.21652 22.03 0.1842

[0189] 11.0629 70.65 0.4093 7.99792 12.99 0.4912 14.4306 67.84 0.4093 6.13814 12.48 0.4912

[0190] 16.0686 98.12 0.1535 5.51591 18.04 0.1842

[0191] 16.6580 141.29 0.2047 5.32205 25.98 0.2456

[0192] 17.7791 99.17 0.6140 4.98891 18.24 0.7368

[0193] 18.3213 136.50 0.1023 4.84247 25.10 0.1228

[0194] 19.4935 274.62 0.1023 4.55386 50.50 0.1228

[0195] 20.3765 100.19 0.3070 4.35845 18.42 0.3684

[0196] 21.0489 79.49 0.3070 4.22072 14.62 0.3684

[0197] 21.7831 62.82 0.3070 4.08009 11.55 0.3684

[0198] 23.9648 32.33 0.3070 3.71337 5.95 0.3684

[0199] 26.3998 189.16 0.1279 3.37613 34.78 0.1535

[0200] 26.6610 232.08 0.1279 3.34365 42.68 0.1535

[0201] 27.1403 141.11 0.2303 3.28567 25.95 0.2763

[0202] 28.0543 147.12 0.1535 3.18067 27.05 0.1842

[0203] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %). In a further embodiment the compound is a hemi-maleate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks:

[0204] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0205] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0206] 5.6099 269.50 0.2558 15.75395 100.00 0.3070

[0207] 6.7751 181.65 0.1535 13.04704 67.40 0.1842

[0208] 8.2693 220.06 0.1023 10.69252 81.65 0.1228

[0209] 14.0558 50.99 0.3070 6.30094 18.92 0.3684

[0210] 17.7186 177.74 0.1535 5.00581 65.95 0.1842

[0211] 18.9592 111.52 0.1535 4.68095 41.38 0.1842

[0212] 20.2532 56.65 0.3070 4.38471 21.02 0.3684

[0213] 22.6761 87.40 0.5117 3.92141 32.43 0.6140 24.4336 228.04 0.1535 3.64318 84.62 0.1842

[0214] 24.9746 170.73 0.1023 3.56546 63.35 0.1228

[0215] 26.2849 146.87 0.1791 3.39063 54.50 0.2149

[0216] 28.0237 52.19 0.2047 3.18408 19.37 0.2456

[0217] 29.7648 35.03 0.3070 3.00167 13.00 0.3684

[0218] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %).

[0219] In a further aspect the present invention relates to a compound of formula (I) selected from a crystalline Form B that is characterized by the following XRPD peaks:

[0220] Pos. Height FWHM d-spacing Rel. Int. Tip width

[0221] [°2Th.] [cts] [°2Th.] [A] [%] [°2Th.]

[0222] 5.4583 1771.22 0.2047 16.19110 100.00 0.2456

[0223] 8.6494 1003.10 0.1023 10.22345 56.63 0.1228

[0224] 9.4935 102.08 0.4093 9.31629 5.76 0.4912

[0225] 9.9758 192.58 0.0768 8.86690 10.87 0.0921

[0226] 11.0201 115.51 0.3070 8.02887 6.52 0.3684

[0227] 11.6273 173.52 0.1023 7.61096 9.80 0.1228

[0228] 12.2790 52.39 0.4093 7.20844 2.96 0.4912

[0229] 13.2330 441.04 0.1023 6.69082 24.90 0.1228

[0230] 14.5131 357.19 0.0768 6.10342 20.17 0.0921

[0231] 14.6913 473.13 0.0768 6.02978 26.71 0.0921 16.0913 1035.95 0.1023 5.50820 58.49 0.1228

[0232] 16.6654 363.87 0.2558 5.31971 20.54 0.3070

[0233] 17.3892 878.47 0.1023 5.09989 49.60 0.1228

[0234] 17.8785 941.14 0.1023 4.96140 53.14 0.1228

[0235] 20.0832 651.93 0.1535 4.42144 36.81 0.1842

[0236] 20.7572 462.60 0.1791 4.27937 26.12 0.2149

[0237] 21.1411 598.90 0.1535 4.20252 33.81 0.1842

[0238] 21.8912 716.19 0.1023 4.06019 40.44 0.1228

[0239] 22.9346 550.71 0.2047 3.87778 31.09 0.2456

[0240] 23.3471 387.81 0.1023 3.81019 21.89 0.1228

[0241] 23.7332 678.76 0.1535 3.74908 38.32 0.1842

[0242] 24.4525 549.32 0.1023 3.64041 31.01 0.1228

[0243] 25.4370 491.34 0.1279 3.50170 27.74 0.1535

[0244] 25.6615 574.16 0.0768 3.47157 32.42 0.0921

[0245] 26.7014 233.11 0.1535 3.33867 13.16 0.1842

[0246] 27.3638 227.94 0.1791 3.25935 12.87 0.2149

[0247] 27.8805 229.98 0.1023 3.20011 12.98 0.1228

[0248] 30.2132 162.40 0.3070 2.95813 9.17 0.3684

[0249] The above XRPD details identifies the specified salt, however in some embodiments the characterizing XRPD peaks are selected from the 10 peaks having the highest relative intensity (Rel. Int %). Herein and throughout the description and claims the XRPD details are measured as described in the section Analytical methods below, wherein the specific wavelength type is Kai 1.540598A.

[0250] X-Ray Powder Diffraction (XRPD)Whenever a “compound of formula (I)” or “COMPOUND OF FORMULA (I)” (used interchangeable) shown by the below structure is used herein it means the compound of formula (I) as the free base, unless otherwise indicated herein or clearly contradicted by context. The compound of formula (I) may for instance be in solid form, such as amorphous or crystalline, or on liquid form.

[0251] The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The treatment may either be performed in an acute or in a chronic way. The patient to be treated is preferably a mammal; in particular a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.

[0252] The term “a pharmaceutically acceptable salt” as used herein is used to specify that the salt is suitable for use in the human or animal body. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. A pharmaceutically acceptable salt of a compound of Formula (I) includes such salts that may be formed within the human or animal body after administration of said compound to said human or animal body.

[0253] The term “a therapeutically effective amount” of a compound of formula (I) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.

[0254] As used herein “pharmaceutically acceptable additive” is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.

[0255] The adjuvants, diluents, excipients and / or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person within the art.

[0256] As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier. In some embodiments, the pharmaceutical compositions comprise from 0.1 to 99.9 weight % of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier and from 0.1 to 99.9 weight % of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.

[0257] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.

[0258] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.

[0259] The composition, particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.

[0260] Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

[0261] The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound for use as a medicament’, or ‘compound for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

[0262] All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0263] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0264] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0265] The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. In particular, the terms “a” and “an” and “the” can be exchanged with “at least one” or “one or more” and has such meaning unless clearly contradicted by context.

[0266] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by “about,” where appropriate). All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0267] The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

[0268] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and / or enforceability of such patent documents.

[0269] The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0270] This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.

[0271] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.

[0272] EXAMPLES

[0273] General experimental information

[0274] General abbreviations

[0275] CPME Cyclopentyl methyl ether

[0276] DSC Differential scanning calorimetry Eq Equivalent

[0277] Et Ethyl

[0278] L Liter

[0279] M Molar m milli

[0280] TBME tert-Butyl methyl ether

[0281] TGA Thermo-Gravimetric Analysis

[0282] THF Tetrahydrofuran

[0283] IPA Isopropyl alcohol

[0284] PEG 499 Polyethylene glycol 400

[0285] RT Room temperature

[0286] XRPD X-ray power diffraction

[0287] Analytical methods

[0288] X-Ray Powder Diffraction (XRPD)

[0289] X-Ray Powder Diffraction patterns were collected on a PANalytical diffractometer using Cu Ka radiation (45kV, 40mA), 9 - 9 goniometer, focusing mirror, divergence slit (1 / 2”), seller slits at both incident and divergent beam (4mm) and a PIXcel detector. Herein, the specific wavelength type is Kai 1.549598A. The software used for data collection was X’Pert Data Collector, version 2.2f and the data was presented using X’Pert Data Viewer, version 1.2d. XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimide - Kapton, 12.7pm thickness film) under ambient conditions using a PANalytical X’Pert PRO. The data collection range was 2.994 - 35°29 with a continuous scan speed of 9.2929940s_1.

[0290] Differential Scanning Calorimetry (DSC)

[0291] DSC data was collected on a PerkinElmer Pyris 6999 DSC equipped with a 45° position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 9.5-3.9 mg, was placed in a pin holed aluminium pan and heated at 29°C / min from 39 to 359 °C, or varied as experimentation dictated. A purge of dry nitrogen at 29mL / min was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris Software vl 1.1.1 Revision H. Thermo-Gravimetric Analysis (TGA)

[0292] TGA data were collected on a PerkinElmer Pyris 1 TGA equipped with a 20° position auto-sampler. The instrument was calibrated using a certified weight and certified Alumel and Perkalloy for temperature. A predefined amount of the sample, 1-5 mg, was loaded onto a pre-tared aluminium crucible and was heated at 20°C / min from ambient temperature to 400°C. A nitrogen purge at 20mL / min was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris Software vl 1.1.1 Revision H.

[0293] Example 1 : preparation of compounds of the invention

[0294] Initial screen of salt formation and crystallization

[0295] Ethyl acetate, ethanol and acetonitrile / water (4: 1) were selected as the solvents for the salt screen based on solubility information derived from chemical development performed in-house. A range of acid counter ions were selected based upon the estimated pKa value of COMPOUND OF FORMULA (I) and acceptability / use in marketed drugs. COMPOUND OF FORMULA (I) free base (50 mg) was charged to 36 crystallization tubes followed by the relevant solvent (lmL / 20 volumes). The reaction mixtures were heated to 60°C to achieve dissolution of the compound. To these solutions was dosed the relevant acid either as a IM solution in ethanol or as a solid charge. The mixtures were held at 60°C for one hour and then cooled gradually to RT and equilibrated for 16 hours. For each resulting suspension, the solids were isolated by vacuum filtration and dried in vacuo at 40°C for 16 hours and analyzed by XRPD. For mixtures remaining in solution, the solvent volume was reduced by slow evaporation under nitrogen and, if no precipitation occurred after approximately 50% reduction of the solvent volume, allowed to fully evaporate and diethyl ether or heptane (20 volumes) was added. The solids were isolated by vacuum filtration and dried in vacuo at 40°C for 16 hours and analyzed by XRPD.

[0296] Scale up of selected salt formations

[0297] The initial salt screens identified several crystalline and amorphous salt versions that demonstrated favourable characteristics in terms of aqueous solubility and pH. Experiments were conducted to demonstrate that each salt formation could be successfully reproduced on a larger scale. Each salt formation was conducted on 150 mg of COMPOUND OF FORMULA (I) free base mirroring the successful conditions employed in the initial salt screen. Quantitative solubility investigation in various aqueous media

[0298] An assessment of the solubility of the HC1, hemi-succinate, hemi-maleate, hemi-citrate and hemitartrate salts of COMPOUND OF FORMULA (I) and the COMPOUND OF FORMULA (I) free base in water containing one equivalent of 50 mM lactic acid with and without the inclusion of PEG 400 was conducted. The stability of the compound in aqueous media at RT was also assessed following a period of ageing. Each salt (15 mg) was agitated in aqueous media (A: water / 50 mM lactic acid, B: water / 50 mM lactic acid / 2% w / v PEG 400) (1 mL) for 24 hours at 25°C. Any solids were isolated by vacuum filtration. The COMPOUND OF FORMULA (I) content of the filtrates was determined by HPLC assay. The filtrates were aged for one week with regular observations made for any re-precipitation and chemical purity assessed. The filtrates were aged for a further two weeks and reassessed.

[0299] The results of the solubility assessment are presented below:

[0300] Example 2: Preparation of crystalline forms of the free base of COMPOUND OF FORMULA (I) Saturated solution cooling crystallization

[0301] Solid COMPOUND OF FORMULA (I) (30 mg) was charged to 12 x crystallization tubes. Solvents (ImL) were added. Entries 1-8 (Table below) were heated to 70°C and where a solution was obtained, clarified into pre-warmed tubes and cooled slowly to 25°C and equilibrated for 24 hours. Where dissolution of the material was not achieved, the suspensions were filtered hot to isolate the solids. Entries 9-12 were heated to 40°C for 15 minutes to achieve dissolution and the solutions clarified into pre-warmed tubes, cooled and equilibrated at 25°C for 24 hours. Where suspensions were obtained, the solids were isolated by filtration in vacuo. Solutions were cooled to -5 °C and the solvent volume reduced by 50% to induce precipitation. Solids were dried in vacuo at 55°C for 24 hours. Results and observations of saturated solution cooling crystallizations in various solvents and solvent mixtures are presented below: The solid isolated from THF (Table, Entry 3) had an XRPD pattern that corresponded with form A, characterized by the peaks listed in below:

[0302] Pos. [°2Th.] Height [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]

[0303] 3.4677 580.15 0.8187 25.48014 30.67

[0304] 6.1740 1687.75 0.0768 14.31589 89.22

[0305] 7.3329 737.51 0.0768 12.05568 38.99

[0306] 9.1433 504.37 0.1023 9.67225 26.66 10.0516 464.24 0.1023 8.80024 24.54

[0307] 11.2563 318.16 0.2047 7.86094 16.82

[0308] 11.8181 395.06 0.1535 7.48850 20.89

[0309] 12.2188 222.16 0.0768 7.24381 11.74

[0310] 12.8392 488.54 0.1023 6.89511 25.83

[0311] 13.4004 273.79 0.2047 6.60761 14.47

[0312] 14.5982 590.02 0.1535 6.06804 31.19

[0313] 15.3487 333.64 0.2047 5.77297 17.64

[0314] 16.1663 1891.59 0.1279 5.48279 100.00

[0315] 17.5096 328.61 0.1791 5.06508 17.37

[0316] 18.0144 884.53 0.1279 4.92427 46.76

[0317] 18.3962 842.06 0.1023 4.82291 44.52

[0318] 18.6945 923.65 0.0768 4.74665 48.83

[0319] 19.4459 1287.54 0.1279 4.56488 68.07

[0320] 20.5485 1039.68 0.1535 4.32236 54.96

[0321] 21.2509 1058.34 0.1023 4.18106 55.95

[0322] 21.4986 807.99 0.0768 4.13345 42.71

[0323] 22.7311 474.25 0.2047 3.91203 25.07

[0324] 23.9985 645.70 0.1279 3.70823 34.14

[0325] 24.2805 506.87 0.1023 3.66580 26.80

[0326] 25.6779 1183.94 0.1535 3.46939 62.59

[0327] 26.7805 676.20 0.1791 3.32899 35.75

[0328] 28.1219 316.40 0.1791 3.17318 16.73

[0329] 29.8841 252.67 0.0768 2.98996 13.36

[0330] 30.8148 158.73 0.2047 2.90175 8.39

[0331] 34.3911 89.53 0.2047 2.60774 4.73

[0332] In common with the thermal profiles observed previously, the DSC thermograph of the Form A solid contained a number of thermal events. Thermal analysis by DSC was also obtained for two representative solids that were designated as Form B by XRPD. These solids were isolated from cooling crystallizations in IPA and in ethanol / water.

[0333] These thermal data suggested a single solid phase. The thermal profile of these Form B solids with a much higher melt temperature was more favourable than the thermal profile of Form A and suggested that this was the preferred solid form of the COMPOUND OF FORMULA (I).

[0334] Mixed solvent cooling crystallizations

[0335] Stock solutions of COMPOUND OF FORMULA (I) (150mg) in ethyl acetate (A) (5.63 mL), ethanol (B) (5.63 mL), acetonitrile (1.88 mL) and 3-methyl-2-butanone (5.63 mL) were prepared at 55°C. The solutions were clarified via a 0.45pm syringe filter and aliquots (~25mg active) were charged to pre-warmed tubes. The solutions were equilibrated to 55°C and anti-solvents (0.25 mL) were added slowly. The mixtures were cooled slowly to 25°C and equilibrated for 24 hours. Where suspensions were obtained, the solids were isolated by filtration in vacuo. Solutions were cooled to -5°C and the solvent volume reduced by 50% to induce precipitation. Solids were dried in vacuo at 55°C for 24 hours. Results and observations of mixed solvent crystallizations in various solvents and anti -solvent mixtures are presented below:

[0336] All of the solids resulting from the mixed solvent cooling crystallizations with ethyl acetate and ethanol as solvents were the compound of formula (I) as Form B by XRPD. Notably, the solid returned from the crystallization in ethyl acetate and heptane was single phase Form B by XRPD and DSC.

[0337] Hierarchical equilibrations of forms

[0338] In order to establish the hierarchy of a collection of forms / versions of COMPOUND OF FORMULA (I), competitive equilibrations in a number of solvents were conducted to reveal the preferred form and thereby the metastable versions at a given temperature. Mixtures containing an equal mass of COMPOUND OF FORMULA (I) Form A and Form B were subjected to competitive equilibration in water, IP A, toluene, ethyl acetate, 2 -chlorobutane, benzotrifluoride and CPME. Solids were suspended by agitation and equilibrated at 25 °C for 24 hours. The solids were isolated and dried in vacuo at 55 °C. Results from hierarchical equilibrations of Form A and Form B versions in various solvents at 25 °C are presented in the Table below. Overall, Form B predominated, which further supported its position as the thermodynamically preferred version. Example 3 : Preparation of solid formulation of compounds of the invention.

[0339] Examples of solid formulations were prepared, and three compositions are described in the Table below. Formulations were produced by dissolving the COMPOUND OF FORMULA (I) in the melted vehicle and this mixture poured slowly onto the carrier in a high shear mixer equipped with a l liter bowl, which was cooled with ice. The produced granulate was sieved through Comil sieve 2388, mixed with extra-granular excipients and subsequently compressed.

[0340] Example 4: Preparation of 200 mg / mL concentrate for solution for infusion In one example an appropriate amount of propylene glycol (3500 mL) and lactic acid (315 g) were added to the manufacturing vessel and mixed until the mixture appeared homogenous.

[0341] COMPOUND OF FORMULA (I) (700 g) was added to the mixture during stirring and mixed until all material was dissolved, and the solution appeared as a clear yellowish solution. The bulk solution was filtered through two sterile 0.22 pm membrane filters and filled aseptically into sterile 10 mL injection vials and sealed. This concentrate formulation of 200 mg / mL COMPOUND OF

[0342] FORMULA (I) for solution for infusion is a yellowish viscous solution to be diluted prior to administration in 5% glucose to provide a final 10 mg / mL solution.

Claims

CLAIMS:

1. A compound selected from the group of a lactate salt, a hydrochloride salt, a tartrate salt, a succinate salt, a citrate salt and a maleate salt of the compound of formula (I)2. The compound of claim 1 wherein the compound is a solid form.

3. The compound of claim 1 or 2 wherein the compound is a crystalline form.

4. The compound of any one of the claims 1-3 wherein the compound is selected from the group consisting of salts obtainable by the reaction of the compound of formula (I) with an acid selected from lactic acid, HC1, tartaric acid, succinic acid, citric acid and maleic acid.

5. The compound of any one of the claims 1-4 wherein the compound is selected from the group of a lactic acid salt, hydrochloride salt, a hemi-tartrate salt, a hemisuccinate salt, a hemi -citrate salt and a hemi-maleate salt.

6. The compound of any one of the claims 1-5 wherein the compound is a lactic acid salt that is in a solid form, preferably a form that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 3.2200 Pos. [°2Th.], 5.6248 Pos. [°2Th.], 19.2321 Pos. [°2Th.] and 25.3221 Pos. [°2Th.].

7. The compound of any one of the claims 1-5 wherein the compound is a HC1 salt that is in a crystalline form, preferably a crystalline form that is characterized by thefollowing XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 5.5121 Pos. [°2Th.], 6.3516 Pos. [°2Th.], 7.1200 Pos. [°2Th.], 7.6005 Pos. [°2Th.], 8.9006 Pos. [°2Th.], 9.5707 Pos. [°2Th.], 10.8783 Pos. [°2Th.], 12.6826 Pos. [°2Th.], 13.5397 Pos. [°2Th.], 14.7076 Pos. [°2Th.], 15.3655 Pos. [°2Th.], 15.6498 Pos. [°2Th.], 16.1771 Pos. [°2Th.], 16.3977 Pos. [°2Th.], 16.7038 Pos. [°2Th.], 17.7137 Pos. [°2Th.], 17.9872 Pos. [°2Th.], 18.4715 Pos. [°2Th.], 19.1970 Pos. [°2Th.], 19.3342 Pos. [°2Th.], 19.8371 Pos. [°2Th.], 20.1291 Pos. [°2Th.], 20.6847 Pos. [°2Th.], 21.5920 Pos. [°2Th.], 22.1415 Pos. [°2Th.], 22.9190 Pos. [°2Th.], 24.3724 Pos. [°2Th.], 25.0984 Pos. [°2Th.], 25.4518 Pos. [°2Th.], 26.0917 Pos. [°2Th.], 26.4768 Pos. [°2Th.], 27.0813 Pos. [°2Th.], 27.3489 Pos. [°2Th.], 28.3910 Pos. [°2Th.], 30.0421 Pos. [°2Th.], 31.3214 Pos. [°2Th.], 31.9249 Pos. [°2Th.], 33.1039 Pos. [°2Th.].

8. The compound of any one of the claims 1-5 wherein the compound is a hemitartrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 5.4038 Pos. [°2Th.], 6.1493 Pos. [°2Th.], 7.3131 Pos. [°2Th.], 9.1195 Pos. [°2Th.], 10.0257 Pos. [°2Th.], 11.1230 Pos. [°2Th.], 12.7984 Pos. [°2Th.], 13.8675 Pos. [°2Th.], 14.6409 Pos. [°2Th.], 15.4125 Pos. [°2Th.], 16.1065 Pos. [°2Th.], 17.3943 Pos. [°2Th.], 18.3377 Pos. [°2Th.], 18.6233 Pos. [°2Th.], 19.1123 Pos. [°2Th.], 19.3903 Pos. [°2Th.], 19.6856 Pos. [°2Th.], 20.1147 Pos.[°2Th.], 20.5016 Pos. [°2Th.], 20.8607 Pos. [°2Th.], 21.8794 Pos. [°2Th.], 22.4461Pos. [°2Th.], 23.9178 Pos. [°2Th.], 24.3693 Pos. [°2Th.], 24.9312 Pos. [°2Th.], 25.5910 Pos. [°2Th.], 26.7010 Pos. [°2Th.], 28.0426 Pos. [°2Th.], 29.3745 Pos.[°2Th.], 29.7308 Pos. [°2Th.], 30.7073 Pos. [°2Th.], 31.2874 Pos. [°2Th.], 32.6855Pos. [°2Th.], 33.6562 Pos. [°2Th.], 34.2587 Pos. [°2Th.].

9. The compound of any one of the claims 1-5 wherein the compound is a hemisuccinate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 5.6580 Pos. [°2Th.], 7.3357 Pos. [°2Th.], 8.1986 Pos. [°2Th.], 10.7259 Pos. [°2Th.], 11.6171 Pos. [°2Th.], 12.2091 Pos. [°2Th.], 12.4728 Pos. [°2Th.], 12.9965 Pos. [°2Th.], 13.7663 Pos. [°2Th.], 14.7434 Pos. [°2Th.], 15.8677Pos. [°2Th.], 16.4811 Pos. [°2Th.], 17.0683 Pos. [°2Th.], 18.0981 Pos. [°2Th.], 18.4433 Pos. [°2Th.], 18.8245 Pos. [°2Th.], 19.0046 Pos. [°2Th.], 19.9192 Pos. [°2Th.], 21.0571 Pos. [°2Th.], 21.4078 Pos. [°2Th.], 22.3724 Pos. [°2Th.], 22.9593 Pos. [°2Th.], 23.8409 Pos. [°2Th.], 24.1665 Pos. [°2Th.], 24.5771 Pos. [°2Th.], 24.8406 Pos. [°2Th.], 25.1205 Pos. [°2Th.], 25.5645 Pos. [°2Th.], 25.8133 Pos. [°2Th.], 26.2217 Pos. [°2Th.], 26.4674 Pos. [°2Th.], 26.5978 Pos. [°2Th.], 27.7801 Pos. [°2Th.], 27.9340 Pos. [°2Th.], 29.7462 Pos. [°2Th.], 30.3368 Pos. [°2Th.], 30.9059 Pos. [°2Th.], 31.1610 Pos. [°2Th.], 32.0284 Pos. [°2Th.], 32.4917 Pos. [°2Th.], 33.0368 Pos. [°2Th.], 34.7039 Pos. [°2Th.].

10. The compound of any one of the claims 1-5 wherein the compound is a hemi-citrate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 5.5866 Pos. [°2Th.], 7.1866 Pos. [°2Th.], 8.6152 Pos. [°2Th.], 9.5965 Pos. [°2Th.], 11.0629 Pos. [°2Th.], 14.4306 Pos. [°2Th.], 16.0686 Pos. [°2Th.], 16.6580 Pos. [°2Th.], 17.7791 Pos. [°2Th.], 18.3213 Pos. [°2Th.], 19.4935 Pos. [°2Th.], 20.3765 Pos. [°2Th.], 21.0489 Pos. [°2Th.], 21.7831 Pos. [°2Th.], 23.9648 Pos. [°2Th.], 26.3998 Pos. [°2Th.], 26.6610 Pos. [°2Th.], 27.1403 Pos. [°2Th.], 28.0543 Pos. [°2Th.].

11. The compound of any one of the claims 1-5 wherein the compound is a hemimaleate salt that is in a crystalline form, preferably a crystalline form that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A: 5.6099 Pos. [°2Th.], 6.7751 Pos. [°2Th.], 8.2693 Pos. [°2Th.], 14.0558 Pos. [°2Th.], 17.7186 Pos. [°2Th.], 18.9592 Pos. [°2Th.], 20.2532 Pos. [°2Th.], 22.6761 Pos. [°2Th.], 24.4336 Pos. [°2Th.], 24.9746 Pos. [°2Th.], 26.2849 Pos. [°2Th.], 28.0237 Pos. [°2Th.], 29.7648 Pos. [°2Th.].

12. The compound of any one of the claims 1-11 wherein the compound is a salt that is obtainable by a process comprising: c) adding lactic acid, HC1, tartaric acid, succinic acid, citric acid or maleic acid as a solution or as a suspension, to the compound in formula (I) as a free base or asalt thereof, such as a solid, as a solution or as a suspension, to provide a solution or a suspension of the corresponding salt; d) obtaining the salt as a solid by precipitation or crystallization, such as by cooling, evaporation of solvent, addition of an antisolvent or addition to an antisolvent, or by addition of a co-crystallizing agent, followed by filtration or centrifugation and optionally purifying the salt.

13. The compound of any one of the claims 1-12 wherein the compound is a salt that is obtainable by the process as described in the experimental section herein.

14. The compound of any one of the claims 1-13 wherein the compound has a solubility in a mixture solution of water and lactic acid at room temperature of at least 5 mg / mL, such as from 5-20 mg / mL.

15. A compound of formula (I)selected from a crystalline Form B that is characterized by the following XRPD peaks wherein the specific wavelength type is Kai 1.540598A:5.4583 Pos. [°2Th.], 8.6494 Pos. [°2Th.], 9.4935 Pos. [°2Th.], 9.9758 Pos. [°2Th.], 11.0201 Pos. [°2Th.], 11.6273 Pos. [°2Th.], 12.2790 Pos. [°2Th.], 13.2330 Pos. [°2Th.],14.5131 Pos. [°2Th.], 14.6913 Pos. [°2Th.], 16.0913 Pos. [°2Th.], 16.6654 Pos. [°2Th.],17.3892 Pos. [°2Th.], 17.8785 Pos. [°2Th.], 20.0832 Pos. [°2Th.], 20.7572 Pos. [°2Th.],21.1411 Pos. [°2Th.], 21.8912 Pos. [°2Th.], 22.9346 Pos. [°2Th.], 23.3471 Pos. [°2Th.],23.7332 Pos. [°2Th.], 24.4525 Pos. [°2Th.], 25.4370 Pos. [°2Th.], 25.6615 Pos. [°2Th.],26.7014 Pos. [°2Th.], 27.3638 Pos. [°2Th.], 27.8805 Pos. [°2Th.], 30.2132 Pos. [°2Th.].

16. A pharmaceutical composition comprising the compound of any of the claims 1-15, and optionally a pharmaceutically acceptable additive, such as carrier or excipient.

17. The pharmaceutical composition of claim 16 wherein the composition is a solid oral form, such as a tablet.

18. The pharmaceutical composition of claim 16 wherein the composition is a liquid solution, such as an IV solution.

19. A liquid composition, such as an IV solution, comprising a compound of formula (I)and lactic acid, and optionally an acid selected from HC1, tartaric acid, succinic acid, citric acid and maleic acid, and optionally a water-soluble PEG, such as PEG400.

20. The liquid composition of claim 19 wherein the composition is an IV solution comprising from 1 mg / mL to 10 mg / mL of the compound of formula (I), such as from 2-8 mg / mL, preferably 5-8 mg / mL, more preferred 8-10 mg / mL.

21. The liquid composition of claim 19 wherein the composition is a liquid concentrate for the solution for infusion comprising from 10 mg / mL to 200 mg / mL of the compound of formula (I), such as from 10-50 mg / mL, preferably 50-100 mg / mL, more preferred 100-200 mg / mL.

22. The compound of any one of the claims 1-15 or composition of any one of claims 16-21 for use in a method for treating a cardiac disease, disorder or condition in a mammal, such as a human.

23. The compound of any one of the claims 1-15 or composition of any one of claims16-21 for use in a method for treating the cardiac disease, disorder or condition wherein the disease, disorder or condition is associated with an abnormal rhythm of the heart.

24. The compound of any one of the claims 1-15 or composition of any one of claims16-21 for use in a method for treating the cardiac disease, disorder or condition selected from the group consisting of cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmias, and an abnormal rhythm arising after cardiac surgery or a cardiac ablation procedure.

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