Patent Application
20250129087
The present invention relates to acid addition salts and salt crystals of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one, composition comprising the same and the method of making and using such salts and salt crystals.
The compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one is disclosed in WO 2009/075784 (U.S. Pub. No. 2010/0273754). This compound has been found to be a potent and selective phosphodiesterase 1 (PDE 1) inhibitor useful for the treatment or prophylaxis of disorders characterized by low levels of cAMP and/or cGMP in cells expressing PDE1, and/or reduced dopamine D1 receptor signalling activity (e.g., Parkinson's disease, Tourette's Syndrome, Autism, fragile X syndrome, ADHD, restless leg syndrome, depression, cognitive impairment of schizophrenia, narcolepsy); and/or any disease or condition that may be ameliorated by the enhancement of progesterone signalling. This list of disorders is exemplary and not intended to be exhaustive.
The publication WO 2009/075784 discloses (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one in free base form and generally in pharmaceutically acceptable salt form, but no specific salt was shown to have particular stability or desired properties. Because many pharmaceutical compounds can exist in different physical forms (e.g., liquid or solid in different crystalline, amorphous, polymorphous, hydrate or solvate forms) which can vary the stability, solubility, bioavailability or pharmacokinetics (absorption, distribution, metabolism, excretion or the like) and/or bioequivalence of a drug, it is of critical importance in the pharmaceutical development to identify a pharmaceutical compound of optimal physical form (e.g., free base or salt in solid, liquid, crystalline, hydrate, solvate, amorphous or polymorphous forms).
In a first aspect, the present disclosure is directed to salt forms, e.g., crystalline salt forms, of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound A) acid addition salts. These salts and salt crystals are especially advantageous in the preparation of galenic formulations of various and diverse kind. In various embodiments, the Salt Crystals of the Disclosure are selected from the group consisting of hydrochloride, malate, fumarate, sulfate, esylate, galactarate, adipate, lactate, oxalate, palmitate, 2-oxo-glutarate, xinafoate, tosylate, tartrate, succinate, mesylate, napadisylate, edisylate, propionate, caprylate, besylate, benzoate, nicotinate, isonicotinate, orotate, camsylate, salicylate, aminosalicylate, mandelate, acetamido-benzoate, trifluoroacetate, dichloroacetate, caproate, or laurate salts. The various salt crystals according to the present disclosure may be in anhydrous or solvate form.
In a second aspect, the present disclosure further provides a method for the production of stable acid addition salts of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (“Compound A”), e.g., crystallinic acid addition salts with particular acids comprising the steps of reacting Compound A in free base form with an acid in a solvent and isolating the salt obtained. In various embodiments, the method further comprises the step of forming a slurry of Compound A with the acid in the solvent at a temperature between about 30° C. to 70° C., e.g., for a period of at least one hour. In various embodiments, the method further comprises the step of cooling the solution to a temperature of about −10° C. to about 20° C. In various embodiments, the method further comprises the step of drying the solution by evaporation. In various embodiments, the obtained salt is crystalline, and are dissolved in a second solvent and are subjected to one or more cooling cycles.
In a third aspect, the present disclosure provides a method for the prophylaxis or treatment of a patient, e.g., a human, suffering from a disorder selected from one or more of neurodegenerative diseases; mental disorders; circulatory and cardiovascular disorders; respiratory and inflammatory disorders; diseases which may be alleviated by the enhancement of progesterone signalling; a disease or disorder such as psychosis, glaucoma, or elevated intraocular pressure; a traumatic brain injury; a cancer or tumor; a renal disorder; any disease or condition characterized by low levels of cAMP and/or cGMP; and any disease or condition characterized by reduced dopamine D1 receptor signalling activity, wherein the method comprises the step of administering to a patient in need thereof a therapeutically effective amount of the compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound A) in acid addition salt form, e.g., according to any of the Salt Crystals of the Disclosure.
As use herein, the term “crystal” or “crystals” or “crystalline” or “crystallinic” refers to any solid that has a short- or long-range order of the molecules, atoms or ions in a fixed lattice arrangement. Salt Crystals of the Disclosure may be in a single crystal form. Therefore, the Salt Crystals of the Disclosure may be in a triclinic, monoclinic, orthorhombic, tetragonal, rhombohedral, hexagonal or cubic crystal form or mixtures thereof. In particular, the Salt Crystals of the Disclosure are in dry crystalline form. In a particular embodiment, the Salt Crystals of the Disclosure are substantially free of other forms, e.g., free of amorphous or other crystal forms.
The term “substantially free” of other crystal forms refer to less than about 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of other forms or other crystal forms, e.g., amorphous or other crystal forms.
The term “predominantly” or “substantially entirely in a single form” refers to less than about 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of other solid forms, e.g., amorphous or other crystal forms.
In particular embodiment, the Salt Crystals of the Disclosure may contain trace amounts of solvent, e.g., in solvate form, or trace amounts of water, e.g., in hydrate form. Preferably, the Salt Crystals of the disclosure are in non-solvate form. Still preferably, the crystals of the disclosure are in non-solvate and non-hydrate form.
The Salt Crystals of the Disclosure may have a free base to acid ratio of 1 to 1, 1 to 0.5 or 1 to >1, e.g., 1 to 1.3 or 1 to 2, etc.
The term “solvate” refers to crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. Therefore, the term “non-solvate” form herein refers to salt crystals that are free or substantially free of solvent molecules within the crystal structures of the disclosure.
The term “amorphous” form refers to solids of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
Unless further modified, the term “Compound A” refers to (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one in free base form, having the following structure:
The crystallinity or the morphology of the crystals of the Present Disclosure may be determined by a number of methods, including, but not limited to single crystal X-ray diffraction, X-ray powder diffraction, polarizing optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared adsorption spectroscopy and Raman spectroscopy. Characterization of solvates or hydrates or lack thereof may also be determined by DSC and/or TGA.
It is to be understood that X-ray powder diffraction pattern or the differential scanning calorimetry pattern of a given sample may vary a little (standard deviation) depending on the instrument used, the time and temperature of the sample when measured and standard experimental errors. Therefore, the temperature or the 2-theta values, d-spacing values, heights and relative intensity of the peaks as set forth herein in the Tables or in the Figures will have an acceptable level of deviation. For example, the values may have an acceptable deviation of e.g., about 20%, 15%, 10%, 5%, 3%, 2% or 1%. In particular embodiment, the 2-theta values or the d-spacing values of the XRPD pattern of the crystals of the current disclosure may have an acceptable deviation of ±0.2 degrees and/or ±0.2 Å. Further, the XRPD pattern of the crystals of the disclosure may be identified by the characteristic peaks as recognized by one skilled in the art. For example, the crystals of the disclosure may be identified by e.g., at least five characteristic peaks, e.g., at least three or at least five peaks, e.g., at least three or at least five 2-theta values and/or at least three or at least five d-spacing values as set forth in the XRPD patterns set forth herein. Therefore, the term “corresponding with or substantially as” set forth in any of the Tables or depicted in any of the Figures refers to any crystals which has an XRPD having the major or characteristic peaks as set forth in the tables/figures.
The term “about” in front of a numerical value refers to the numerical value itself ±20%, ±15%, ±10%, preferably ±5%, preferably ±3%, preferably ±2%, preferably ±1% of that value. When referencing temperature, the term about refers to the temperature value itself ±10° C., preferably ±5° C., preferably ±3° C. of the reference temperature. In another example, when referencing 2-theta angle values, the term “about” refers to the numerical 2-theta angle value itself ±0.2 degrees of the reference 2-theta angle value. In still another example, when referencing d-spacing values, the term “about” refers to the numerical 2-theta angle value itself ±0.2 Å of the reference d-spacing value.
The crystals of the disclosure are selective PDE1 inhibitors. Therefore, the crystals of the disclosure are useful for the treatment of PDE1 related disorders as set forth in e.g., WO 2014/151409, WO 2018/049417, WO 2019/227004, WO 2019/152697, WO 2009/075784, WO 2010/132127, WO 2006/133261 and WO 2011/153129, the contents of each of which are incorporated by reference in their entireties.
The term “patient” includes human and non-human. In one embodiment, the patient is a human. In another embodiment, the patient is a non-human.
In a first aspect, the present disclosure is directed to a salt of the compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Compound A) in acid addition salt form [Salt 1]. These salts may be in the form of salt crystals and are especially advantageous in the preparation of galenic formulations of various and diverse kind. Therefore, in the first aspect, the invention provides the following:
It has also been surprisingly found that particular Salts of the Present Invention are in crystalline form, and therefore are preferred for galenic and/or therapeutic use. Therefore, in a further embodiment, the invention provides a hydrochloride salt [Hydrochloride Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second hydrochloride salt [Hydrochloride Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a third hydrochloride salt [Hydrochloride Salt 3] of Compound A.
In a further embodiment, the present disclosure provides for a fourth hydrochloride salt [Hydrochloride Salt 4] of Compound A.
In a further embodiment, the present disclosure provides for a fifth hydrochloride salt [Hydrochloride Salt 5] of Compound A.
In a further embodiment, the present disclosure provides for a sixth hydrochloride salt [Hydrochloride Salt 6] of Compound A.
In a further embodiment, the present disclosure provides for a seventh hydrochloride salt [Hydrochloride Salt 7] of Compound A.
In a further embodiment, the present disclosure provides for an eighth hydrochloride salt [Hydrochloride Salt 8] of Compound A.
In a further embodiment, the present disclosure provides for a malate salt [Malate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a fumarate salt [Fumarate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first sulfate salt [Sulfate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second sulfate salt [Sulfate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for an esylate salt [Esylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a galactarate salt [Galactarate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first adipate salt [Adipate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second adipate salt [Adipate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a third adipate salt [Adipate Salt 3] of Compound A.
In a further embodiment, the present disclosure provides for a lactate salt [Lactate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first oxalate salt [Oxalate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second oxalate salt [Oxalate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a third oxalate salt [Oxalate Salt 3] of Compound A.
In a further embodiment, the present disclosure provides for a fourth oxalate salt [Oxalate Salt 4] of Compound A.
In a further embodiment, the present disclosure provides for a palmitate salt [Palmitate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a 2-oxo-glutarate salt [2-Oxo-glutarate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first xinafoate salt [Xinafoate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second xinafoate salt [Xinafoate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a third xinafoate salt [Xinafoate Salt 3] of Compound A.
In a further embodiment, the present disclosure provides for a first tosylate salt [Tosylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first tartrate salt [Tartrate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first tartrate salt [Tartrate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a first succinate salt [Succinate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second succinate salt [Succinate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a first mesylate salt [Mesylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a napadisylate salt [Napadisylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for an edisylate salt [Edisylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a propionate salt [Propionate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a caprylate salt [Caprylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a besylate salt [Besylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a benzoate salt [Benzoate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a nicotinate salt [Nicotinate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for an isonicotinate salt [Isonicotinate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for an orotate salt [Orotate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first camsylate salt [Camsylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second camsylate salt [Camsylate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a first salicylate salt [Salicylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a second salicylate salt [Salicylate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for an aminosalicylate salt [Aminosalicylate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first mandelate salt [Mandelate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first mandelate salt [Mandelate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a first acetamido benzoate salt [Acetamido Benzoate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a first acetamido benzoate salt [Acetamido Benzoate Salt 2] of Compound A.
In a further embodiment, the present disclosure provides for a trifluoroacetate salt [Trifluoroacetate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a dichloroacetate salt [Dichloroacetate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a caproate salt [Caproate Salt 1] of Compound A.
In a further embodiment, the present disclosure provides for a laurate salt [Laurate Salt 1] of Compound A.
Collectively, the salt crystals named above (i.e., Hydrochloride Salts 1-8, et seq.; Malate Salt 1, et seq.; Fumarate Salt 1, et seq.; Sulfate Salt 1, et seq.; Esylate Salt 1, et seq.; Galactarate Salt 1, et seq.; Adipate Salts 1-3, et seq.; Lactate Salt 1, et seq.; Oxalate Salts 1-4, et seq.; Palmitate Salt 1, et seq.; 2-Oxo-glutarate Salt 1, et seq.; Xinafoate Salts 1-3, et seq.; tosylate Salts 1-2, et seq.; Tartrate Salts 1-2, et seq.; Succinate Salts 1-2, et seq.; Mesylate Salt 1, et seq.; Napadisylate Salt 1, et seq.; Edisylate Salt 1, et seq.; Propionate Salt 1, et seq.; Caprylate Salt 1, et seq.; Besylate Salt 1, et seq.; Benzoate Salt 1, et seq.; Nicotinate Salt 1, et seq.; Isonicotinate Salt 1, et seq.; Orotate Salt 1, et seq.; Camsylate Salts 1-2, et seq.; Salicylate Salts 1-2, et seq.; Aminosalicylate Salt 1, et seq.; Mandelate Salts 1-2, et seq.; Acetamido Benzoate Salts 1-2, et seq.; Trifluoroacetate Salt 1, et seq.; Dichloroacetate Salt 1, et seq.; Caproate Salt 1, et seq.; and Laurate Salt 1, el seq.) are referred to as the Salt Crystals of the Disclosure.
In some embodiments, the Salt Crystals of the Disclosure are in a single crystal form and are free or substantially free of any other form, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of amorphous form.
In some embodiments, the Salt Crystals of the Disclosure are in a single crystal form and are free or substantially free of any other form, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of other crystal forms.
In some embodiments, the Salt Crystals of the Disclosure are in a single crystal form and are free or substantially free of any other form, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of amorphous and other crystal forms.
The present disclosure further provides a method [Method 1] for the production of stable acid addition salts of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (“Compound A”), e.g., crystallinic acid addition salts with particular acids comprising the steps of reacting Compound A in free base form with an acid in a solvent and isolating the salt obtained. In particular embodiments, the present disclosure provides the following:
The present disclosure further provides for Salt Crystals of the Disclosure which are obtained or obtainable by any of Methods 1, et seq. or any of Examples 1-4.
A method [Method 2] for the prophylaxis or treatment of a patient, e.g., a human, suffering from a disorder selected from the following disorders:
Studies are carried out to identify crystal forms for salts of Compound 1, which is (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one, having the following structure:
Counter ions are dissolved in either methanol or water to obtain 2M solutions. The counter ions that do not dissolve are added as solid. 20 mg of Compound 1 Free Base is dispensed in wells of a master plate, followed by the counter ions such that the mixtures have a molar ratio of 1:1. Solvents (800 μl) as identified below are subsequently added to the wells. The master plate is then stored on a thermoshaker and is shaken at 50° C. for 2 hours.
The clear liquids in the master plate wells are divided and placed over a cooling plate, an evaporation plate or an HPLC plate. The cooling plate is cooled to 5° C. and the sample is stored at this temperature for about 16 hours. The evaporation plate is stored in a vacuum oven to obtain complete evaporation of the solvents. The remaining liquids are absorbed by filter paper and the solids were dried in vacuum. All samples on each of the master plate, cooling plate and evaporation plate are analyzed using High Throughput (HT)-XRPD.
XRPD data analyses show various new crystalline patterns. Some counter ions show multiple patterns, which is influenced by the solvent and may indicate polymorphism or solvate formation. After defining all XRPD patterns, the crystalline patterns are analyzed by thermogravimetric analysis and differential scanning calorimetry.
XRPD is measured using a Bruker AXS D2 PHASER in Bragg-Brentano configuration with a scan range of 5-45° 2-theta. TGA measurements are performed using a Mettler Toledo TGA/DSC-3+ machine. DSC measurements are performed using a Mettler Toledo DSC-3+ machine. The sample is heated from 20° C. to 350° C. in an aluminium (pierced) cup, and a heating rate of 10° C./min is applied.
Aqueous hydrochloric acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resultant salt is a solvate and is obtained as a white to off-white powder. The XRPD pattern of Hydrochloride Salt 1 has peaks as set forth in Table 1 below.
The above crystal exhibits a thermal melting event between about 169° C. and 172° C., e.g., at about 170° C., according to differential scanning calorimetry. Hydrochloride Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.9.
A second hydrochloride salt is obtained when hydrochloric acid in cyclopentyl methyl ether is combined with 25 mg of Compound 1 in acetonitrile, and is cooled to 5° C. over an 8 hour period. The resultant salt is a solvate and is obtained as an off-white powder following evaporation. The XRPD pattern of Hydrochloride Salt 2 has peaks as set forth in Table 2 below.
The above crystal exhibits thermal events between about 140° C. and 142° C., e.g., at about 141° C., and between about 190° C. and 192° C., e.g., at about 191° C., according to differential scanning calorimetry. Hydrochloride Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.9.
A third hydrochloride salt is obtained when aqueous hydrochloric acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently cooled to 5° C. over an 8 hour period. The resultant salt is a solvate and is obtained as an off-white powder following evaporation. The XRPD pattern of Hydrochloride Salt 3 has peaks as set forth in Table 3 below.
The above crystal exhibits thermal events between about 155° C. and 157° C., e.g., at about 156° C., and between about 275° C. and 277° C., e.g., at about 276° C., according to differential scanning calorimetry. Hydrochloride Salt 3 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.9.
A fourth hydrochloride salt is obtained when hydrochloric acid in isopropyl alcohol is combined with 25 mg of Compound 1 in 2-butanone, and is cooled to 5° C. over an 8 hour period. The resultant salt is a solvate and is obtained as a crystalline slurry. The XRPD pattern of Hydrochloride Salt 4 has peaks as set forth in Table 4 below.
The above crystal exhibits thermal events between about 194° C. and 196° C., e.g., at about 195° C., and between about 209° C. and 211° C., e.g., at about 210° C., according to differential scanning calorimetry. Hydrochloride Salt 4 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.9.
An L-malate salt is obtained when L-malic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is a solvate and is obtained as an off-white powder. The XRPD pattern of L-Malate Salt 1 has peaks as set forth in Table 5 below.
The above crystal exhibits a thermal melting event between about 94° C. and 96° C., e.g., at about 95° C., according to differential scanning calorimetry. L-Malate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.7.
A fumarate salt is obtained when fumaric acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is a solvate and is obtained as a white powder. The XRPD pattern of Fumarate Salt 1 has peaks as set forth in Table 6 below.
The above crystal exhibits thermal events between about 110° C. and 112° C., e.g., at about 111° C., and between about 141° C. and 143° C., e.g., at about 142° C., and between about 164° C. and 166° C., e.g., at about 165° C., according to differential scanning calorimetry. Fumarate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.5.
A sulfate salt is obtained when sulfuric acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is a solvate and is obtained as an off-white powder after evaporation. The XRPD pattern of Sulfate Salt 1 has peaks as set forth in Table 7 below.
The above crystal exhibits thermal events between about 132° C. and 134° C., e.g., at about 133° C., and between about 227° C. and 229° C., e.g., at about 228° C., according to differential scanning calorimetry. Fumarate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.4.
A second sulfate salt is obtained when sulfuric acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resultant salt is a solvate and is obtained as an off-white powder after evaporation. The XRPD pattern of Sulfate Salt 2 has peaks as set forth in Table 8 below.
The above crystal exhibits thermal events between about 69° C. and 71° C., e.g., at about 70° C., and between about 114° C. and 116° C., e.g., at about 115° C., according to differential scanning calorimetry. Sulfate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.5.
An esylate salt is obtained when ethane sulfonic acid is combined with 25 mg of Compound 1 in acetone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Esylate Salt 1 has peaks as set forth in Table 9 below.
The above crystal exhibits a thermal event between about 304° C. and 306° C., e.g., at about 305° C., according to differential scanning calorimetry. Esylate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:1.
A galactarate salt is obtained when galactaric acid is combined with 25 mg of Compound 1 in methanol and water (9:1), and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as an off-white powder. The XRPD pattern of Galactarate Salt 1 has peaks as set forth in Table 10 below.
The above crystal exhibits a thermal event between about 204° C. and 206° C., e.g., at about 205° C., according to differential scanning calorimetry. Galactarate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of 1:0.9.
An adipate salt is obtained when adipic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder after evaporation. The XRPD pattern of Adipate Salt 1 has peaks as set forth in Table 11 below.
The above crystal exhibits thermal events between about 119° C. and 121° C., e.g., at about 120° C., and between about 159° C. and 161° C., e.g., at about 160° C., according to differential scanning calorimetry. Adipate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of 1:1.
A second adipate salt is obtained when adipic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as an off-white powder. The XRPD pattern of Adipate Salt 2 has peaks as set forth in Table 12 below.
The above crystal exhibits thermal events between about 159° C. and 161° C., e.g., at about 160° C., according to differential scanning calorimetry. Adipate Salt 2 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of 2:1.
A third adipate salt is obtained when adipic acid is combined with 25 mg of Compound 1 in acetone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as an off-white powder. The XRPD pattern of Adipate Salt 2 has peaks as set forth in Table 12 Å below.
The above crystal exhibits thermal events between about 109° C. and 112° C., e.g., at about 109° C., according to differential scanning calorimetry. Adipate Salt 3 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of 1:1.
A lactate salt is obtained when lactic acid is combined with 25 mg of Compound 1 in ethyl acetate or toluene, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Lactate Salt 1 has peaks as set forth in Table 13 below.
The above crystal exhibits thermal events between about 187° C. and 190° C., e.g., at about 187° C. or 188° C., according to differential scanning calorimetry. Lactate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of 1:1.
An oxalate salt is obtained when oxalic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is obtained as an off-white powder. The XRPD pattern of Oxalate Salt 1 has peaks as set forth in Table 14 below.
The above crystal exhibits a thermal event between about 218° C. and 220° C., e.g., at about 219° C., according to differential scanning calorimetry. Oxalate Salt 1 is in anhydrous form.
A second oxalate salt is obtained when oxalic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is obtained as in the form of white needles. The XRPD pattern of Oxalate Salt 2 has peaks as set forth in Table 15 below.
The above crystal exhibits thermal events between about 165° C. and 167° C., e.g., at about 166° C., between about 205° C. and 207° C., e.g., at about 207° C., and between about 214° C. and 216° C., e.g., at about 215° C., according to differential scanning calorimetry. Oxalate Salt 2 is in anhydrous form.
A third oxalate salt is obtained when oxalic acid is combined with 25 mg of Compound 1 in 3-heptanone, 2-butanone or ethyl acetate. The mixture is then either slurried at 50° C. for 2 hours, cooled to 5° C. over an 8 hour period, or subjected to evaporation under vacuum. The resulting salt is obtained as in the form of white needles. The XRPD pattern of Oxalate Salt 3 has peaks as set forth in Table 16 below.
The above crystal exhibits a thermal event between about 214° C. and 220° C., e.g., at about 214° C., 218° C. or 219° C., according to differential scanning calorimetry. Oxalate Salt 3 is in solvate form.
A palmitate salt is obtained when palmitic acid is combined with 25 mg of Compound 1 in ethyl acetate, 2-butanone, acetonitrile or 3-heptanone. The mixture is then either slurried at 50° C. for 2 hours, cooled to 5° C. over an 8 hour period, or subjected to evaporation under vacuum. The resulting salt is obtained as a white to off-white powder. The XRPD pattern of Palmitate Salt 1 has peaks as set forth in Table 17 below.
The above crystal exhibits thermal events between about 59° C. and 66° C., e.g., at about 59° C., 62° C. or 63° C., according to differential scanning calorimetry. Palmitate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A palmitate salt is obtained when palmitic acid is combined with 25 mg of Compound 1 in ethyl acetate. The mixture is then subjected to evaporation under vacuum. The resulting salt is obtained as an off-white powder. The XRPD pattern of 2-Oxo-glutarate Salt has peaks as set forth in Table 18 below.
The above crystal exhibits thermal events between about 124° C. and 126° C., e.g., at about 125° C., and between about 157° C. and 159° C., e.g., at about 158° C., according to differential scanning calorimetry. 2-Oxo-glutarate Salt is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.1.
A xinafoate salt is obtained when 1-hydroxy-2-napthoic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a brown powder. The XRPD pattern of Xinafoate Salt 1 has peaks as set forth in Table 19 below.
The above crystal exhibits thermal events between about 130° C. and 132° C., e.g., at about 131° C., and between about 143° C. and 146° C., e.g., at about 145° C., and between about 171° C. and 174° C., e.g., at about 172° C., according to differential scanning calorimetry. Xinafoate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A second xinafoate salt is obtained when 1-hydroxy-2-napthoic acid is combined with 25 mg of Compound 1 in toluene, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Xinafoate Salt 2 has peaks as set forth in Table 20 below.
The above crystal exhibits thermal events between about 117° C. and 119° C., e.g., at about 118° C., between about 163° C. and 166° C., e.g., at about 164° C., and between about 174° C. and 177° C., e.g., at about 175° C., according to differential scanning calorimetry. Xinafoate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A third xinafoate salt is obtained when 1-hydroxy-2-napthoic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is obtained as a brown powder. The XRPD pattern of Xinafoate Salt 3 has peaks as set forth in Table 21 below.
The above crystal exhibits thermal events between about 131° C. and 133° C., e.g., at about 132° C., and between about 170° C. and 173° C., e.g., at about 172° C., according to differential scanning calorimetry. Xinafoate Salt 3 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A tosylate salt is obtained when p-toluene sulfonic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Tosylate Salt 1 has peaks as set forth in Table 22 below.
The above crystal exhibits a thermal event between about 216° C. and 218° C., e.g., at about 217° C., according to differential scanning calorimetry. Tosylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A second tosylate salt is obtained when p-toluene sulfonic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Tosylate Salt 2 has peaks as set forth in Table 23 below.
The above crystal exhibits thermal events between about 87° C. and 90° C., e.g., at about 89° C., between about 109° C. and 112° C., e.g., at about 111° C., and between about 217° C. and 220° C., e.g., at about 219° C., according to differential scanning calorimetry. Tosylate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A tartrate salt is obtained when tartaric acid is combined with 25 mg of Compound 1 in acetone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Tartrate Salt 1 has peaks as set forth in Table 24 below.
The above crystal exhibits a thermal event between about 134° C. and 136° C., e.g., at about 135° C., according to differential scanning calorimetry. The free base and counter ion of Tartrate Salt 1 are present in the crystal in a ratio of about 1:1.
A succinate salt is obtained when succinic acid is combined with 25 mg of Compound 1 in acetone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Succinate Salt 1 has peaks as set forth in Table 25 below.
The above crystal exhibits thermal events between about 153° C. and 155° C., e.g., at about 154° C., between about 172° C. and 175° C., e.g., at about 173° C., and between about 178° C. and 181° C., e.g., at about 180° C., according to differential scanning calorimetry. Succinate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.7.
A second succinate salt is obtained when succinic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Succinate Salt 2 has peaks as set forth in Table 26 below.
The above crystal exhibits thermal events between about 150° C. and 152° C., e.g., at about 151° C., between about 163° C. and 165° C., e.g., at about 164° C., between about 172° C. and 175° C., e.g., at about 174° C., and between about 178° C. and 181° C., e.g., at about 179° C., according to differential scanning calorimetry. Succinate Salt 2 is in anhydrous form, and he free base and counter ion are present in the crystal in a ratio of about 1:0.8.
A mesylate salt is obtained when methanesulfonic acid is combined with 25 mg of Compound 1 in acetone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Mesylate Salt 1 has peaks as set forth in Table 27 below.
The above crystal exhibits a thermal event between about 310° C. and 312° C., e.g., at about 311° C., according to differential scanning calorimetry. Mesylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A mesylate salt is obtained when naphthalene disulfonic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a brown sticky solid. The XRPD pattern of Napadisylate Salt 1 has peaks as set forth in Table 28 below.
The above crystal exhibits a thermal event between about 103° C. and 107° C., e.g., at about 105° C., according to differential scanning calorimetry. Napadisylate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.2.
An edisylate salt is obtained when ethane disulfonic acid is combined with 25 mg of Compound 1 in 2-butanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as an off-white powder. The XRPD pattern of Edisylate Salt 1 has peaks as set forth in Table 29 below.
The above crystal exhibits a thermal event between about 295° C. and 298° C., e.g., at about 296° C. or 297° C., according to differential scanning calorimetry. Edisylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A propionate salt is obtained when propionic acid is combined with 25 mg of Compound 1 in methanol and water (9:1), and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a brown powder obtained following evaporation. The XRPD pattern of Propionate Salt 1 has peaks as set forth in Table 30 below.
The above crystal exhibits a thermal event between about 109° C. and 112° C., e.g., at about 111° C., and between about 135° C. and 137° C., e.g., at about 136° C. according to differential scanning calorimetry. Propionate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.7.
A caprylate salt is obtained when caprylic acid is combined with 25 mg of Compound 1 in methanol and water (9:1), and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained initially as a clear liquid, which presents as a hard solid following evaporation. The XRPD pattern of Caprylate Salt 1 has peaks as set forth in Table 31 below.
The above crystal exhibits a thermal event between about 102° C. and 105° C., e.g., at about 104° C., according to differential scanning calorimetry. Caprylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.4.
A besylate salt is obtained when benzenesulfonic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a brown powder. The XRPD pattern of Besylate Salt 1 has peaks as set forth in Table 32 below.
The above crystal exhibits a thermal event between about 237° C. and 240° C., e.g., at about 238° C., according to differential scanning calorimetry. Besylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A benzoate salt is obtained when benzoic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently subjected to evaporation under vacuum. The resulting salt is obtained as a brown/red powder. The XRPD pattern of Benzoate Salt 1 has peaks as set forth in Table 33 below.
The above crystal exhibits thermal events between about 59° C. and 62° C., e.g., at about 60° C., between about 81° C. and 84° C., e.g., at about 83° C., and between about 115° C. and 118° C., e.g., at about 116° C., according to differential scanning calorimetry. Benzoate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.1.
A nicotinate salt is obtained when nicotinic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is obtained as a white powder. The XRPD pattern of Nicotinate Salt 1 has peaks as set forth in Table 34 below.
The above crystal exhibits a thermal event between about 135° C. and 138° C., e.g., at about 137° C., according to differential scanning calorimetry. Nicotinate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
An isonicotinate salt is obtained when isonicotinic acid is combined with 25 mg of Compound 1 in toluene, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a light brown powder. The XRPD pattern of Isonicotinate Salt 1 has peaks as set forth in Table 35 below.
The above crystal exhibits thermal events between about 111° C. and 114° C., e.g., at about 113° C., and between about 128° C. and 130° C., e.g., at about 129° C., according to differential scanning calorimetry. Isonicotinate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.7.
An orotate salt is obtained when orotic acid is combined with 25 mg of Compound 1 in 2-butanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Orotate Salt 1 has peaks as set forth in Table 36 below.
The above crystal exhibits a thermal event between about 137° C. and 140° C., e.g., at about 138° C., according to differential scanning calorimetry. Orotate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:2.
A camsylate salt is obtained when camphor-10-sulfonic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Camsylate Salt 1 has peaks as set forth in Table 37 below.
The above crystal exhibits thermal events between about 227° C. and 230° C., e.g., at about 228° C., and between about 253° C. and 256° C., e.g., at about 254° C., according to differential scanning calorimetry. Camsylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A second camsylate salt is obtained when camphor-10-sulfonic acid is combined with 25 mg of Compound 1 in toluene, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Camsylate Salt 2 has peaks as set forth in Table 38 below.
Camsylate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A salicylate salt is obtained when salicylic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Salicylate Salt 1 has peaks as set forth in Table 39 below.
The above crystal exhibits thermal events between about 146° C. and 150° C., e.g., at about 147° C., between about 153° C. and 156° C., e.g., at about 155° C., between about 196° C. and 199° C., e.g., at about 197° C., and between about 244° C. and 247° C., e.g., at about 245° C., according to differential scanning calorimetry. Salicylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A second salicylate salt is obtained when salicylic acid is combined with 25 mg of Compound 1 in toluene, which is subsequently cooled to 5° C. over an 8 hour period. The resulting salt is obtained as a white powder. The XRPD pattern of Salicylate Salt 2 has peaks as set forth in Table 40 below.
The above crystal exhibits thermal events between about 127° C. and 130° C., e.g., at about 128° C., between about 143° C. and 146° C., e.g., at about 144° C., between about 180° C. and 183° C., e.g., at about 181° C., between about 196° C. and 199° C., e.g., at about 197° C., and between about 244° C. and 247° C., e.g., at about 247° C., according to differential scanning calorimetry. Salicylate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
An aminosalicylate salt is obtained when amino salicylic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as an off-white powder. The XRPD pattern of Aminosalicylate Salt 1 has peaks as set forth in Table 42 below.
The above crystal exhibits thermal events between about 130° C. and 133° C., e.g., at about 132° C., and between about 161° C. and 164° C., e.g., at about 162° C., according to differential scanning calorimetry. Aminosalicylate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A mandelate salt is obtained when mandelic acid is combined with 25 mg of Compound 1 in toluene, and is subsequently cooled to 5° C. over an 8 hour period. An off-white powder is obtained. Alternatively, the salt is obtained by subjecting the mixture to evaporation under vacuum. Under this method, the material is not dissolved prior to evaporation. After centrifugation, the supernatant is separated using a pipette and placed under vacuum until a dry solid is obtained. The XRPD pattern of Mandelate Salt 1 has peaks as set forth in Table 43 below.
The above crystal exhibits a thermal event between about 119° C. and 128° C., e.g., at about 120° C. or 126° C., according to differential scanning calorimetry. Mandelate Salt 1 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A second mandelate salt is obtained when mandelic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently subjected to evaporation under vacuum. The resulting salt is obtained as an orange/brown powder. The XRPD pattern of Mandelate Salt 2 has peaks as set forth in Table 44 below.
The above crystal exhibits a thermal event between about 102° C. and 105° C., e.g., at about 103° C., according to differential scanning calorimetry. Mandelate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A 4-acetamido-benzoate salt is obtained when 4-acetamido-benzoic acid is combined with 25 mg of Compound 1 in ethyl acetate, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of 4-Acetamido-benzoate Salt 1 has peaks as set forth in Table 45 below.
The above crystal exhibits a thermal event between about 168° C. and 171° C., e.g., at about 170° C., according to differential scanning calorimetry. 4-Acetamido-benzoate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.3.
A second 4-acetamido-benzoate salt is obtained when 4-acetamido-benzoic acid is combined with 25 mg of Compound 1 in 3-heptanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of 4-Acetamido-benzoate Salt 2 has peaks as set forth in Table 46 below.
The above crystal exhibits a thermal event between about 127° C. and 130° C., e.g., at about 129° C., and between about 170° C. and 173° C., e.g., at about 172° C., according to differential scanning calorimetry. 4-Acetamido-benzoate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.
A trifluoroacetate salt is obtained when trifluoroacetic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained initially as a clear liquid, and subsequent to evaporation, a white powder. The XRPD pattern of Trifluoroacetate Salt 1 has peaks as set forth in Table 47 below.
The above crystal exhibits a thermal event between about 253° C. and 257° C., e.g., at about 255° C., according to differential scanning calorimetry. Trifluoroacetate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.9.
A dichloroacetate salt is obtained when trifluoroacetic acid is combined with 25 mg of Compound 1 in acetonitrile, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained as a white powder. The XRPD pattern of Dichloroacetate Salt 1 has peaks as set forth in Table 48 below.
The above crystal exhibits thermal events between about 225° C. and 228° C., e.g., at about 227° C., and between about 229° C. and 232° C., e.g., at about 230° C., according to differential scanning calorimetry. Dichloroacetate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.8.
A caproate salt is obtained when caproic acid is combined with 25 mg of Compound 1 in 2-butanone, and is subsequently slurried at 50° C. for 2 hours. The resulting salt is obtained initially as a clear liquid, and as an off-white powder after evaporation. The XRPD pattern of Caproate Salt 1 has peaks as set forth in Table 49 below.
The above crystal exhibits thermal events between about 89° C. and 92° C., e.g., at about 90° C., and between about 104° C. and 107° C., e.g., at about 105° C., according to differential scanning calorimetry. Caproate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.9.
A laurate salt is obtained when lauric acid is combined with 25 mg of Compound 1 in 2-propanol, and is subsequently subjected to evaporation under vacuum. The resulting salt is obtained as a white powder. The XRPD pattern of Laurate Salt 1 has peaks as set forth in Table 50 below.
The above crystal exhibits a thermal event between about 81° C. and 84° C., e.g., at about 83° C., according to differential scanning calorimetry. Laurate Salt 1 is in anhydrous form, and the free base and counter ion are present in the crystal in a ratio of about 1:1.4.
The aqueous solubilities of the salt crystals generated in Example 1 are determined by shaking the salt crystals in water for 24 hours. Samples are filtered and diluted (in a mixture of acetonitrile/water (1/1)) for LC analysis. Solubilities are calculated with the use of a calibration line. Furthermore, the pH values of the filtrated solutions are determined using pH indication paper. The solubilities of the salts are compared against Compound 1 in free base form, as well as a phosphate salt comparator of Compound 1, as disclosed in WO2013192556 Å2.
For the malate, tartrate, oxalate, hydrochloride and the obtained phosphate salts, the aqueous solubility is similar to or higher than the Phosphate Salt Comparator. The hydrochloride salts in particular have good aqueous solubilities (i.e., 112 mg/ml and above).
Further hydrochloride salts are generated following the methods as generally described above in Example 1. 100 mg of Hydrochloride Salt 1 is dissolved in 2-ethyl-1-butanol and subjected to temperature cycles using a Technobis Crystal 16 machine. The salt is subjected to consecutive cycles from 50° C. to 0° C., 40° C. to 0° C., 30° C. to 0° C. and 20° C. to 0° C., with a heating rate of 10° C./min and a cooling rate of 0.5° C./min. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white powder. The XRPD pattern of Hydrochloride Salt 5 has peaks as set forth in Table 52 below.
The above crystal exhibits a thermal event between about 158° C. and 161° C., e.g., at about 159° C., according to differential scanning calorimetry. Hydrochloride Salt 5 is in solvate form. This form is reproducible using an amorphous hydrochloride salt of Compound 1 as well.
A sixth hydrochloride salt is generated following the methods as generally described above in Example 1. 100 mg of Hydrochloride Salt 1 is dissolved in ethyl butyl ketone and subjected to temperature cycles as described above. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white powder. The XRPD pattern of Hydrochloride Salt 6 has peaks as set forth in Table 53 below.
The above crystal exhibits a thermal event between about 129° C. and 133° C., e.g., at about 131° C., according to differential scanning calorimetry. Hydrochloride Salt 6 is in solvate form. This form is reproducible using an amorphous hydrochloride salt of Compound 1 as well.
A seventh hydrochloride salt is generated following the methods as generally described above in Example 1. 100 mg of Hydrochloride Salt 1 is dissolved in anisole and subjected to temperature cycles as described above. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white powder. The XRPD pattern of Hydrochloride Salt 7 has peaks as set forth in Table 54 below.
The above crystal exhibits a thermal event between about 144° C. and 147° C., e.g., at about 145° C., according to differential scanning calorimetry. Hydrochloride Salt 7 is in solvate form. This form is reproducible using an amorphous hydrochloride salt of Compound 1 as well.
An eighth hydrochloride salt is generated following the methods as generally described above in Example 1. 100 mg of Hydrochloride Salt 1 is dissolved in ethyl salicylate and subjected to temperature cycles as described above. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white powder. The XRPD pattern of Hydrochloride Salt 8 has peaks as set forth in Table 55 below.
The above crystal exhibits a thermal event between about 196° C. and 200° C., e.g., at about 198° C., according to differential scanning calorimetry. Hydrochloride Salt 8 is in solvate form. This form is reproducible using an amorphous hydrochloride salt of Compound 1 as well.
A further tartrate salt is generated following the methods as generally described above in Example 1. 100 mg of Tartrate Salt 1 is dissolved in methyl tert-butyl ether and subjected to temperature cycles using a Technobis Crystal 16 machine. The salt is subjected to consecutive cycles from 50° C. to 0° C., 40° C. to 0° C., 30° C. to 0° C. and 20° C. to 0° C., with a heating rate of 10° C./min and a cooling rate of 0.5° C./min. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white solid. The XRPD pattern of Tartrate Salt 2 has peaks as set forth in Table 56 below.
The above crystal exhibits a thermal event between about 103° C. and 106° C., e.g., at about 104° C., according to differential scanning calorimetry. Tartrate Salt 2 is in solvate form, and the free base and counter ion are present in the crystal in a ratio of about 1:0.6. Tartrate Salt 2 is reproducible at 1 g scale of Tartrate Salt 1, but exhibits thermal events between about 120° C. and 123° C., e.g., at about 121° C., and between about 134° C. and 137° C., e.g., at about 136° C.
A further tartrate salt is generated following the methods as generally described above in Example 1. 100 mg of Oxalate Salt 3 is dissolved in ethyl salicylate and subjected to temperature cycles using a Technobis Crystal 16 machine. The salt is subjected to consecutive cycles from 50° C. to 0° C., 40° C. to 0° C., 30° C. to 0° C. and 20° C. to 0° C., with a heating rate of 10° C./min and a cooling rate of 0.5° C./min. The obtained materials were analyzed using XRPD and TGA-DSC. The resulting salt is obtained as an off-white solid. The XRPD pattern of Oxalate Salt 4 has peaks as set forth in Table 57 below.
The above crystal exhibits a thermal event between about 125° C. and 128° C., e.g., at about 126° C., and between about 138° C. and 148° C., e.g., at about 139° C., according to differential scanning calorimetry. Oxalate Salt 4 is in solvate form.
This application is an international application which claims priority to and the benefit of U.S. Provisional Application Ser. No. 63/267,347, filed on Jan. 31, 2022, the contents of which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/061696 | 1/31/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63267347 | Jan 2022 | US |
