New salt forms of sabcomeline

Abstract

The present invention relates to new salt forms of sabcomeline. The new salt forms are lipophilic acid salts of sabcomeline wherein the lipophilic acids used to prepare the new salts may have a Hansen solubility parameter distance from water of at least 20.7. The present invention also relates to new crystalline forms of sabocomeline salts.

Description

NEW SALT FORMS OF SABCOMELINECROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefits of U.S. Provisional Application Serial Nos. 63 / 668,866, 63 / 668,912, 63 / 668,972 and 63 / 668,989, each as filed on July 9, 2024, and U.S. Provisional Application Serial No. 63 / 772,936, as filed on March 17, 2025, the disclosures of which are incorporated herein by reference in their entirety.BACKGROUND TO THE INVENTION

[0001] Sabcomeline is an M1 / M4 muscarinic agonist. Development of its hydrochloride salt form was halted in the late 1990s after the product failed in Phase III studies in the symptomatic treatment of Alzheimer’s disease.

[0002] Methods of manufacturing the compound and its oxalate salt are described in EP392803. A method of manufacturing sabcomeline hydrochloride from sabcomeline base is described in WO9531456. Sabcomeline HC1 is also described in WO9810762 as having very high water solubility. Few other details of the compound’s chemical properties are known.

[0003] Different salts of a drug may possess different properties. For example, different salts may have different processing or handling characteristics, different dissolution profiles, different stabilities, or different shelf-lives. These variations in the properties of different salts may impact the final dosage form, for instance, if they affect bioavailability. Different salts of a drug may also give rise to a variety of polymorphs, which may in turn have unique properties.

[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like sabcomeline, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - “TGA”, or differential scanning calorimetry - “DSC”), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0005] New salts and solid-state forms and solvates of a drug substance can exhibit different properties, such as differences in handling, processing, storage, and purification. In some cases, intermediate solid forms may convert to other salts or polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound can also change performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). This large repertoire of materials creates challenges for scientists, as products havingsurprisingly different properties can arise just by a change in salt or polymorphic form. Improved solid forms of sabcomeline are needed.SUMMARY OF THE INVENTION

[0006] The present invention relates to lipophilic acid salts of sabcomeline and solid-state forms thereof.

[0007] The present invention further encompasses the use of the above-described salts and solid-state forms thereof, for the preparation of other solid-state forms of lipophilic acid salts of sabcomeline, other sabcomeline salts and their solid-state forms thereof.

[0008] The present invention further encompasses compositions comprising lipophilic acid salts of sabcomeline, and solid-state forms thereof, and their preparation. In some embodiments, the composition is a pharmaceutical composition.

[0009] The present invention further encompasses pharmaceutical compositions comprising lipophilic acid salts of sabcomeline, and solid-state forms thereof, and their preparation.

[0010] In one embodiment, the present invention encompasses processes for preparing said pharmaceutical formulation comprising combining lipophilic acid salts of sabcomeline and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline oxalate prepared according to Example 4a.

[0012] Figure 2 shows an X-ray powder diffraction (XRPD) pattern of Form II of sabcomeline oxalate prepared according to Example 4b.

[0013] Figure 3 shows an X-ray powder diffraction (XRPD) pattern of Form III of sabcomeline oxalate prepared according to Example 4c.

[0014] Figure 4 shows an X-ray powder diffraction (XRPD) pattern of Form IV of sabcomeline oxalate prepared according to Example 4d.

[0015] Figure 5 shows an X-ray powder diffraction (XRPD) pattern of Form III + V of sabcomeline oxalate prepared according to Example 4e.

[0016] Figure 6 shows an X-ray powder diffraction (XRPD) pattern of Form I + VI of sabcomeline oxalate prepared according to Example 4h.

[0017] Figure 7 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline stearate prepared according to Example 5.

[0018] Figure 8 shows an X-ray powder diffraction (XRPD) pattern of Form II of sabcomeline stearate prepared according to Example 6.

[0019] Figure 9 shows an X-ray powder diffraction (XRPD) pattern of Form III of sabcomeline stearate prepared according to Example 7.

[0020] Figure 10 shows the photomicrograph of sabcomeline gentisate salt as captured at x200 magnification.

[0021] Figure 11 shows an X-ray powder diffraction (XRPD) pattern of Form II of sabcomeline gentisate prepared according to Examples 9 and 10.

[0022] Figure 12 shows the photomicrograph of sabcomeline pamoate salt as captured at x200 magnification.

[0023] Figure 13 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline pamoate prepared according to Example 11.

[0024] Figure 14 shows an X-ray powder diffraction (XRPD) pattern of Form II of sabcomeline pamoate prepared according to Example 12.

[0025] Figure 15 shows an X-ray powder diffraction (XRPD) pattern of Form III of sabcomeline pamoate prepared according to Example 13.

[0026] Figure 16 shows an X-ray powder diffraction (XRPD) pattern of Form IV of sabcomeline pamoate prepared according to Example 13.

[0027] Figure 17 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline cinnamate prepared according to Example 14.

[0028] Figure 18 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline decanoate prepared according to Example 15.

[0029] Figure 19 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline octanoate prepared according to Example 16.

[0030] Figure 20 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline dodecanoate prepared according to Example 17.

[0031] Figure 21 shows an X-ray powder diffraction (XRPD) pattern of Form I of sabcomeline palmitate prepared according to Example 18.

[0032] Figure 22 shows an X-ray powder diffraction (XRPD) pattern of Form II of sabcomeline palmitate prepared according to Example 19.

[0033] Figure 23 shows an X-ray powder diffraction (XRPD) pattern of Form III of sabcomeline palmitate prepared according to Example 20.

[0034] Figure 24 shows an X-ray powder diffraction (XRPD) pattern of Form IV of sabcomeline palmitate prepared according to Example 22.DETAILED DESCRIPTION OF THE INVENTION

[0035] The present inventions may be understood more readily by reference to the following detailed description taken in connection with any accompanying figures and examples, which form a part of this disclosure. It is to be understood that these inventions are not limited to the specific products, methods, conditions or parameters described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed inventions.

[0036] The entire disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference.

[0037] As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

[0038] In the present disclosure the singular forms “a”, “an”, and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a particle” is a reference to one or more of such particles and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a certain element “may be” X, Y, or Z, it is not intended by such usage to exclude in all instances other choices for the element.

[0039] When values are expressed as approximations, by use of the antecedent “about”, it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” preferably refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” preferably refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as optionally including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included”. The phrase “at least about x” is intended to embrace both “about x” and “at least x”. It is also understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “2 - 5 hours” includes 2 hours, 2.1 hours, 2.2 hours, 2.3 hours etc... up to 5 hours.

[0040] The present invention relates to lipophilic acid salts of sabcomeline.

[0041] As used herein, the term “sabcomeline” shall refer to the chemical compound a- (Methoxyimino)-l-azabicyclo[2.2.2]octane-3-acetonitrile and stereoisomers thereof.Sabcomeline includes one chiral center and can exist as two enantiomers, R and S.Sabcomeline includes one imine bond, which can exist in two geometries, Z and E.

[0042] According to the disclosure, sabcomeline can be present as a single isomer or as a mixture of two, three, or four isomers. Sabcomeline isomer mixtures can include the two, three, or four isomers in any molar amount.

[0043] In one embodiment of the invention, sabcomeline is racemic (aZ)-a-(methoxyimino)-l- azabicyclo[2.2.2]octane-3-acetonitrile. In another embodiment of the invention, sabcomeline is an isomeric mixture of (37?)-a-(methoxyimino)-l-azabicyclo[2.2.2]octane-3-acetonitrile. In another embodiment of the invention, sabcomeline is enantiomerically pure (aZ,3R)-a- (methoxy imino)- 1 -azabicyclo [2.2.2] octane-3 -acetonitrile :

[0044] As used herein, the term “stereoisomer” corresponds to a compound where the same atoms or isotopes connected by bonds of the same type differ in their relative positions in space.

[0045] As used herein, the term “racemic” corresponds to a compound comprising a homogeneous phase composed of equimolar amounts of enantiomeric molecules. It is also contemplated that a racemic compound might also contain geometric bonds such as cis and trans- forms of the compound. In one embodiment of the invention, these geometric isomers will be in equimolar amounts within the compound. In another embodiment of the invention, one geometric isomer will be in excess of any other within the compound. In one embodiment of the invention, a racemic compound could relate to a compound wherein one geometric isomer will comprise at least 50.1% of the compound. In one embodiment of the invention, a racemic compound could relate to a compound wherein one geometric isomer will comprise at least 50.1%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% of the compound. As an example, a racemic compound containing both chiral and geometric bond could be described without any stereochemical nomenclature wherein no geometric isomer is in excess of any other or by denoting a geometric excess of at least one geometric isomer, e.g., (Z)- or cis-.

[0046] As used herein, the term “isomeric mixture” corresponds to a compound comprising a homogeneous phase of equimolar amounts of geometric isomers, that is, equimolar amounts of Z and E geometries. An isomeric mixture might contain (5)- and (R>- enantiomers of the compound, either of which can be present in any molar amount. In one embodiment of the invention, these enantiomers will be in equimolar amounts within the compound. In another embodiment of the invention, one enantiomer will be in excess of any other within the compound. In one embodiment of the invention, an isomeric mixture could relate to a compound wherein one enantiomer will comprise at least 50.1% of the compound. In one embodiment of the invention, an isomeric mixture could relate to a compound wherein one enantiomer will comprise at least 50.1%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% of the compound. As an example, an isomeric mixture of a compound containing both chiral and geometric bonds could be described without any geometric nomenclature, wherein no geometric isomer is in excess of any other, or by denoting an excess of at least one enantiomer, e.g., an excess of either the (R)- or (5)- enantiomer.

[0047] As used herein, the term “enantiomerically pure” corresponds to a compound wherein one stereoisomer is present in excess over all others. For example, an enantiomerically pure form of a compound containing at least one chiral center but not containing any geometric bonds will comprise a single stereoisomer in excess over all other stereoisomeric forms of the compound, whereas an enantiomerically pure form of a compound comprising both chiral and geometric bonds will comprise a single stereoisomer in excess over all other enantiomeric and geometric isomeric forms of the compound. In one embodiment of the invention, an enantiomerically pure compound could relate to a compound wherein one enantiomer will comprise at least 50.1% of the compound. In one embodiment of the invention, an enantiomerically pure compound could relate to a compound wherein one enantiomer will comprise at least 50.1%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, at least99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% of the compound. In one embodiment of the invention, an enantiomerically pure compound could relate to a compound comprising only one enantiomer and one geometric isomer will comprise at least 50.1% of the compound. In one embodiment of the invention, an enantiomerically pure compound could relate to a compound comprising only one enantiomer and one geometric isomer will comprise at least 50.1%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% of the compound. As an example, an enantiomerically pure compound containing single chiral and geometric centers could be denoted by an isomeric excess of both chiral and geometric isomers, e.g., (Z, R>- or cis-(S~).

[0048] As used here, in term "lipophilic acid" refers to an acidic compound that has a Hansen solubility parameter distance from water of at least 20.7. In one embodiment, the term “lipophilic acid” refers to an acidic compound that has a Hansen solubility parameter distance from water of at least 20.7, at least 21, at least 23, at least 25, at least 28, at least 31, at least 34 or at least 37.

[0049] The Hansen solubility parameter of a compound is a well-established measure of a compound’s total energy of vaporization of a liquid and consists of several individual parts arising from (atomic) dispersion forces, (molecular) permanent dipole-permanent dipole forces and (molecular) hydrogen bonding (electron exchange) (Hansen Solubility Parameters: A User’s Handbook, 2ndedition, ed. CM Hansen, CRC Press, Boca Raton, FL, 2007, Stefanis et al, Int J Thermophys (2008) 29:568-585).

[0050] The parameter, as a function of the distance of the compound from a solvent, can be calculated from the following equation:Ra = 4( Sdl - 3d2)2+ (dpi - <5p2)2+ ( dhbl - Shb2)2wherein Rarepresents the distance of the compound from the solvent, 5di represents the dispersion Hansen solubility parameter of the solvent, 5di represents the dispersion Hansen solubility parameter of the compound, 5pirepresents the polar Hansen solubility parameter of the solvent, 5pj represents the polar Hansen solubility parameter of the compound, 5hbi represents the Hydrogen-bonding Hansen solubility parameter of the solvent and 5hbi represents the Hydrogen-bonding Hansen solubility parameter of the compound.

[0051] Examples of Hansen solubility parameter distances from water for a variety of acidic compounds are shown in Table 1 along with their respective references.Table 1a - Hansen Solubility Parameters: A User’s Handbook, 2ndedition, CRC Press, 2007 b - calculated from Stefanis et al, Int J Thermophys (2008) 29:568-585 3 - De La Pena-Gil et al, Food Biophysics (2016) 11:283-291

[0052] As used herein, the term “sabcomeline stearate” means sabcomeline stearate salt.

[0053] As used herein, the term “sabcomeline gentisate” means sabcomeline gentisate salt.

[0054] As used herein, the term “sabcomeline pamoate” means sabcomeline pamoate salt.

[0055] As used herein, the term “sabcomeline cinnamate” means sabcomeline cinnamate salt.

[0056] As used herein, the term “sabcomeline decanoate” means sabcomeline decanoate salt.

[0057] As used herein, the term “sabcomeline octanoate” means sabcomeline octanoate salt.

[0058] As used herein, the term “sabcomeline dodecanoate” means sabcomeline dodecanoate salt.

[0059] As used herein, the term “sabcomeline palmitate” means sabcomeline palmitate salt.

[0060] As used herein, a crystal form or a crystalline form may be referred to as being characterized by graphical data “as depicted in” a Figure. Such data may include, for example, powder X- ray diffractograms. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid-state form (a so- called “fingerprint”) which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form, mixtures comprising one or more of the same crystal forms or different crystal forms.

[0061] Lipophilic acid salts of sabcomeline, or crystal forms of lipophilic acid salts of sabcomeline as referred to herein, as being characterized by graphical data “as depicted in” a Figure, will thus be understood to include any crystal form of a lipophilic acid salts of sabcomeline,characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0062] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuKa radiation, X = 1.5418 A, preferably, XRPD peaks reported herein are measured using CuK a radiation, X = 1.5418 A, at a temperature of 25 ± 3°C.

[0063] A process or step may be referred to herein as being carried out “overnight”. This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.

[0064] As used herein, and unless stated otherwise, the term “anhydrous” in relation to a lipophilic acid salt of sabcomeline, a crystalline lipophilic acid salts of sabcomeline or a solid-state form thereof, which does not include any crystalline water (or other solvents) in a defined / non- defined, stoichiometric / non-stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than about 1% (w / w) of either water or organic solvents as measured for example by thermal gravimetric analysis (TGA).

[0065] As used herein, and unless indicated otherwise, the term “solvate” refers to a crystal form that incorporates a solvent in the crystal structure. The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0066] As used herein, and unless indicated otherwise, the term “isolated” corresponds to a lipophilic acid salt of sabcomeline or solid-state form(s) thereof that is physically separated from the reaction mixture in which it is formed.

[0067] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization may be referred to herein as a number of “volumes” or “vol” or “V”. For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “v / v” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding methyl tert- butyl ether (MTBE) (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0068] As used herein, and unless indicated otherwise the term “non-hygroscopic” in relation to a lipophilic acid salt of sabcomeline, or a crystal form thereof, refers to less than about 1.0% (w / w) absorption of water at about 25°C and about 80% relative humidity (RH) by a lipophilic acid salt of sabcomeline, or a crystal form thereof, as determined, for example, by TGA. Water can be, for example, atmospheric water.

[0069] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure, for example, a pressure of about 10 mbar to about 500 mbar.

[0070] As used herein, and unless indicated otherwise, the term “thermo-dynamical stability” in relation to a lipophilic acid salt of sabcomeline and its solid-state forms refers to resistance of the solid-state form to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than about 20% (w / w), about 10% (w / w), about 5% (w / w), about 1% (w / w), about 0.5% (w / w), or about 0% (w / w) conversion of a crystal form of a lipophilic acid salt of sabcomeline to any other solid-state form of sabcomeline, or a salt thereof, as measured by XRPD, over a selected time-period. In some embodiments, the conversion is about 1% (w / w) to about 20% (w / w), about 1% (w / w) to about 10% (w / w), or about 1% (w / w) to about 5% (w / w).

[0071] The present invention relates to lipophilic acid salts of sabcomeline and to solid state forms thereof, processes for preparation thereof, pharmaceutical compositions and formulations thereof.

[0072] In one embodiment, the present invention comprises a lipophilic acid salt of sabcomeline. The lipophilic acid salt of sabcomeline may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0073] In one embodiment, the present invention comprises a crystalline lipophilic acid salt of sabcomeline exhibiting two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks, each with a relative intensity of more than about 10%, of more than about 15%, of more than about 20%, or of more than about 30%.

[0074] In one embodiment, the present invention comprises sabcomeline stearate. The sabcomeline stearate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0075] In another embodiment, the present invention comprises a crystalline form of sabcomeline stearate designated as Form I. The crystalline Form I of sabcomeline stearate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 5; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 5; as depicted in Figure 7; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline stearate designated as Form II. The crystalline Form II of sabcomeline stearate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 6; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 6; as depicted in Figure 8; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline stearate designated as Form III. The crystalline Form III of sabcomeline stearate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuringin Table 7; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 7; as depicted in Figure 9; or as a combination thereof.

[0076] In one embodiment, the present invention comprises crystalline sabcomeline stearate exhibiting two, three, four or more of the following peaks, 11.1, 13.1, 13.9, 14.2, 14.9, 15.9, 17.5, 18.9, 19.4, 19.9, 21.8, 22.5, 23.3, 23.4, 25.0, 25.6, 29.4 °29 ± 0.2 °29. In one embodiment, the present invention comprises crystalline sabcomeline stearate exhibiting at least peaks at 11.1, 14.2, 18.9, 19.4 °29 ± 0.2 °29 and optionally exhibit one, two, three, four, five, six, seven, eight, nine, ten or more of the following peaks, 13.1, 13.9, 14.9, 15.9, 17.5, 19.9, 21.8, 22.5, 23.3, 23.4, 25.0, 25.6, 29.4 °29 ± 0.2 °29.

[0077] In one embodiment, the present invention comprises sabcomeline stearate and wherein less than 5 % w / w of said crystalline sabcomeline stearate exhibits peaks at 15.8, 16.5, 18.8 and 22.3 °29 ± 0.2 °29. In a further embodiment, the present invention comprises sabcomeline stearate and wherein less than 5 % w / w, less than 4 % w / w, less than 3 % w / w, less than 2 % w / w, less than 1 % w / w or less than 0.5 % w / w of said sabcomeline stearate exhibits peaks at 15.8, 16.5, 18.8 and 22.3 °29 ± 0.2 °29. In a still further embodiment, the present invention comprises sabcomeline stearate which does not exhibit peaks at 15.8, 16.5, 18.8 and 22.3 °29 ± 0.2 °29.

[0078] In one embodiment, the present invention comprises solid state sabcomeline stearate wherein the sabcomeline stearate comprises a single polymorphic form of sabcomeline. In other embodiments, the solid state sabcomeline stearate comprises two or more sabcomeline stearate polymorphic forms. In a further embodiment, the solid state sabcomeline stearate comprises about 50-100% Form III.

[0079] In one embodiment, the present invention comprises sabcomeline gentisate. The sabcomeline gentisate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0080] In another embodiment, the present invention comprises a crystalline form of sabcomeline gentisate designated as Form I. The crystalline Form I of sabcomeline gentisate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 8; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 8; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline gentisate designated as Form II. The crystalline Form II of sabcomeline gentisate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 9; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 9; as depicted in Figure 11; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline gentisate designated as Form III. The crystalline mixture of sabcomeline gentisate Forms II and III of sabcomeline gentisate is characterized by data selected from one or more of the following: anXRPD pattern substantially as featuring in Table 10 or two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 10.

[0081] In one embodiment, the present invention comprises solid state sabcomeline gentisate wherein the sabcomeline gentisate comprises a single polymorphic form of sabcomeline. In other embodiments, the solid state sabcomeline gentisate comprises two or more sabcomeline gentisate polymorphic forms. In a further embodiment, the solid state sabcomeline gentisate comprises about 50-100% Form II.

[0082] In one embodiment, the present invention comprises crystalline sabcomeline gentisate exhibiting two, three, four or more of the following peaks, 12.1, 12.5, 14.5, 14.6, 17.3, 17.4, 17.5, 18.3, 20.7, 20.9, 22.3, 22.9, 27.9, 28.4 °29 ± 0.2 °29. In one embodiment, the present invention comprises crystalline sabcomeline gentisate exhibiting at least peaks at 14.6, 17.4, 17.5, 22.9 °29 ± 0.2 °29 and optionally exhibit one, two, three, four, five, six, seven, eight, nine, ten or more of the following peaks, 12.1, 12.5, 14.5, 17.3, 18.3, 20.7, 20.9, 22.3, 27.9, 28.4 °29 ± 0.2 °29.

[0083] In one embodiment, the present invention comprises sabcomeline pamoate. The sabcomeline pamoate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0084] In another embodiment, the present invention comprises a crystalline form of sabcomeline pamoate designated as Form I. The crystalline Form I of sabcomeline pamoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 11; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 11; as depicted in Figure 13; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline pamoate designated as Form II. The crystalline Form II of sabcomeline pamoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 12; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 12; as depicted in Figure 14; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline pamoate designated as Form III. The crystalline Form III of sabcomeline pamoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 13; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 13; as depicted in Figure 15; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline pamoate designated as Form IV. The crystalline Form IV of sabcomeline pamoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 14; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 14; as depicted in Figure 16; or as a combination thereof.

[0085] In one embodiment, the present invention comprises solid state sabcomeline pamoate wherein the sabcomeline pamoate comprises a single polymorphic form of sabcomeline. In other embodiments, the solid state sabcomeline pamoate comprises two or more sabcomeline pamoate polymorphic forms. In a further embodiment, the solid state sabcomeline pamoate comprises about 50-100% Form II.

[0086] In one embodiment, the present invention comprises crystalline sabcomeline pamoate exhibiting two, three, four or more of the following peaks, 7.1, 9.4, 9.6, 10.0, 10.2, 12.6, 14.5, 16.3, 17.6, 17.8, 19.0, 19.7, 20.0, 20.4, 20.6, 21.5, 22.1, 22.9 °20 ± 0.2 °20. In one embodiment, the present invention comprises crystalline sabcomeline pamoate exhibiting at least peaks at 7.1, 19.0, 19.7, 20.6 °20 ± 0.2 °20 and optionally exhibit one, two, three, four, five, six, seven or more of the following peaks, 9.4, 9.6, 10.0, 10.2, 12.6, 14.5, 16.3, 17.6, 17.8, 20.0, 20.4, 21.5, 22.1, 22.9 °20 ± 0.2 °20. In a further embodiment, the present invention comprises crystalline sabcomeline pamoate exhibiting at least peaks at 7.1, 19.0, 19.7, 20.6 °20 ± 0.2 °20 and two, three, four, five, six, seven or more of the following peaks, 9.4, 9.6, 10.0, 10.2, 12.6, 14.5, 16.3, 17.6, 17.8, 20.0, 20.4, 21.5, 22.1, 22.9 °20 ± 0.2 °20. In a still further embodiment, the present invention comprises crystalline sabcomeline pamoate exhibiting at least four, five, six, seven, eight or more of the following peaks 7.1, 8.0, 9.4, 9.6, 10.0, 10.2, 12.0, 12.6, 14.5, 15.8, 16.3, 17.2, 17.6, 19.0, 19.7, 20.0, 20.4, 21.5, 22.1, 22.9 °20 ± 0.2 °20.

[0087] In one embodiment, the present invention comprises sabcomeline pamoate and wherein less than 5 % w / w of said crystalline sabcomeline pamoate exhibits peaks at 6.0, 15.4, 18.8 and 26.0 °20 ± 0.2 °20. In a further embodiment, the present invention comprises sabcomeline pamoate and wherein less than 5 % w / w, less than 4 % w / w, less than 3 % w / w, less than 2 % w / w, less than 1 % w / w or less than 0.5 % w / w of said sabcomeline pamoate exhibits peaks at 6.0, 15.4, 18.8 and 26.0 °20 ± 0.2 °20. In a still further embodiment, the present invention comprises sabcomeline pamoate which does not exhibit peaks at 6.0, 15.4, 18.8 and 26.0 °20 ± 0.2 °20.

[0088] In one embodiment, the present invention comprises sabcomeline pamoate and wherein less than 5 % w / w of said sabcomeline pamoate exhibits peaks at 14.3, 18.2 and 22.6 °20 ± 0.2 °20. In a further embodiment, the present invention comprises sabcomeline pamoate and wherein less than 5 % w / w, less than 4 % w / w, less than 3 % w / w, less than 2 % w / w, less than 1 % w / w or less than 0.5 % w / w of said sabcomeline pamoate exhibits peaks at 14.3, 18.2 and 22.6 °20 ± 0.2 °20. In a still further embodiment, the present invention comprises sabcomeline pamoate which does not exhibit peaks at 14.3, 18.2 and 22.6 °20 ± 0.2 °20.

[0089] In one embodiment, the present invention comprises sabcomeline cinnamate. The sabcomeline cinnamate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0090] In another embodiment, the present invention comprises a crystalline form of sabcomeline cinnamate designated as Form I. The crystalline Form I of sabcomeline cinnamate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 15; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 15; as depicted in Figure 17; or as a combination thereof.

[0091] In one embodiment, the present invention comprises crystalline sabcomeline cinnamate exhibiting two, three, four or more of the following peaks, 8.7, 10.7, 12.2, 14.9, 15.0, 15.7,18.6, 18.8, 19.3, 21.5, 22.5, 23.3, 26.4, 26.5 °29 ± 0.2 °29. In one embodiment, the present invention comprises crystalline sabcomeline cinnamate exhibiting at least peaks at 14.9, 15.7,19.3, 21.5 °29 ± 0.2 °29 and optionally exhibit one, two, three, four, five, six, seven, eight, nine or more of the following peaks, 8.7, 10.7, 12.2, 15.0, 18.6, 18.8, 22.5, 23.3, 26.4, 26.5 °29 ± 0.2 °29.

[0092] In one embodiment, the present invention comprises sabcomeline decanoate. The sabcomeline decanoate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0093] In another embodiment, the present invention comprises a crystalline form of sabcomeline decanoate designated as Form I. The crystalline Form I of sabcomeline decanoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 16; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 16; as depicted in Figure 18; or as a combination thereof.

[0094] In one embodiment, the present invention comprises crystalline sabcomeline decanoate exhibiting two, three, four or more of the following peaks, 9.7, 12.2, 13.4, 14.8, 17.8, 18.3,18.7, 19.2, 19.4, 22.1, 22.5, 23.2, 23.7, 26.1 °29 ± 0.2 °29. In one embodiment, the present invention comprises crystalline sabcomeline decanoate exhibiting at least peaks at 14.8, 17.8,18.3, 22.5 °29 ± 0.2 °29 and optionally exhibit one, two, three, four, five, six, seven, eight, nine or more of the following peaks, 9.7, 12.2, 13.4, 18.7, 19.2, 19.4, 22.1, 23.2, 23.7, 26.1 °29 ± 0.2 °29.

[0095] In one embodiment, the present invention comprises sabcomeline octanoate. The sabcomeline octanoate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0096] In another embodiment, the present invention comprises a crystalline form of sabcomeline octanoate designated as Form I. The crystalline Form I of sabcomeline octanoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 17; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 17; as depicted in Figure 19; or as a combination thereof.

[0097] In one embodiment, the present invention comprises crystalline sabcomeline octanoate exhibiting two, three, four or more of the following peaks, 11.5, 12.2, 13.4, 14.8, 17.8, 18.3,18.7, 19.4, 22.5, 23.1, 26.1, 27.0, 27.2, 31.6 °20 ± 0.2 °20. In one embodiment, the present invention comprises crystalline sabcomeline octanoate exhibiting at least peaks at 13.4, 14.8,17.8, 31.6 °20 ± 0.2 °20 and optionally exhibit one, two, three, four, five, six, seven, eight, nine or more of the following peaks, 11.5, 12.2, 18.3, 18.7, 19.4, 22.5, 23.1, 26.1, 27.0, 27.2 °20 ± 0.2 °20.

[0098] In one embodiment, the present invention comprises sabcomeline dodecanoate. The sabcomeline dodecanoate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0099] In another embodiment, the present invention comprises a crystalline form of sabcomeline dodecanoate designated as Form I. The crystalline Form I of sabcomeline dodecanoate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 18; two, three, four, five, six, seven, eight, nine, ten or more 20 ± 0.2° 20 peaks as featuring in Table 18; as depicted in Figure 20; or as a combination thereof.

[0100] In one embodiment, the present invention comprises crystalline sabcomeline dodecanoate exhibiting two, three, four or more of the following peaks, 7.5, 13.4, 14.1, 14.9, 17.8, 18.4,19.8, 21.0, 21.5, 21.7, 22.5, 23.7, 24.1, 25.7 °20 ± 0.2 °20. In one embodiment, the present invention comprises crystalline sabcomeline dodecanoate exhibiting at least peaks at 14.9, 18.4, 21.0, 21.5 °20 ± 0.2 °20 and optionally exhibit one, two, three, four, five, six, seven, eight, nine or more of the following peaks, 7.5, 13.4, 14.1, 17.8, 19.8, 21.7, 22.5, 23.7, 24.1, 25.7 °20 ± 0.2 °20.

[0101] In one embodiment, the present invention comprises sabcomeline palmitate. The sabcomeline palmitate may be isolated, preferably as a solid, and more preferably as a crystalline form.

[0102] In another embodiment, the present invention comprises a crystalline form of sabcomeline palmitate designated as Form I. The crystalline Form I of sabcomeline palmitate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 19; two, three, four, five, six, seven, eight, nine, ten or more 20 ± 0.2° 20 peaks as featuring in Table 19; as depicted in Figure 21; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline palmitate designated as Form II. The crystalline Form II of sabcomeline palmitate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 20; two, three, four, five, six, seven, eight, nine, ten or more 20 ± 0.2° 20 peaks as featuring in Table 20; as depicted in Figure 22; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline palmitate designated as Form III. The crystalline Form III ofsabcomeline palmitate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 21; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 21; as depicted in Figure 23; or as a combination thereof. In another embodiment, the present invention comprises a crystalline form of sabcomeline palmitate designated as Form IV. The crystalline Form IV of sabcomeline palmitate is characterized by data selected from one or more of the following: an XRPD pattern substantially as featuring in Table 23; two, three, four, five, six, seven, eight, nine, ten or more 29 ± 0.2° 29 peaks as featuring in Table 23; as depicted in Figure 24; or as a combination thereof.

[0103] In one embodiment, the present invention comprises crystalline sabcomeline palmitate exhibiting two, three, four or more of the following peaks, 8.9, 11.9, 13.2, 14.9, 16.2, 17.1, 18.6, 19.0, 19.6, 20.1, 20.2, 21.4, 22.1, 23.0, 25.3, 25.4, 25.5, 25.6, 25.7 °29 ± 0.2 °29. In one embodiment, the present invention comprises crystalline sabcomeline palmitate exhibiting at least peaks at 11.9, 14.9, 19.0, 19.6 °29 ± 0.2 °29 and optionally exhibit one, two, three, four, five, six, seven, eight, nine, ten or more of the following peaks, 8.9, 13.2, 16.2, 17.1, 18.6, 20.1, 20.2, 21.4, 22.1, 23.0, 25.3, 25.4, 25.5, 25.6, 25.7 °29 ± 0.2 °29.

[0104] In one embodiment, the present invention comprises sabcomeline palmitate and wherein less than 5 % w / w of said crystalline sabcomeline palmitate exhibits peaks at 5.1, 10.2, 15.9 and 16.7 °29 ± 0.2 °29. In a further embodiment, the present invention comprises sabcomeline palmitate and wherein less than 5 % w / w, less than 4 % w / w, less than 3 % w / w, less than 2 % w / w, less than 1 % w / w or less than 0.5 % w / w of said sabcomeline palmitate exhibits peaks at 5.1, 10.2, 15.9 and 16.7 °29 ± 0.2 °29. In a still further embodiment, the present invention comprises sabcomeline palmitate which does not exhibit peaks at 5.1, 10.2, 15.9 and 16.7 °29 ± 0.2 °29.

[0105] In one embodiment, the present invention comprises solid state sabcomeline palmitate wherein the sabcomeline palmitate comprises a single polymorphic form of sabcomeline. In other embodiments, the solid state sabcomeline palmitate comprises two or more sabcomeline palmitate polymorphic forms. In a further embodiment, the solid state sabcomeline palmitate comprises about 50-100% Form III.

[0106] The present invention also encompasses the use of lipophilic acid salts of sabcomeline, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0107] The present invention also encompasses the use of sabcomeline stearate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0108] The present invention also encompasses the use of sabcomeline gentisate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0109] The present invention also encompasses the use of sabcomeline pamoate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0110] The present invention also encompasses the use of sabcomeline cinnamate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0111] The present invention also encompasses the use of sabcomeline decanoate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0112] The present invention also encompasses the use of sabcomeline octanoate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0113] The present invention also encompasses the use of sabcomeline dodecanoate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0114] The present invention also encompasses the use of sabcomeline palmitate, and solid-state forms thereof, for the preparation of compositions and pharmaceutical compositions.

[0115] While the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredient(s) in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliaries.

[0116] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising lipophilic acid salts of sabcomeline and solid-state forms thereof.

[0117] In another embodiment, the present invention encompasses pharmaceutical compositions comprising lipophilic acid salts of sabcomeline, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0118] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline stearate and solid-state forms thereof.

[0119] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline stearate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0120] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline gentisate and solid-state forms thereof.

[0121] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline gentisate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0122] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline pamoate and solid-state forms thereof.

[0123] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline pamoate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0124] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline cinnamate and solid-state forms thereof.

[0125] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline cinnamate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0126] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline decanoate and solid-state forms thereof.

[0127] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline decanoate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0128] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline octanoate and solid-state forms thereof.

[0129] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline octanoate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0130] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline dodecanoate and solid-state forms thereof.

[0131] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline dodecanoate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0132] In one embodiment of the invention, the present invention encompasses pharmaceutical compositions comprising sabcomeline palmitate and solid-state forms thereof.

[0133] In another embodiment, the present invention encompasses pharmaceutical compositions comprising sabcomeline palmitate, and solid-state forms thereof, and at least one pharmaceutically acceptable excipient.

[0134] The excipient(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0135] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.EXAMPLESExample 1: Aqueous solubility of sabcomeline HC1

[0136] An excess amount of the sabcomeline HC1 substance solid powder (Chemieliva biotech Co.) was added to HPLC glass vials (20-100 mg), and USP buffers at pH 1.6, 3, 5, 7, 9, and 11 were added (0.1-0.5 mL). Subsequently, the prepared samples were vortexed for 5 minutes, sonicated and stirred at 300 rpm at 25°C.

[0137] To chase the equilibrium solubility, any significant change in the pH of the buffer (i.e., > 0.5 pH unit) was treated by adding acid (HC1) or base (NaOH) to get it back to the nominal value. In addition, any clear solution was treated by adding additional powder. The samples were stirred at 25°C for 24 hours at 300 rpm. To remove any undissolved drug after the stirrer time, the samples were centrifuged for 15 minutes at 13,300 rpm speed. The supernatant was then removed and filtered via 0.2 pm centrifugal filter tubes. The obtained clear solutions were measured for pH and then diluted before HPLC injection.

[0138] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode on a 96 well plate and held on mylar polymer film. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. The results of the solubility screen are described in Table 2 and demonstrate that according to USP definitions, sabcomeline HC1 is considered to be freely water soluble (100 - 1000 mg / ml).Table 2Example 2: Hygroscopicity study of sabcomeline HC1

[0139] An empty vessel and stopper were weighted (Ml). Sabcomeline HC1 salt was placed in the vessel and closed by stopper and the vessel re-weighed (M2). The vessel was placed without the stopper in a desiccator for 24 hours at 25 °C and at 80 ± 2% relative humidity (RH). The vessel was then removed from the desiccator, the stopper added directly to the vessel and thetotal weight rerecorded (M3). The percentage increase in the mass was calculated according to the following equation: (M3-M2) / (M2-M1) xlOO.

[0140] The material was found to undergo deliquescence, changing from a white powder to a transparent solid. The calculated increase in mass was found to be 33.8%, thereby classifying sabcomeline HC1 under European Pharmacopoeia definitions as H-4 very hygroscopic (> 15% increase in mass at 80% RH / 24 hours).Example 3: Synthesis of sabcomeline free base

[0141] 50 mg of sabcomeline HC1 salt (Chemieliva biotech Co.) was weighed in a glass vial and dissolved in 40 pL of water. 35 mg of sodium carbonate was added to the solution and the resultant suspension vortexed until it mixed, after which it was allowed to evaporate to dryness and then dried further under vacuum overnight. 500 pL of methanol was then added to the resultant dried residue and stirred at ambient temperatures for 15 minutes. Solid residue was removed via centrifugal filtration and the filtrate transferred to a glass vial. The solids were washed with 200 pL of methanol and removed via centrifugal filtration. The combined filtrates were added together within a glass vial and died under nitrogen before being transferred to a vacuum desiccator for further drying overnight. The resultant oil was analyzed by proton NMR spectroscopy and the spectrum found to be consistent with that of sabcomeline free base.Example 4: Synthesis of sabcomeline oxalate

[0142] Attempts to synthesize sabcomeline oxalate were undertaken with the resultant forms assayed by NMR and XRPD.Example 4a: Synthesis of Sabcomeline Oxalate Form I

[0143] 30 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of 0. IM oxalic acid aqueous stock solution, mixed and stirred with a magnetic stirrer at ambient temperature. No precipitation was observed after two days, following which the vial was uncapped and left to evaporate at ambient temperature to yield a solid precipitate. The precipitate was isolated and NMR analysis of the isolate confirmed the compound to be sabcomeline oxalate. XRPD analysis of the isolated salt identified it as sabcomeline oxalate Form I and showed it to be crystalline with the XRPD pattern as shown in Figure 1.Example 4b: Synthesis of Sabcomeline Oxalate Form II

[0144] 25 mg of sabcomeline free base was combined within a glass vial together with an excess amount of 0. IM oxalic acid aqueous stock solution. The resultant solution was evaporated in a dessicator under vacuum to yield a solid precipitate. The precipitate was isolated and NMR analysis of the isolate confirmed the compound to be sabcomeline oxalate. XRPD analysis of the isolated salt identified it as sabcomeline oxalate Form II and showed it to be crystalline with the XRPD pattern as shown in Figure 2.Example 4c: Synthesis of Sabcomeline Oxalate Form III

[0145] 30 mg of sabcomeline free base was combined within a glass vial together with a twice equimolar amount of 0.1 M oxalic acid stock solution, mixed and stirred with a magnetic stirrer at ambient temperature. No precipitation was observed after two days, following which the vial was uncapped and left to evaporate at ambient temperature. As no precipitate was observed following the evaporation, the dried residue was slurried at room temperature in methanol to yield a solid precipitate. The precipitate was isolated and NMR analysis of the isolate confirmed the compound to be sabcomeline oxalate. XRPD analysis of the isolated salt identified it as sabcomeline oxalate Form III and showed it to be crystalline with the XRPD pattern as shown in Figure 3.Example 4d: Synthesis of Sabcomeline Oxalate Form IV

[0146] 30 mg of sabcomeline free base was combined within a glass vial together with 0.5 mol equivalent of 0. IM oxalic acid stock solution and THF, mixed and stirred with a magnetic stirrer at ambient temperature overnight to yield a solid precipitate. The precipitate was isolated and NMR analysis of the isolate confirmed the compound to be sabcomeline oxalate. XRPD analysis of the isolated salt identified it as sabcomeline oxalate Form IV and showed it to be crystalline with the XRPD pattern as shown in Figure 4.Example 4e: Synthesis of Sabcomeline Oxalate Form III + V (1:1 methanol: acetone)

[0147] 30 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of 0.1M oxalic acid stock solution and 250 pL of 1:1 methanol: acetone, mixed and stirred with a magnetic stirrer on a hot plate at 40 °C until dissolution was observed to occur, following which the sample was left to cool to yield a solid precipitate which was isolated. XRPD analysis of the isolated salt identified it as a mixture of sabcomeline oxalate Form III and Form V and showed it to be crystalline with the XRPD pattern as shown in Figure 5.Example 4f: Synthesis of Sabcomeline Oxalate Forms I + IV (1:1 methanokacetone)

[0148] 30 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of 0.1M oxalic acid stock solution and 250 pL of 1:1 methanokacetone, mixed and stirred with a magnetic stirrer for 2 days, following which the vial was uncapped and allowed to evaporate in a fume hood at ambient temperature to yield a solid precipitate which was isolated. XRPD analysis of the isolated salt identified it as a mixture of sabcomeline oxalate Form I and Form IV and showed it to be crystalline.Example 4g: Synthesis of Sabcomeline Oxalate Forms I + III (3:1 methanokacetone)

[0149] 30 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of 0.1M oxalic acid stock solution and 250 pL of 3:1 methanokacetone, mixed and stirred with a magnetic stirrer at ambient temperature for 2 days to yield a solid precipitate, following which the sample was left to cool to yield a solid precipitate which was isolated. XRPD analysis of the isolated salt identified it as a mixture of sabcomeline oxalate Form I and Form III and showed it to be crystalline.Example 4h: Synthesis of Sabcomeline Oxalate Forms I + VI (1:3 methanokacetone)

[0150] 285 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of 0.1M oxalic acid stock solution and 1.2 mF of 1:3 methanokacetone and the suspension was slurried overnight to yield a solid precipitate. The precipitate was isolated and NMR analysis of the isolate confirmed the compound to be sabcomeline oxalate. XRPD analysis of the isolated salt identified it as a mixture of sabcomeline oxalate Form I and Form VI and showed it to be crystalline with the XRPD pattern as shown in Figure 6.Example 4i: Melting Temperature Range Analysis of Sabcomeline Oxalate

[0151] The melting temperature range of the forms of sabcomeline oxalate, as prepared according to Examples la-h, were each identified using TG / DTA and the results shown in Table 3.Table 3

[0152] Three small samples of the compound of Example 4h were also placed into glass capillaries, introduced into a Biichi B-545 Melting Point Apparatus and heated at a constant ramp rate of l°C / min. The range of melting points, as recorded by visual observation, was 152.4 - 152.7°C.Example 4j : Aqueous solubility of sabcomeline oxalate

[0153] The aqueous solubility of sabcomeline oxalate Forms I - IV and I + VI were each estimated via the aliquot addition method. A weighed aliquot of about 10 mg of each form of sabcomeline oxalate were added to glass vials and aliquots of water added until dissolution was observed. The first 100 pL was added in 20 p L aliquots. The volume was made up to 200 pL in 50 pL aliquots, and the volume was made up to 1 mL in 100 pL aliquots with the aqueous solubility of the salt forms determined as shown in Table 4. The results of the solubility screen demonstrate that according to USP definitions, sabcomeline oxalate is considered to be freely water soluble (100-1000 mg / ml).Table 4Example 5: Synthesis of sabcomeline stearate (20 mg scale)

[0154] 20 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of stearic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of THF, following which precipitation was observed. The precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline monostearate with a melting temperature range of 31 - 48 °C as identified by TG / DTA.

[0155] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated stearate salt identified it as sabcomeline stearate Form I and showed it to be highly crystalline with the XRPD pattern as shown in Figure 7 and as having peaks as reported in Table 5.Table 5Example 6: Synthesis of sabcomeline stearate (100 mg scale)

[0156] 100 mg of sabcomeline free base together with an equimolar amount of stearic acid were weighed into a vial. 666 pL of THF was added and the suspension stirred at ambient temperature overnight producing a cloudy suspension. This suspension was then seeded with sabcomeline stearate Form I and stirred together for a further five days. Solids precipitated from the suspension and were isolated via centrifugation and decantation followed by air drying. NMR analysis of the isolate confirmed the compound to be sabcomeline monostearate with a melting temperature range of 42 - 50 °C as identified by TG / DTA.

[0157] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated stearate salt identified it as sabcomeline stearate Form II and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 8 and as reported in Table 6.Table 6Example 7: Synthesis of sabcomeline stearate (300 mg scale)

[0158] 300 mg of sabcomeline free base together with an equimolar amount of stearic acid were weighed into a vial. 1998 pF p L of THF was added and the suspension stirred overnight. The suspension dissolved forming a solution to which seeds of sabcomeline Form I were added and the mixture stirred overnight. The resultant solution became cloudy without observable precipitation. The solution was evaporated under a stream of Nj and additional seeds added with the resultant, concentrated solution stirred at ambient temperatures for four days after which the vial was uncapped, the solution allowed to evaporate and a gel recovered which was stirred in 400 pL of heptane for five days following which solid material precipitated. NMR analysis of the material confirmed the compound to be sabcomeline monostearate with a melting temperature range of 44 - 48 °C as identified by TG / DTA.

[0159] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated stearate salt identified it as sabcomeline stearate Form III and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 9 and as reported in Table 7.Table 7Example 8: Synthesis of sabcomeline gentisate (20 mg scale)Example 8a

[0160] A 0.1M solution of 15 mg of sabcomeline free base was combined within a virgin glass vial together with an equimolar amount of gentisic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of methanol, following which the vial was uncapped and the suspension allowed to evaporate. A gel was recovered which was stirred overnight in heptane following which the precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline monogentisate with a melting temperature range of 151 - 158 °C as identified by TG / DTA.

[0161] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated gentisate salt identified it as sabcomeline gentisate Form I and showed it to be crystalline with the XRPD pattern having peaks as reported in Table 8.Table 8Example 8b

[0162] A 0.1M solution of 30 mg of sabcomeline free base was combined within a virgin glass vial together with an equimolar amount of gentisic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of methanol, following which the vial was uncapped and the suspension allowed to evaporate. A gel was recovered which was stirred overnight in heptane following which the precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline monogentisate with approximately 0.6mol eq of heptane present with a melting temperature range of 150 - 161 °C as identified by TG / DTA.

[0163] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated gentisate salt identified it as sabcomeline gentisate Form II and showed it to be crystalline with the XRPD pattern having peaks as reported in Table 9.Table 9Example 9: Synthesis of sabcomeline gentisate (100 mg scale)

[0164] 100 mg of sabcomeline free base together with an equimolar amount of gentisic acid were weighed into a vial. 666 pL of Heptane was added and the suspension stirred at ambient temperature overnight. Solids precipitated from the suspension and were isolated via centrifugation and decantation followed by air drying with a melting temperature range of 108 - 123 °C as identified by TG / DTA.

[0165] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated gentisate salt identified it as a mixture of sabcomeline gentisate Forms II and III and showed it to be crystalline having peaks as reported in Table 10.Table 10

[0166] The remaining material was stirred at ambient temperatures for an additional five days following which a repeat XRPD analysis was performed which indicated that the material remained a mixture of sabcomeline gentisate Forms II and III.Example 10: Synthesis of sabcomeline gentisate (300 mg scale)

[0167] 300 mg of sabcomeline free base and an equimolar amount of gentistic acid were weighed into a glass vial. 2.4 mL of methanol was added and the material slurried overnight prior to its recovery. As shown in Figure 10, the isolate was found to be composed of small solid particles that formed aggregates or agglomerates. NMR analysis of the isolate confirmed the compound to be sabcomeline monogentisate with a melting temperature range of 160 - 163 °C as identified by TG / DTA.

[0168] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated gentisate salt which identified it as sabcomeline gentisate Form II and showed it to be highly crystalline and with the XRPD pattern as shown in Figure 11 and as having the XRPD pattern having peaks as reported in Table 9.Example 11: Synthesis of sabcomeline pamoate (20 mg scale)

[0169] 20 mg of sabcomeline free base was combined within a virgin glass vial together with an equimolar amount of pamoic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of THF (200 pF), following which precipitation was observed. The precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline pamoate with a stoichiometry of -1:1.8 sabcomeline:pamoic acid and approximately ~0.5mol eq of THF and with a melting temperature range of 126 - 140 °C as identified by TG / DTA.

[0170] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated pamoate salt identified it as sabcomeline pamoate Form I and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 13 and as reported in Table 11.Table 11Example 12: Synthesis of sabcomeline pamoate (100 mg scale)

[0171] 100 mg of sabcomeline free base together with an equimolar amount of pamoic acid were weighed into a vial. 666 pL of THF was added and the suspension stirred at ambient temperature overnight. Solids precipitated from the suspension and were isolated viacentrifugation and decantation followed by air drying. As shown in Figure 12, the isolate was found to be crystalline. NMR analysis of the isolate confirmed the compound to be sabcomeline monopamoate with a melting temperature range of 211 - 220 °C as identified by TG / DTA.

[0172] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated pamoate salt identified it as sabcomeline pamoate Form II and showed it to be crystalline with the XRPD pattern as shown in Figure 14 and as having peaks as reported in Table 12.Table 12Example 13: Synthesis of sabcomeline pamoate (300 mg scale)

[0173] 300 mg of sabcomeline free base together with an equimolar amount of pamoic acid were weighed into a vial. 1998pL of THF was added and the suspension stirred overnight. An aliquot of the slurry was removed and the solid isolated via centrifugal filtration. NMR analysis of the isolate confirmed the compound to be sabcomeline monopamoate.

[0174] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated pamoate salt identified it as sabcomeline pamoate Form III and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 15 and as reported in Table 13.Table 13

[0175] The remaining solids were isolated via centrifugation and decantation and air dried. XRPD analysis of the isolated pamoate salt identified it as sabcomeline pamoate Form IV and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 16 and as reported in Table 14.Table 14Example 14: Synthesis of sabcomeline cinnamate (20 mg scale)

[0176] A 0.1M solution of 20 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of cinnamic acid resulting in a gel which was stirred over night with a magnetic stirrer at ambient temperature in an excess of Heptane, following which precipitation was observed. The precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline monocinnamate with a melting temperature range of 72 - 79 °C as identified by TG / DTA.

[0177] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plusv4.9 software. XRPD analysis of the isolated cinnamate salt identified it as sabcomeline cinnamate Form I and showed it to be crystalline with the XRPD pattern as shown in Figure 17 and as having peaks as reported in Table 15.Table 15Example 15: Synthesis of sabcomeline decanoate (20 mg scale)

[0178] A 0.1M solution of 20 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of decanoic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of methanol. No precipitation was observed after one day, following which the vial was uncapped and left to evaporate at ambient temperature to yield a solid precipitate. The precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline decanoate with a stoichiometry of -1:1.3 sabcomeline:decanoic acid with a melting temperature range of 88 - 93 °C as identified by TG / DTA.

[0179] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated decanoate salt identified it as sabcomeline decanoate Form I and showed it to be crystalline with the XRPD pattern as shown in Figure 18 and as having peaks as reported in Table 16.Table 16Example 16: Synthesis of sabcomeline octanoate (20 mg scale)

[0180] A 0.1M solution of 20 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of octanoic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of ethanol. No precipitation was observed so the vial was uncapped and left to evaporate at ambient temperature to yield a gel, which was then stirred overnight in Heptane (200pL) and a precipitate isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline octanoate with a stoichiometry of ~1: 1.3 sabcomelineioctanoate acid with a melting temperature range of 71 - 78 °C as identified by TG / DTA.

[0181] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system.The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated octanoate salt identified it as sabcomeline octanoate Form I and showed it to be crystalline with the XRPD pattern as shown in Figure 19 and as having peaks as reported in Table 17.Table 17Example 17: Synthesis of sabcomeline dodecanoate (20 mg scale)

[0182] A 0.1M solution of 20 mg of sabcomeline free base was combined within a glass vial together with an equimolar amount of dodecanoic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of methanol. No precipitation was observed after one day, following which the vial was uncapped and left to evaporate at ambient temperature to yield a solid precipitate. The precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline dodecanoate with a stoichiometry of ~1: 1.4 sabcomelineidodecanoic acid with a melting temperature range of 89 - 97 °C as identified by TG / DTA.

[0183] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated dodecanoate salt identified it as sabcomeline dodecanoate Form I and showed it to be crystalline with the XRPD pattern as shown in Figure 20 and as having peaks as reported in Table 18.Table 18Example 18: Synthesis of sabcomeline palmitate (20 mg scale)

[0184] A 0.1M solution of 20 mg of sabcomeline free base was combined within a virgin glass vial together with an equimolar amount of palmitic acid and stirred over night with a magnetic stirrer at ambient temperature in an excess of methanol, following which the vial was uncapped and the suspension allowed to evaporate. A gel was recovered which was stirred overnight in heptane following which the precipitate was isolated. NMR analysis of the isolate confirmed the compound to be sabcomeline palmitate with a stoichiometry of sabcomelineipalmitic acid of -1:1.6.

[0185] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated pamoate salt identified it as sabcomeline palmitate Form I and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 21 and as reported in Table 19.Table 19Example 19: Synthesis of sabcomeline palmitate (100 mg scale)

[0186] 100 mg of sabcomeline free base and an equimolar amount of palmitic acid were weighed into a vial. Heptane / EtOAc (90: 10) was added and the suspension stirred at ambient temperature overnight. Solids precipitated from the suspension. An aliquot was isolated viafrom the precipitation by centrifugal filtration and analyzed by XRPD. 50 pL of EtOAc was added to the remaining solid and the suspension stirred for a further 5 days. NMR analysis confirmed the structure to be sabcomeline monopalmitate with a melting temperature range of 31 - 35 °C as identified by TG / DTA. Isolated precipitate of the solid was then analyzed by XRPD.

[0187] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of both isolated salt samples identified it as sabcomeline palmitate Form II and showed it to be highly crystalline and with the XRPD pattern as shown in Figure 22 and as having peaks as reported in Table 20.Table 20Example 20: Synthesis of sabcomeline palmitate (300 mg scale)

[0188] 300 mg of sabcomeline free base together with an equimolar amount of palmitic acid were weighed into a vial. 1998pL of Heptane / EtOAc (90: 10) was added and the suspension stirred overnight. The resultant solution was blown down and concentrated under N2, seeded with sabcomeline palmitate Form II and stirred for four days at ambient temperature. An aliquot of the slurry was removed and the solid isolated via centrifugal filtration. NMR analysis of the isolate confirmed the compound to be sabcomeline monopalmitate with a melting temperature range of 38 - 42 °C as identified by TG / DTA.

[0189] XRPD analyses of the residual particles were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held on polymer films. XRPD patterns were sorted, manipulated, and indexed using HighScore Plus v4.9 software. XRPD analysis of the isolated palmitate salt identified it as sabcomeline palmitate Form III and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 23 and as reported in Table 21.Table 21Example 21: Solvent solubility of lipophilic acid salts of sabcomelineExample 21a: aliquot method

[0190] The solubility of various lipophilic acid salts of sabcomeline in a variety of solvents was estimated via the aliquot addition method. A weighed aliquot of 10 - 20 mg of the lipophilic sabcomeline salt was added to a virgin glass vial and aliquots of solvent added until dissolution was observed. The first 100 pL was added in in 20 pL aliquots. The volume was made up to 200 pL in 50 pL aliquots, and the volume was made up to 1 mL in 100 pL aliquots. The results of the solubility screen are shown in Table 22.Table 22DMSO - dimethyl sulfoxideDCM - DichloromethaneEtOAc - ethyl acetateNMP - N-methyl-2-2pyrrolidoneExample 21b: HPLC method

[0191] 50 mg of sabcomeline pamoate, stearate and palmitate were transferred into separate 20 mL vials to which 5 mL of water was individually then added to each. The resultant solution was shaken at 37 °C in water bath and sampled by HPLC at 24 hours to assay each salts solubility. The results of the solubility screen demonstrate that according to USP definitions, each of sabcomeline pamoate (2.0 mg / ml), stearate (9.4 mg / ml) and palmitate (8.7 mg / ml) are considered to be slightly soluble (1-10 mg / ml).Example 22: Hygroscopicity study of lipophilic acid salts of sabcomeline

[0192] The hygroscopicity of about 40 mg of sabcomeline stearate Form III, sabcomeline gentisate Form II, sabcomeline pamoate Form II and sabcomeline palmitate Form III were assayed according to the methods described in Sihorkar et al (Pharmaceutical Dev. & Technol. (2013), 18(2), 348-358) as a step profile of 10 % increments from 40 to 90 % relative humidity followed by desorption from 90 to 0 % relative humidity and a second sorption cycle from 0 to 40 % relative humidity. The weight change was monitored during the sorption cycle by Dynamic Vapour Sorption (DVS). Sabcomeline gentisate and sabcomeline pamoate were found to increase in weight only 0.12% and 0.02%, respectively, thereby classifying the salts under European Pharmacopoeia definitions as H-l non hygroscopic (< 0.2% increase in mass at 80% RH / 24 hours). Sabcomeline stearate and sabcomeline palmitate were found to increase in weight 0.61% and 0.94%, respectively, thereby classifying the salts under European Pharmacopoeia definitions as H-2 slightly hygroscopic (> 0.2% but < 2% increase in mass at 80% RH / 24 hours).

[0193] A Post DVS XRPD analysis was conducted with the XRPD analysis of the isolated palmitate salt and identified it as sabcomeline palmitate Form IV and showed it to be crystalline with the XRPD pattern having peaks as shown in Figure 24 and as reported in Table 23. Table 23

[0194] The invention described herein may be practiced in the absence of any element or limitation which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms “comprising,” “consisting essentially of’ and “consisting of’ may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, andthat such modifications and variations are considered to be within the scope of this invention as defined by the appended claims

Claims

What is claimed is:

1. A lipophilic acid salt of sabcomeline.

2. Sabcomeline Stearate.

3. Sabcomeline Gentisate.

4. Sabcomeline Pamoate.

5. Sabcomeline Cinnamate.

6. Sabcomeline Decanoate.

7. Sabcomeline Octanoate.

8. Sabcomeline Dodecanoate.

9. Sabcomeline Palmitate.

10. The lipophilic acid salt of sabcomeline having an XRPD substantially as depicted in any of Figures 7 - 9, 11 or 13 - 24.

11. A pharmaceutical composition comprising a lipophilic acid salt of sabcomeline and at least one pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11, wherein the lipophilic acid salt of sabcomeline is present in the composition as a single polymorphic form.

13. The pharmaceutical composition of claim 11, wherein the lipophilic acid salt of sabcomeline is present in the composition as a mixture of two or more polymorphic forms.

14. A solid state form of a lipophilic acid salt of sabcomeline.

15. A method of preparing a lipophilic acid salt of sabcomeline as described herein.

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