Solid state forms of buntanetap and process for preparation thereof

Abstract

The present disclosure encompasses solid state forms of Buntanetap, in embodiments crystalline polymorphs of Buntanetap or salts of Buntanetap, particularly Buntanetap tartrate, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF BUNTANETAP AND PROCESS FOR PREPARATIONTHEREOFFIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Buntanetap, in embodiments crystalline polymorphs of Buntanetap or salts of Buntanetap, particularly Buntanetap tartrate, processes for preparation thereof, and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0002] Buntanetap, (3aR,8aS)-l,3a,8-trimethyl-l,2,3,3a,8,8a-hexahydropyrrolo(2,3- b)indol-5-yl phenylcarbamate, has the following chemical structure:

[0003] Buntanetap is a translational inhibitor of neurotoxic aggregating proteins (TINAPs), and it is developed for the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

[0004] The compound is described in Heterocycles 1988, 27(3), 745-750 and Medicinal Chemistry Research (1995) 5(4), 265-70. The process for preparation of Buntanetap is provided in The Journal of Organic Chemistry 2012, 77, 1, 725-728.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule 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 diffraction (XRD) pattern, infrared 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.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemi cal / phy si cal stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Buntanetap.SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Buntanetap, Buntanetap salts, particularly Buntanetap tartrate and their solid state forms.

[0009] The present disclosure also provides uses of the said solid state forms of Buntanetap in the preparation of other solid state forms of Buntanetap or salts of Buntanetap, particularly Buntanetap tartrate.

[0010] The present disclosure provides crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate for use in medicine, including for the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

[0011] The present disclosure also encompasses the use of crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate may be used as medicaments, such as for the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

[0015] The present disclosure also provides methods of treating Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries, or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g. Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Buntanetap Form A.

[0018] Figure 2 shows a characteristic XRPD of Buntanetap D-tartrate Form BT1.

[0019] Figure 3 shows a characteristic XRPD of Buntanetap D- tartrate Form BT2.

[0020] Figure 4 shows a characteristic XRPD of Buntanetap L-tartrate Form BT3.

[0021] Figure 5 shows a characteristic XRPD of Buntanetap L-tartrate amorphous form.

[0022] Figure 6 shows a characteristic XRPD of Buntanetap D-tartrate Form BT4.

[0023] Figure 7a shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT1 (full scan).

[0024] Figure 7b shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT1 (at the range of 0-100 ppm).

[0025] Figure 7c shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT1 (at the range of 100-200 ppm).

[0026] Figure 8a shows solid state13C NMR spectrum of Buntanetap L-tartrate Form BT3 (full scan).

[0027] Figure 8b shows solid state13C NMR spectrum of Buntanetap L-tartrate Form BT3 (at the range of 0-100 ppm).

[0028] Figure 8c shows solid state13C NMR spectrum of Buntanetap L-tartrate Form BT3 (at the range of 100-200 ppm).

[0029] Figure 9a shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT4 (full scan).

[0030] Figure 9b shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT4 (at the range of 0-100 ppm).

[0031] Figure 9c shows solid state13C NMR spectrum of Buntanetap D-tartrate Form BT4 (at the range of 100-200 ppm).DETAILED DESCRIPTION OF THE DISCLOSURE

[0032] The present disclosure encompasses solid state forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, including crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, processes for preparation thereof, and pharmaceutical compositions thereof. In embodiments, the present disclosure provides crystalline form of Buntanetap designated as Form A, Buntanetap L-tartrate designated as Form BT3, and Buntanetap D-tartrate designated as Form BT1, Form BT2 and Form BT4 (defined herein).

[0033] Solid state properties of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and crystalline polymorphs thereof can be influenced by controlling the conditionsunder which Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and crystalline polymorphs thereof are obtained in solid form.

[0034] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate. In some embodiments of the disclosure, the described crystalline polymorph of Buntanetap, or salts of Buntanetap. Particularly Buntanetap tartrate may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate. Thus, for example, a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate. As another example, a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate. Thus, a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate. Alternatively, a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate according to any aspect or embodiment of the present invention may be polymorphically pure and may contain greater than about 80% (w / w),greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate.

[0035] The crystalline forms of Buntanetap D-tartrate, Buntanetap L-tartrate, or Buntanetap as described in any aspect or embodiment, is polymorphically pure, or substantially free of any other forms of Buntanetap D-tartrate, Buntanetap L-tartrate, or Buntanetap, respectively.

[0036] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. Particularly, the crystalline forms of Buntanetap D-tartrate, Buntanetap L-tartrate, or Buntanetap as described in any aspect or embodiment, may be advantageously stable, for example to storage under different relative humidity conditions, or may be thermally stable, or may be stable to pharmaceutically processing steps, such as grinding, or compaction steps.

[0037] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. 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 cannot 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 certain factors such as, but not limited to, 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 or two different crystal forms. A crystal form of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” aFigure will thus be understood to include any crystal forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0038] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate, relates to a crystalline form of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0039] The term “solvate,” as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a “hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0040] As used herein, the term “isolated” in reference to crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure corresponds to a crystalline polymorph of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate that is physically separated from the reaction mixture in which it is formed.

[0041] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuKa radiation, = 1.5418 A, typically at a temperature of 25 ± 3 °C.

[0042] As used herein, unless stated otherwise,13C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency a>r / 2.n = 11 kHz, preferably at a temperature of at 293 K ± 3 °C.

[0043] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT .” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0044] 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 10 V) 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 a 5 grams of a materialin 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 “N / N” 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 solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0045] 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 10-18 hours, in some cases about 16 hours.

[0046] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0047] As used herein and unless indicated otherwise, the term “ambient conditions” refer to atmospheric pressure and a temperature of 22-24 °C.

[0048] The present disclosure includes a crystalline polymorph of Buntanetap, designated Form A. The crystalline Form A of Buntanetap may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 8.0, 12.1, 17.5, 19.0 and 24.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0049] Crystalline Form A of Buntanetap may be further characterized by an X-ray powder diffraction pattern having peaks at 8.0, 12.1, 17.5, 19.0 and 24.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 13.2, 16.7, and 21.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] According to any aspect or embodiment, crystalline Form A of Buntanetap may be further characterized by an X-ray powder diffraction pattern having an absence of peaks at: 2.5 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 2.8 to 7.3 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 8.5 to 11.6 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 8.8 to 11.3 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 14.4 to 15.0 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 14.6 to 14.8 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 25.4 to 25.6 degrees 2-theta ± 0.2 degrees 2- theta.

[0051] In one embodiment of the present disclosure, crystalline Form A of Buntanetap is isolated. Crystalline Form A of Buntanetap as described according to any aspect or embodiment may preferably be isolated.

[0052] Crystalline Form A of Buntanetap may be anhydrous form. Crystalline Form A of Buntanetap as described according to any aspect or embodiment may preferably be an anhydrous form.

[0053] Crystalline Form A of Buntanetap may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 8.0, 12.1, 17.5, 19.0 and 24.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0054] The present disclosure includes crystalline Buntanetap D-tartrate.

[0055] The crystalline Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] The present disclosure includes a crystalline polymorph of Buntanetap D-tartrate, designated BT1. The crystalline Form BT1 of Buntanetap D-tartrate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 26.0, 73.2, 74.6, 122.6, 124.5, 127.6, 131.3, 134.9, 139.8, 145.3, 154.5, 154.9 and 175.1 ppm ± 0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 27.6, 19.6, 21.0, 69.0, 70.9, 74.0, 77.7, 81.3, 86.2, 91.7, 100.9, 101.3 and 121.5 ppm ± 0.1; a solid state13C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c; and combinations of these data.

[0057] Crystalline Form BT1 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, crystalline Form BT1 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at: 8.5, 12.0, 16.1, 17.4, 18.6, 19.6, 20.0 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0058] Alternatively, Crystalline Form BT1 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BT1 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6 and20.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 15.0, 15.5, and 17.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0059] Crystalline Form BT1 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 15.0, 15.5, 17.4, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] According to any aspect or embodiment, the crystalline Form BT1 of Buntanetap D-tartrate may be characterized by any of the X-ray powder diffraction having the peaks disclosed herein, and further characterized by one, two or three of: an X-ray powder diffraction pattern having an absence of peaks at 2.5 to 3.8 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 2.8 to 3.6 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 4.9 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 5.2 to 7.8 degrees 2-theta ± 0.2 degrees 2- theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 9.0 to 11.0 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 9.2 to 10.5 degrees 2- theta ± 0.2 degrees 2-theta).

[0061] In one embodiment of the present disclosure, crystalline Form BT1 of Buntanetap D-tartrate is isolated. Crystalline Form BT1 of Buntanetap as described according to any aspect or embodiment may preferably be isolated.

[0062] Crystalline Form BT1 of Buntanetap D-tartrate may be anhydrous form. Crystalline Form BT1 of Buntanetap as described according to any aspect or embodiment may preferably be an anhydrous form.

[0063] Crystalline Form BT1 of Buntanetap D-tartrate may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0064] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT1 of Buntanetap D-tartrate may comprise reacting Buntanetap with D-(-)- Tartaric acid in acetone.

[0065] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT1 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap and D-(-)-Tartaric acid in acetone;(ii) optionally isolating; and(iii) optionally drying.

[0066] The process may particularly comprise:(i) preparing a solution of Buntanetap and D-(-)-Tartaric acid in acetone, optionally with heating;(ii) isolating; and(iii) drying.

[0067] According to any aspect or embodiment of the disclosed processes for preparing Form BT1 of Buntanetap D-tartrate, the acetone may be used in an amount of: about 30 ml to about 70 ml, about 40 ml to about 60 ml, or about 50 ml, per gram of Buntanetap.

[0068] According to an aspect or embodiment of the process for making Form BT1 of Buntanetap D-tartrate, D-(-)-Tartaric acid is preferably used in excess. Particularly, D-(-)- Tartaric acid may be used in an amount of: about 0.3 g to about 0.7 g, or about 0.5g, per gram of Buntanetap. The solution in step (i) may be at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The solution in step (i) may be stirred at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The stirring may be carried out over a period of about 1 hour to about 3 hours, to about 1.5 hours to about 3.5 hours or, to about 2 hours. During this time, Buntanetap D-tartrate may precipitate from the solution, forming a slurry. The slurry may be maintained at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C, optionally for period of: about 1 hours to about 3 hours, to about 1.5 hours to about 3.5 hours or, to about 2 hours. The slurry may be cooled, preferably to a temperature of: about 20 °C to about 45 °C, about 22 °C to about 40 °C, or about 25 °C.

[0069] The process may further include isolating the obtained Buntanetap D-tartrate, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration at a temperature of: about 15 °C to about 35 °C, about 20 °C to about 30 °C, or about 25 °C for period of about 5 minutes to about 30 minutes; 10 minutes to about 20 minutes; or about 15 minutes. Following isolation, the Buntanetap D-tartrate may be dried. The drying may be carried out under vacuum at a temperature of: about 50 °C to about 80 °C, about 55 °C to about 70 °C, or about 60 °C for the period of: about 1 hour to about 4 hours, about 1 hour to about 3 hours to about 1 hour to about 2.5 hours or about 2 hours.

[0070] According to any aspect or embodiment of the disclosed processes for preparing Form BT1 of Buntanetap D-tartrate, the process may further comprise combining the Form BT1 of Buntanetap D-tartrate with at least one pharmaceutically acceptable excipient to prepare pharmaceutical composition.

[0071] The crystalline Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] The present disclosure includes a crystalline polymorph of Buntanetap D-tartrate, designated BT2. The crystalline Form BT2 of Buntanetap D-tartrate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0073] Crystalline Form BT2 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Alternatively, Crystalline Form BT2 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Form BT2 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 13.2, 13.7 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0075] Crystalline Form BT2 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 13.2, 13.7, 14.6, 18.2 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] According to any aspect or embodiment, the crystalline Form BT2 of Buntanetap D-tartrate may be characterized by any of the X-ray powder diffraction having the peaks disclosed herein, and further characterized by one, two or three of: an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 3.5 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 3.2 to 3.4 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 4.5 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 4.7 to 7.2 degrees 2-theta ± 0.2 degrees 2- theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 16.5 to 16.9 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 16.6 to 16.8 degrees 2-theta ± 0.2 degrees 2-theta).

[0077] In one embodiment of the present disclosure, crystalline Form BT2 of Buntanetap D-tartrate is isolated. Crystalline Form BT2 of Buntanetap as described according to any aspect or embodiment may preferably be isolated.

[0078] Crystalline Form BT2 of Buntanetap D-tartrate may be hydrate form. Crystalline Form BT2 of Buntanetap as described according to any aspect or embodiment may preferably be a hydrate form.

[0079] Crystalline Form BT2 of Buntanetap D-tartrate may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0080] The present disclosure includes a crystalline polymorph of Buntanetap L-tartrate, designated BT3. The crystalline Form BT3 of Buntanetap L-tartrate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 24.5, 27.3, 37.0, 55.7, 97.2, 99.3, 128.1, 137.6, 143.6, 152.1, 173.1, 176.0 and 178.7 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.3 ppm ± 2 ppm of 28.8, 26.0, 16.3, 2.4, 43.9, 46.0, 74.8, 84.3, 90.3, 98.8, 119.8, 122.7 and 125.4 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 8a, 8b or 8c and combinations of these data.

[0081] Crystalline Form BT3 of Buntanetap L-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1 and 22.7 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 15.3, 20.5 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0082] Crystalline Form BT3 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 15.3, 16.0, 17.1, 19.1, 20.5, 21.1, 22.7 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0083] According to any aspect or embodiment, the crystalline Form BT3 of Buntanetap D-tartrate may be characterized by any of the X-ray powder diffraction having the peaks disclosed herein, and further characterized by one, two or three of: an absence of peaks at 3.5 to 3.9 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 3.6 to 3.8 degrees 2-theta ± 0.2 degrees 2-theta); and / or an absence of peaks at 4.9 to 8.1 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 5.2 to 7.8 degrees 2-theta ± 0.2 degrees 2- theta); and / or an absence of peaks at 14.0 ± 0.2 degrees 2-theta.

[0084] In one embodiment of the present disclosure, crystalline Form BT3 of Buntanetap L-tartrate is isolated. Crystalline Form BT3 of Buntanetap as described according to any aspect or embodiment may preferably be isolated.

[0085] Crystalline Form BT3 of Buntanetap L-tartrate may be anhydrous form. Crystalline Form BT3 of Buntanetap as described according to any aspect or embodiment may preferably be an anhydrous form.

[0086] Crystalline Form BT3 of Buntanetap L-tartrate may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 16.0, 17.1, 19.1, 21.1 and 22.7 degrees 2 -theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0087] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT3 of Buntanetap L-tartrate may comprise reacting Buntanetap with L-(+)- Tartaric acid in acetone.

[0088] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT3 of Buntanetap L-tartrate may comprise:(i) dissolving Buntanetap and L-(+)-Tartaric acid in acetone;(ii) optionally isolating Buntanetap L-tartrate; and(iii) optionally drying.

[0089] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT3 of Buntanetap L-tartrate may comprise:(i) preparing a solution of Buntanetap and L-(+)-Tartaric acid in acetone, optionally with heating;(ii) isolating; and(iii) drying.

[0090] According to any aspect or embodiment of the disclosed processes for preparing Form BT3 of Buntanetap L-tartrate, the acetone may be used in an amount of: about 30 ml to about 70 ml, about 40 ml to about 60 ml, or about 50 ml, per gram of Buntanetap.

[0091] According to an aspect or embodiment of the process for making Form BT3 of Buntanetap L-tartrate, L-(+)-Tartaric acid is preferably used in excess. Particularly, L-(+)- Tartaric acid is used in an amount of: about 0.3 g to about 0.7 g, or about 0.5g, per gram of Buntanetap. The solution in step (i) may be at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The solution in step (i) may be stirred at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The stirring may be carried out over a period ofabout 1 hour to about 3 hours, to about 1.5 hours to about 3.5 hours or, to about 2 hours. During this time, Buntanetap D-tartrate may precipitate from the solution, forming a slurry. The slurry may be maintained at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C, optionally for period of: about 1 hours to about 3 hours, to about 1.5 hours to about 3.5 hours or, to about 2 hours. The slurry may be cooled, preferably to a temperature of: about 20 °C to about 45 °C, about 22 °C to about 40 °C, or about 25 °C.

[0092] The process may further include isolating the obtained Buntanetap L-tartrate, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration at a temperature of: about 15 °C to about 35 °C, about 20 °C to about 30 °C, or about 25 °C for period of about 5 minutes to about 30 minutes; 10 minutes to about 20 minutes; or about 15 minutes. Following isolation, the Buntanetap L-tartrate may be dried. The drying may be carried out under vacuum at a temperature of: about 50 °C to about 80 °C, about 55 °C to about 70 °C, or about 60 °C for the period of: about 4 hours, about 1 hour to about 3 hours to about 1 hour to about 2.5 hours or about 2 hours.

[0093] According to any aspect or embodiment of the disclosed processes for preparing Form BT3 of Buntanetap L-tartrate, the process may further comprise combining the Form BT3 of Buntanetap L-tartrate with at least one pharmaceutically acceptable excipient to prepare pharmaceutical composition.

[0094] The present disclosure includes a crystalline polymorph of Buntanetap D-tartrate, designated BT4. The crystalline Form BT4 of Buntanetap D-tartrate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 23.8, 72.3, 96.0, 97.7, 106.3, 118.9, 129.1, 138.4, 144.2, 148.3, 152.5 and 179.7 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 29.8, 18.7, 42.4, 44.1, 52.7, 65.3, 75.5, 84.8, 90.6, 152.5 and 126.1 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 9a, 9b or 9c and combinations of these data.

[0095] Crystalline Form BT4 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0096] Alternatively, Crystalline Form BT4 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BT4 of Buntanetap D-tartrate may be further characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 8.5, 15.7, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0097] Crystalline Form BT4 of Buntanetap D-tartrate may be characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.5, 10.3, 11.2, 15.7, 26.3, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0098] According to any aspect or embodiment, the crystalline Form BT4 of Buntanetap D-tartrate may be characterized by any of the X-ray powder diffraction having the peaks disclosed herein, and further characterized by one, two, three, four, or five of: an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 4.6 degrees 2-theta ± 0.2 degrees 2-theta an absence of peaks at 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 5.6 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 5.8 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 9.0 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 9.2 to 9.6 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 13.9 to 14.2 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 14.0 to 14.2 degrees 2-theta ± 0.2 degrees 2-theta); and / or an X-ray powder diffraction pattern having an absence of peaks at 18.5 to 19.2 degrees 2-theta ± 0.2 degrees 2-theta (preferably an absence of peaks at 18.8 to 19.0 degrees 2-theta ± 0.2 degrees 2-theta).

[0099] In one embodiment of the present disclosure, crystalline Form BT4 of Buntanetap D-tartrate is isolated. Crystalline Form BT4 of Buntanetap as described according to any aspect or embodiment may preferably be isolated.

[0100] Crystalline Form BT4 of Buntanetap D-tartrate may be hydrate form. Crystalline Form BT4 of Buntanetap as described according to any aspect or embodiment may preferably be a hydrate form.

[0101] Crystalline Form BT4 of Buntanetap D-tartrate may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern havingpeaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0102] According to any aspect or embodiment, the process for preparing Form BT4 of Buntanetap L-tartrate may comprise reacting Buntanetap with D-(-)-Tartaric acid in a mixture of acetone and water. The product may be precipitated from the reaction mixture by the addition of a suitable antisolvent, preferably methyl tert-butyl ether (MTBE).

[0103] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT4 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap and D-(-)-Tartaric acid in a mixture of water and acetone;(ii) combining the solution of step (i) with MTBE(iii) optionally isolating; and(iv) optionally drying.

[0104] According to any aspect or embodiment of the disclosed processes for preparing Form BT4 of Buntanetap D-tartrate, the acetone may be used in an amount of: about 3 ml to about 7 ml, about 4 ml to about 6 ml, or about 5.4 ml, per gram of Buntanetap. The water may be used in an amount of: about 0.3 ml to about 0.7 ml, about 0.4 ml to about 0.65 ml, or about 0.6 ml, per gram of Buntanetap. The mixture of water and acetone comprise about 2% to about 20% water, about 5% to about 15% water, or about 10% water. The solution in step (i) may be at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The solution in step (i) is combined with MTBE, preferably by addition of the solution in step (i) to MTBE. The MTBE may be at a temperature of: about 15 °C to about 40 °C, about 20 °C to about 30 °C, or about 25 °C. The MTBE may be used in an amount of: about 10 ml to about 60 ml, about 15 ml to about 50 ml, or about 30 ml per gram of Buntanetap. The resulting mixture may be stirred, preferably at a temperature of: about 15 °C to about 60 °C, about 20 °C to about 40 °C, or about 25 °C. The stirring may be carried out for a period of: about 2 hours to about 10 hours, about 3 hours to about 8 hours, or about 4 hours to about 6 hours.

[0105] According to an aspect or embodiment of the process for making Form BT4 of Buntanetap D-tartrate, D-(-)-Tartaric acid is preferably used in excess, preferably in an amount of: about 0.3 g to about 0.7 g, or about 0.5g, per gram of Buntanetap.

[0106] The process may further include isolating the obtained Buntanetap D-tartrate, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration at a temperature of: about 15 °C to about 35 °C, about 20 °C to about 30 °C, or about 25 °C for period of about 5 minutes to about 30 minutes; 10 minutesto about 20 minutes; or about 15 minutes. Following isolation, the Buntanetap D-tartrate may be dried. The drying may be carried out under vacuum at a temperature of: about 45 °C to about 75 °C, about 50 °C to about 70 °C, or about 60 °C for the period of: about 1 hour to about 3 hour, to about 1.5 hours to about 3.5 hours or, to about 2 hours.

[0107] According to any aspect or embodiment, Form BT4 of Buntanetap L-tartrate may alternatively be prepared by crystallizing Buntanetap D-tartrate in water.

[0108] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT4 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap D-tartrate in water;(ii) optionally isolating; and(iii) optionally drying.

[0109] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT4 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap D-tartrate in water, optionally with heating;(ii) isolating; and(iii) optionally drying.

[0110] According to any aspect or embodiment of the disclosed processes for preparing Form BT4 of Buntanetap D-tartrate, the water may be used in an amount of: about 5 ml to about 20 ml, about 7 ml to about 15 ml, or about 10 ml, per gram of Buntanetap D-tartrate. The solution in step (i) may be at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 60 °C, or about 50 °C. The solution may be cooled, optionally to temperature of: about 15 °C to about 60 °C, about 20 °C to about 40 °C, or about 25 °C. The cooling may be carried out over a period of about 10 minutes to about 60 minutes, about 15 minutes to about 50 minutes, about 20 minutes to about 40 minutes or about 30 minutes. The resulting slurry may be maintained at a temperature of: about 15 °C to about 60 °C, about 20 °C to about 40 °C, or about 25 °C, optionally for period of 1 hours to about 4 hours, to about 4 hours to about 7 hours or, to about 2 hours.

[0111] The process may further include isolating the obtained Buntanetap D-tartrate, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration at a temperature of: about 15 °C to about 35 °C, about 20 °C to about 30 °C, or about 25 °C for period of about 5 minutes to about 30 minutes; 10 minutes to about 20 minutes; or about 15 minutes. Following isolation, the Buntanetap D-tartrate may be dried. The drying may be carried out under vacuum at a temperature of: about 45 °C to about75 °C, about 50 °C to about 70 °C, or about 60 °C for the period of: about 1 hour to about 3 hour, to about 1.5 hours to about 3.5 hours or, to about 2 hours.

[0112] According to any aspect or embodiment, Form BT4 of Buntanetap L-tartrate may alternatively be prepared by crystallizing Buntanetap D-tartrate in ethanol with an antisolvent, preferably MTBE.

[0113] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT4 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap D-tartrate in ethanol(ii) combining the solution of step (i) with MTBE(iii) optionally isolating; and(iv) optionally drying

[0114] According to any aspect or embodiment of the disclosed process, the process for preparing Form BT4 of Buntanetap D-tartrate may comprise:(i) dissolving Buntanetap D-tartrate in ethanol, optionally with heating;(ii) adding the solution of step (i) with MTBE(iii) isolating; and(iv) optionally drying.

[0115] According to any aspect or embodiment of the disclosed processes for preparing Form BT4 of Buntanetap D-tartrate, the ethanol may be used in an amount of: about 2 ml to about 7 ml, about 3 ml to about 6 ml, or about 4 ml, per gram of Buntanetap D-tartrate. The solution in step (i) may be at a temperature of: about 25 °C to about 75 °C, about 30 °C to about 70 °C, about 40 °C to about 65 °C, or about 60 °C. The solution in step (i) may be added to MTBE. The MTBE may be used in an amount of : about 10 ml to about 60 ml, about 15 ml to about 50 ml, or about 20 ml per gram of Buntanetap D-tartrate, The mixture may be stirred at a temperature of: about 15 °C to about 60 °C, about 20 °C to about 40 °C, or about 25 °C, optionally for period of about 3 hours to about 8 hours, to about 4 hours to about 7 hours or about 5 hours. The process may further include isolating the obtained form BT4 of Buntanetap D-tartrate, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration at a temperature of: about 15 °C to about 35 °C, about 20 °C to about 30 °C, or about 25 °C for period of about 5 minutes to about 30 minutes; 10 minutes to about 20 minutes; or about 15 minutes. Following isolation, the Buntanetap D-tartrate may be dried. The drying may be carried out under vacuum at a temperature of: about 45 °C to about 75 °C, about 50 °C to about 70 °C, or about 60 °C for theperiod of: about 1 hour to about 3 hour, to about 1.5 hours to about 3.5 hours or, to about 2 hours.

[0116] According to any aspect or embodiment of the disclosed processes for preparing Form BT4 of Buntanetap D-tartrate, the process may further comprise combining the Form BT4 of Buntanetap D-tartrate with at least one pharmaceutically acceptable excipient to prepare pharmaceutical composition.

[0117] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and their solid state forms.

[0118] The present disclosure encompasses a process for preparing other solid state forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and their solid state forms thereof.

[0119] The present disclosure provides the above described crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate salts for use in the preparation of pharmaceutical compositions comprising Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate salts and / or crystalline polymorphs thereof.

[0120] The present disclosure also encompasses the use of crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and / or crystalline polymorphs thereof.

[0121] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure with at least one pharmaceutically acceptable excipient.

[0122] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0123] Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate,tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0124] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0125] The dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[0126] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0127] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0128] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that canbe included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0129] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0130] In liquid pharmaceutical compositions of the present invention, Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0131] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0132] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0133] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0134] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0135] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0136] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral,buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0137] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0138] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0139] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0140] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and then screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0141] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0142] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0143] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0144] A pharmaceutical formulation of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate can be administered. Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate may be formulated for administration to a mammal, in embodiments to a human, by injection. Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent’s physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0145] The crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate and the pharmaceutical compositions and / or formulations of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure can be used as medicaments, in embodiments in the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

[0146] The present disclosure also provides methods of treating Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries. by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Buntanetap, or salts of Buntanetap, particularly Buntanetap tartrate of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0147] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way. Powder X-ray Diffraction (“XRPD”) methodX-ray diffraction was performed on X-Ray powder diffractometer:

[0148] Bruker D8 Advance; Copper Ka radiation ( = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the sampleswere gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.Measurement parameters:Scan range: 2 - 40 degrees 2-theta;Scan mode: continuous;Step size: 0.05 degrees;Time per step: 0.5 s;Sample spin: 30 rpm;Sample holder: PMMA specimen holder ring.

[0149] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.SSNMR Method:

[0150] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) with 3.2 mm probehead. The13C CP / MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 15 kHz and a room temperature (300 K). The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The13C scale was referenced to a- glycine (176.03 ppm for13C). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(NO3)2.The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Au 1 / 2 was less than 3.5 Hz at 250 ms of acquisition time).EXAMPLESPreparation of starting materials

[0151] Buntanetap can be prepared according to methods known from the literature, for example Heterocycles 1988, 27, 745 750 and The Journal of Organic Chemistry 2012, 77, 1, 725-728.Example 1: Preparation of Buntanetap Form A

[0152] Buntanetap (0.1g) was dissolved in dichloromethane (0.3 mL) at a temperature of about 25 °C in a test tube. The clear solution was kept for slow solvent evaporation at a temperature of about 22 °C to about 25 °C for period of about 1 hour. The obtained solid wasanalyzed by XRPD. Crystalline Buntanetap Form A was obtained. An XRPD pattern is shown in Figure 1.Example 2: Preparation of Buntanetap D-tartrate Form BT1

[0153] Buntanetap (0.05g) and D-(-)-Tartaric acid (0.025g) were dissolved in Acetone (2.5 mL) at a temperature of about 50 °C. The clear solution was stirred at a temperature of about 50 °C. Solid was obtained after 2hrs and the slurry was maintained at 50 °C for about 2 hours than cooled to temperature of about 25 °C. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes. The solid further dried under vacuum at a temperature of about 60 °C for period of about 2 hours. The obtained solid was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT1 was obtained. An XRPD pattern is shown in Figure 2.Example 3: Preparation of Buntanetap D-tartrate Form BT2

[0154] Buntanetap (0.05g) and D-(-)-Tartaric acid (0.025g) were dissolved in Acetonitrile (1 mL) at a temperature of about 50 °C. The clear solution was stirred at a temperature of about 50 °C. Solid was obtained after 20 min and the slurry was maintained at 50 °C for about 1 hour than cooled to temperature of about 25 °C. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT2 was obtained. An XRPD pattern is shown in Figure 3.Example 4: Preparation of Buntanetap D-tartrate Form BT2

[0155] Buntanetap D-tartrate Form-BTl (0.05g) was exposed at 100% RH for about 24hrs and solid was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT2 was obtained.Example 5: Preparation of Buntanetap D-tartrate Form BT2

[0156] Buntanetap (0.04 g) and D-(-)-Tartaric acid (0.02 g) were dissolved in 0.5 mL of 10% of water in Isopropyl alcohol (IP A) at a temperature of about 50 °C. The clear solution was stirred at a temperature of about 50 °C for period of about 30 minutes and cooled to temperature of about 25 °C and maintained for period of about 16 hours at a temperature of about 25 °C. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT2 was obtained.Example 6: Preparation of Buntanetap L-tartrate Form BT3

[0157] Buntanetap (0.05g) and L-(+)-Tartaric acid (0.025g) were dissolved in Acetone (2.5 mL) at a temperature of about 50 °C. The clear solution was stirred at a temperature of about 50 °C. Solid was obtained after period of about 2 hours and the slurry was maintained at atemperature of about 50 °C for period of about 2 hours than cooled to temperature of about 25 °C. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes. The solid was further dried under vacuum at a temperature of about 60 °C for period of about 2 hours. The obtained solid was analyzed by XRPD. Crystalline Buntanetap L-tartrate Form BT3 was obtained. An XRPD pattern is shown in Figure 4.Example 7: Preparation of Buntanetap L-tartrate Amorphous Form

[0158] Buntanetap (0.05 g) and L-(+)-Tartaric acid (0.025 g) were taken in a 50 mL Buchi flask and was dissolved in 4 mL of Acetone at a temperature of about 50 °C. The clear solution was distilled at a temperature of about 50 °C with 50mbar vacuum for period of about 60 min and dried. The obtained Solid was isolated and dried under vacuum at a temperature of about 25 °C for period of about 2 hours. The obtained solid was analyzed by XRPD. Amorphous Buntanetap L-tartrate was obtained. An XRPD pattern is shown in Figure 5.Example 8: Preparation of Buntanetap D-tartrate Form BT4

[0159] Buntanetap D-tartrate (0.05g) was dissolved in Water (0.5 mL) at 50 °C. The clear solution was cooled to temperature of about 25 °C in period of about 30 minutes. Solid was obtained and maintained at a temperature of about 25 °C for period of about 2 hours. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes. The solid was further dried under vacuum at a temperature of about 60 °C for period of about 2 hours. The obtained solid was analyzed by XRPD. Crystalline Buntanetap D- tartrate Form BT4 was obtained. An XRPD pattern is shown in Figure 6.Example 9: Preparation of Buntanetap D-tartrate Form BT4

[0160] Buntanetap D-tartrate (0.05 g) was dissolved in 0.2 mL of Ethanol at a temperature of about 60 °C. The clear solution was added to 1 mL of MTBE which was kept at a temperature of about 25 °C and stirred at a temperature of about 25 °C for period of about 5 hours. Solid obtained was filtered and dried suction at a temperature of about 25 °C for period of about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT4 was obtained.Example 10: Preparation of Buntanetap D-tartrate Form BT4

[0161] Buntanetap (0.1 g) and D-(-)-Tartaric acid (0.05 g) were dissolved in 0.6 mL of 10% of water in Acetone at a temperature of about 50 °C. The clear solution was added to 3 mL of MTBE which was kept at a temperature of about 25 °C and stirred at a temperature of about 25 °C for period of about 4 hours to about 6 hours. The obtained solid was filtered under suction at a temperature of about 25 °C for period of about 15 minutes, and was analyzed by XRPD. Crystalline Buntanetap D-tartrate Form BT4 was obtained.Example 11: Stability ExperimentsStorage stability at different relative humidities

[0162] Samples of Forms BT1, BT3 and BT4 were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:Table 1

[0163] These results demonstrate that Forms BT1, BT3 and BT4 are stable after exposure to high and low relative humidity for at least 7 days.

[0164] Samples of Forms BT1, BT3 and BT4 were subjected to 60% relative humidity at 25 °C. XRPD analysis was performed on the samples after 6 months. The results are shown in Table 2 below:Table 2

[0165] The results demonstrate that Forms BT1, BT3 and BT4 are stable after exposure to relative humidity at ambient temperature for at least 6 months, indicating that the crystalline forms have good storage stability.Grinding experiments

[0166] Samples of Forms BT1, BT3 and BT4 were subjected to strong grinding. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. XRPD analysis was performed on each of the samples after the grinding experiment, and confirmed no change in the starting material (Table 3):Table 3

[0167] The results demonstrate that Forms BT1, BT3 and BT4 are resistant to polymorphic changes and are highly suitable for preparing pharmaceutical formulations.Thermal stability

[0168] Samples of Forms BT1, BT3 and BT4 were subjected to heating up to 100 °C for 30 minutes. XRPD analysis of the samples confirmed no change in the starting material (Table 4):Table 4

[0169] The results demonstrate the advantageous thermal stability of Forms BT1, BT3 and BT4.Stability to Compression

[0170] Samples of Forms BT1, BT3 and BT4 were subjected to a pressure of 2 tons. (Atlas® Autopress hydraulic press, set to 2 tons). XRPD analysis was performed on the samples after 2 minutes. The results are shown in Table 5 below:Table 5

[0171] Accordingly Forms BT1, BT3 and BT4 exhibit good stability to compression, further demonstrating their suitability for pharmaceutical processing.

[0172] Further aspects and embodiments of the present disclosure are set out in the numbered clauses below:1. Crystalline Buntanetap D-tartrate or crystalline Buntanetap L-tartrate.2. Crystalline Buntanetap D-tartrate according to Clause 1, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.3. Crystalline Buntanetap D-tartrate according to Clause 1 or Clause 2, which is designated form BT1, which is characterized by data selected from: a) an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta; c) an X-ray powder diffraction pattern substantially as depicted in Figure 2; d) a solid state13C NMR spectrum having peaks at 26.0, 73.2, 74.6, 122.6, 124.5, 127.6, 131.3, 134.9, 139.8, 145.3, 154.5, 154.9 and 175.1 ppm ± 0.2 ppm; e) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 27.6, 19.6, 21.0, 69.0, 70.9, 74.0, 77.7, 81.3, 86.2, 91.7, 100.9, 101.3 and 121.5 ppm ± 0.1 ppm; f) a solid-state13C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c; or g) any combination of two or more of: a, b, c, d, e, or f.4. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 2 or 3, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 4, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 5, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 16.1, 17.4, 18.6, 19.6, 20.0, and 21.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 3, or 4, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6, and 20.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 7, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6, and 20.0 degrees 2-theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaks selected from 15.0, 15.5 and 17.4 degrees 2-theta ± 0.2 degrees 2- theta. Crystalline Buntanetap D-tartrate according to Clause 8, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 15.0, 15.5, 17.4, 18.6, 19.6, and 20.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 15.0, 15.5, 16.1, 17.4, 18.6, 19.6, 20.0, and 21.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, or 10, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 2.5 to 3.8 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 2.8 to 3.6 degrees 2-theta ± 0.2 degrees 2-theta.Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, or 11, which is further characterized by an X~ray powder diffraction pattern having an absence of peaks at 4.9 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 5.2 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, 11, or12, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 9.0 to 11.0 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 9.2 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2. Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, 11, 12,13, or 14, which is further characterized by a solid state13C NMR spectrum having peaks at 26.0, 73.2, 74.6, 122.6, 124.5, 127.6, 131.3, 134.9, 139.8, 145.3, 154.5, 154.9 and 175.1 ppm ± 0.2 ppm. Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, which is further characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 27.6, 19.6, 21.0, 69.0, 70.9, 74.0, 77.7, 81.3, 86.2, 91.7, 100.9, 101.3 and 121.5 ppm ± 0.1 ppm Crystalline Buntanetap D-tartrate according to any of Clauses 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, which is further characterized by a solid-state13C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the crystalline form is an anhydrous form. Crystalline Buntanetap D-tartrate according to Clause 1 or Clause 2, designated form BT4, which is characterized by data selected from:a) an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta c) an X-ray powder diffraction pattern substantially as depicted in Figure 6; d) a solid state13C NMR spectrum having peaks at 23.8, 72.3, 96.0, 97.7, 106.3, 118.9, 129.1, 138.4, 144.2, 148.3, 152.5 and 179.7 ppm ± 0.2 ppm; e) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 29.8, 18.7, 42.4, 44.1, 52.7, 65.3, 75.5, 84.8, 90.6, 152.5 and 126.1 ppm± 0.1 ppm; f) a solid-state13C NMR spectrum substantially as depicted in Figures 9a, 9b or 9c; or g) any combination of two or more of: a, b, c, d, e, or f. Crystalline Buntanetap D-tartrate according to Clause 19, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 20, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 21, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 16.1, 17.4, 21.4, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 1 or Clause 19, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 23, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaksselected from 8.5, 15.7, and 26.3 degrees 2-theta ± 0.2 degrees 2- theta. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 19, 20, 21, 22, 23, or24, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.5, 10.3, 11.2, 15.7, 26.3, 27.1, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 19, 20, 21, 22, 23, 24, or25, characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.5, 10.3, 11.2, 15.7, 16.1, 17.4, 21.4, 26.3, 27.1, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, or26, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 4.6 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26, or 27, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 5.6 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 5.8 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26,27, or 28, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 9.0 to 9.8 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 9.2 to 9.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 13.9 to 14.2 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 14.0 to 14.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 18.5 to 19.2 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 18.8 to 19.0 degrees 2-theta ± 0.2 degrees 2-theta.Crystalline Buntanetap D-tartrate according to any of Clauses 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, or 31, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 6. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, or 32, which is further characterized by solid state13C NMR spectrum having peaks at 23.8, 72.3, 96.0, 97.7, 106.3, 118.9, 129.1, 138.4, 144.2, 148.3, 152.5 and 179.7 ppm ± 0.2 ppm. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, which is further characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 29.8, 18.7, 42.4, 44.1, 52.7, 65.3, 75.5, 84.8, 90.6, 152.5 and 126.1 ppm± 0.1 ppm. Crystalline Buntanetap D-tartrate according to any of Clauses 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, which is further characterized by a solid-state13C NMR spectrum substantially as depicted in Figures 9a, 9b or 9c. Crystalline Buntanetap D-tartrate according to any of Clauses 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the crystalline form is an anhydrous form. A crystalline Buntanetap L-tartrate according to Clause 1, which is designated Form BT3, which is characterized by data selected from: a) an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern substantially as depicted in Figure 4; c) a solid state13C NMR spectrum having peaks at 24.5, 27.3, 37.0, 55.7, 97.2, 99.3, 128.1, 137.6, 143.6, 152.1, 173.1, 176.0 and 178.7 ppm; d) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.3 ppm ± 2 ppm of 28.8, 26.0, 16.3, 2.4, 43.9, 46.0, 74.8, 84.3, 90.3, 98.8, 119.8, 122.7, and 125.4 ppm ± 0.1 ppm;e) a solid state13C NMR spectrum substantially as depicted in Figures 8a, 8b or 8c; or f) any combination of two or more of a, b, c, d, or e. Crystalline Buntanetap L-tartrate according to Clause 37, which is characterized by an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1, and 22.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 15.3, 20.5 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap L-tartrate according to Clause 38, which is characterized by an X-ray powder diffraction pattern having peaks at 15.3, 16.0, 17.1, 19.1, 20.5, 21.1, 22.7, and 25.3 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap L-tartrate according to any of Clauses 38 or 39, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.5 to 3.9 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 3.6 to 3.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap L-tartrate according to any of Clauses 38, 39 or 40, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 4.9 to 8.1 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 5.2 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap L-tartrate according to any of Clauses 38, 39, 40, or 41, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 14.0 ± 0.2 degrees 2-theta. Crystalline Buntanetap L-tartrate according to any of Clauses 37, 38, 39, 40, 41, or 42, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4. Crystalline Buntanetap L-tartrate according to any of Clauses 37. 38, 39, 40, 41, 42, or 43, which is isolated.Crystalline Buntanetap L-tartrate according to any of Clauses 37, 38, 39, 40, 41, 42, 43, or 44, which is an anhydrous form. Crystalline Buntanetap L-tartrate according to any of Clauses 37, 38, 39, 40, 41, 42, 43, 44, or 45, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Buntanetap L-tartrate. Crystalline Buntanetap L-tartrate according to any of Clauses 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Buntanetap L-tartrate. A crystalline Buntanetap D-tartrate according to Clause 1, designated Form BT2, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 48, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 4.0, 8.0, 11.7, 14.6 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 48 or Clause 49, which is characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6, 16.1, 17.4, 18.2, and 21.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 1, designated Form BT2, which is characterized by X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6, and 18.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 51, which is characterized by X- ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 14.6, and 18.2 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaksselected from 13.2, 13.7 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to Clause 52, which is characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 13.2, 13.7, 14.6, 18.2 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 48, 49, 50, 51, 52, or53, which is characterized by an X-ray powder diffraction pattern having peaks at 4.0, 8.0, 11.7, 13.2, 13.7, 14.6, 16.1, 17.4, 18.2 and 23.4 degrees 2-theta ± 0.2 degrees 2- theta. Crystalline Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, or54, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 3.5 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 3.2 to 3.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, 54, or 55, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 4.5 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 4.7 to 7.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystall ine Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, 54,55, or 56, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 16.5 to 16.9 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 16.6 to 16.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3. Crystalline Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, which is isolated.Crystalline Buntanetap D-tartrate according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, which is a hydrate form. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Buntanetap D- tartrate. Crystalline Buntanetap D-tartrate according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Buntanetap D-tartrate. A crystalline form of Buntanetap, designated Form A, which is characterized by an X- ray powder diffraction pattern having peaks at 8.0, 12.1, 17.5, 19.0 and 24.4 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data. A crystalline form of Buntanetap according to Clause 63, which is characterized by an X-ray powder diffraction pattern having peaks at 8.0, 12.1, 17.5, 19.0 and 24.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 13.2, 16.7, and 21.6 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Buntanetap according to Clause 63 or Clause 64, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 2.5 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 2.8 to 7.3 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Buntanetap according to any of Clauses 63, 64, or 65 which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 8.5 to 11.6 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 8.8 to 11.3 degrees 2-theta ± 0.2 degrees 2-thetaA crystalline form of Buntanetap according to any of Clauses 63, 64, 65, or 66, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 14.4 to 15.0 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 14.6 to 14.8 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Buntanetap according to any of Clauses 63, 64, 65, 66, or 67, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 25.4 to 25.6 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Buntanetap according to any of Clauses 63, 64, 65, 66, 67, or 68, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1. A crystalline form of Buntanetap according to any of Clauses 63, 64, 65, 66, 67, 68, or69, which is isolated. A crystalline form of Buntanetap according to any of Clauses 63, 64, 65, 66, 67, 68, 69, or 70, which is an anhydrous form. Crystalline Buntanetap according to any of Clauses 63, 64, 65, 66, 67, 68, 69, 70, or 71, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Buntanetap D-tartrate. Crystalline Buntanetap D-tartrate according to any of Clauses 63, 64, 65, 66, 67, 68, 69,70, 71, or 72, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Buntanetap D-tartrate. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1 to 73.Use of a crystalline product according to any of Clauses 1 to 73 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is oral formulation. A pharmaceutical formulation comprising a crystalline product according to any of Clauses 1 to 73, or a pharmaceutical composition of Clause 74, with at least one pharmaceutically acceptable excipient. A process for preparing a pharmaceutical formulation according to Clause 76, comprising combining a crystalline product according to any of Clauses 1 to 73, or a pharmaceutical composition of Clause 74, with at least one pharmaceutically acceptable excipient. A crystalline product according to any of Clauses 1 to 73, a pharmaceutical composition according to Clause 74, or a pharmaceutical formulation according to Clause 76, for use as a medicament. A crystalline product according to any of Clauses 1 to 73, a pharmaceutical composition according to Clause 74, or a pharmaceutical formulation according to Clause 76, for use in the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries. A method of treating Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1 to 73, a pharmaceutical composition according to Clause 74, or a pharmaceutical formulation according to Clause 76, to a subject in need of the treatment. A crystalline product according to any of Clauses 1 to 73, a pharmaceutical composition according to Clause 74, or a pharmaceutical formulation according to Clause 76, for the manufacture of a medicament for Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome,Frontotemporal dementia, Stroke and Traumatic brain injuries. Use of a crystalline product according to any of Clauses 1 to 73, in the preparation of another solid state form of Buntanetap D-tartrate or Buntanetap L-tartrate, or another salt or solid state form thereof.

Claims

CLAIMS1. Crystalline Buntanetap D-tartrate or crystalline Buntanetap L-tartrate.

2. Crystalline Buntanetap D-tartrate according to Claim 1, which is characterized by an X- ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

3. Crystalline Buntanetap D-tartrate according to Claim 1 or Claim 2, which is designated form BT1, which is characterized by data selected from: a) an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta; c) an X-ray powder diffraction pattern substantially as depicted in Figure 2; d) a solid state13C NMR spectrum having peaks at 26.0, 73.2, 74.6, 122.6, 124.5, 127.6, 131.3, 134.9, 139.8, 145.3, 154.5, 154.9 and 175.1 ppm ± 0.2 ppm; e) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 27.6, 19.6, 21.0, 69.0, 70.9, 74.0, 77.7, 81.3, 86.2, 91.7, 100.9, 101.3 and 121.5 ppm ± 0.1 ppm; f) a solid-state13C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c; or g) any combination of two or more of: a, b, c, d, e, or f.

4. Crystalline Buntanetap D-tartrate according to any of Claims 1, 2 or 3, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta.

5. Crystalline Buntanetap D-tartrate according to Claim 4, which is characterized by an X- ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.5, 12.0, 18.6, 19.6 and 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

6. Crystalline Buntanetap D-tartrate according to Claim 5, which is characterized by an X- ray powder diffraction pattern having peaks at 8.5, 12.0, 16.1, 17.4, 18.6, 19.6, 20.0, and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

7. Crystalline Buntanetap D-tartrate according to any of Claims 1, 3, or 4, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6, and 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

8. Crystalline Buntanetap D-tartrate according to Claim 7, which is characterized by an X- ray powder diffraction pattern having peaks at 8.5, 12.0, 18.6, 19.6, and 20.0 degrees 2- theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaks selected from 15.0, 15.5 and 17.4 degrees 2-theta ± 0.2 degrees 2- theta.

9. Crystalline Buntanetap D-tartrate according to Claim 8, which is characterized by an X- ray powder diffraction pattern having peaks at 8.5, 12.0, 15.0, 15.5, 17.4, 18.6, 19.6, and 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

10. Crystalline Buntanetap D-tartrate according to any of Claims 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is characterized by an X-ray powder diffraction pattern having peaks at 8.5, 12.0, 15.0, 15.5, 16.1, 17.4, 18.6, 19.6, 20.0, and 21.4 degrees 2-theta ± 0.2 degrees 2-theta.

11. Crystalline Buntanetap D-tartrate according to any of Claims 4, 5, 6, 7, 8, 9, or 10, which is further characterized by a solid state13C NMR spectrum having peaks at 26.0, 73.2, 74.6, 122.6, 124.5, 127.6, 131.3, 134.9, 139.8, 145.3, 154.5, 154.9 and 175.1 ppm ± 0.2 ppm.

12. Crystalline Buntanetap D-tartrate according to any of Claims 4, 5, 6, 7, 8, 9, 10, or 11, which is further characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 27.6, 19.6, 21.0, 69.0, 70.9, 74.0, 77.7, 81.3, 86.2, 91.7, 100.9, 101.3 and 121.5 ppm ± 0.1 ppm.

13. Crystalline Buntanetap D-tartrate according to any of Claims 4, 5, 6, 7, 8, 9, 10, 11, or 12, which is further characterized by a solid-state13C NMR spectrum substantially asdepicted in Figures 7a, 7b or 7c.

14. Crystalline Buntanetap D-tartrate according to any of Claims 1, 2, 3, 4, 5, 6, / , 8, 9, 10, 11, 12, or 13, wherein the crystalline form is an anhydrous form.

15. Crystalline Buntanetap D-tartrate according to Claim 1 or Claim 2, designated form BT4, which is characterized by data selected from: a) an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta c) an X-ray powder diffraction pattern substantially as depicted in Figure 6; d) a solid state13C NMR spectrum having peaks at 23.8, 72.3, 96.0, 97.7, 106.3, 118.9, 129.1, 138.4, 144.2, 148.3, 152.5 and 179.7 ppm ± 0.2 ppm; e) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 29.8, 18.7, 42.4, 44.1, 52.7, 65.3, 75.5, 84.8, 90.6, 152.5 and 126.1 ppm± 0.1 ppm; f) a solid-state13C NMR spectrum substantially as depicted in Figures 9a, 9b or 9c; or g) any combination of two or more of: a, b, c, d, e, or f.

16. Crystalline Buntanetap D-tartrate according to Claim 15, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta.

17. Crystalline Buntanetap D-tartrate according to Claim 16, which is characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

18. Crystalline Buntanetap D-tartrate according to Claim 17, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 16.1, 17.4, 21.4, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

19. Crystalline Buntanetap D-tartrate according to Claim 1 or Claim 15, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

20. Crystalline Buntanetap D-tartrate according to Claim 19, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 10.3, 11.2, 27.1 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaks selected from 8.5, 15.7, and 26.3 degrees 2-theta ± 0.2 degrees 2- theta.

21. Crystalline Buntanetap D-tartrate according to any of Claims 1, 15, 16, 17, 18, 19, or20, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.5, 10.3, 11.2, 15.7, 26.3, 27.1, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

22. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18, 19, 20, or21, characterized by an X-ray powder diffraction pattern having peaks at 5.1, 8.5, 10.3, 11.2, 15.7, 16.1, 17.4, 21.4, 26.3, 27.1, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

23. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18, 19, 20, 21, or 22, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 6.

24. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18, 19, 20, 21,22, or 23, which is further characterized by solid state13C NMR spectrum having peaks at 23.8, 72.3, 96.0, 97.7, 106.3, 118.9, 129.1, 138.4, 144.2, 148.3, 152.5 and 179.7 ppm ± 0.2 ppm.

25. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18.

19. 20, 21, 22, 23, or 24, which is further characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.6 ppm ± 2 ppm of 29.8, 18.7, 42.4, 44.1, 52.7, 65.3, 75.5, 84.8, 90.6, 152.5 and 126.1 ppm± 0.1 ppm.

26. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18.

19. 20, 21, 22, 23, 24, or 25, which is further characterized by a solid-state13C NMR spectrumsubstantially as depicted in Figures 9a, 9b or 9c.

27. Crystalline Buntanetap D-tartrate according to any of Claims 15, 16, 17, 18.

19. 20, 21 , 22, 23, 24, 25, or 26, wherein the crystalline form is an anhydrous form.

28. A crystalline Buntanetap L-tartrate according to Claim 1, which is designated Form BT3, which is characterized by data selected from: a) an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; b) an X-ray powder diffraction pattern substantially as depicted in Figure 4; c) a solid state13C NMR spectrum having peaks at 24.5, 27.3, 37.0, 55.7, 97.2, 99.3, 128.1, 137.6, 143.6, 152.1, 173.1, 176.0 and 178.7 ppm; d) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 53.3 ppm ± 2 ppm of 28.8, 26.0, 16.3, 2.4, 43.9, 46.0, 74.8, 84.3, 90.3, 98.8, 119.8, 122.7, and 125.4 ppm ± 0.1 ppm; e) a solid state13C NMR spectrum substantially as depicted in Figures 8a, 8b or 8c; or f) any combination of two or more of a, b, c, d, or e.

29. Crystalline Buntanetap L-tartrate according to Claim 28, which is characterized by an X-ray powder diffraction pattern having peaks at 16.0, 17.1, 19.1, 21.1, and 22.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 15.3, 20.5 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

30. Crystalline Buntanetap L-tartrate according to Claim 29, which is characterized by an X-ray powder diffraction pattern having peaks at 15.3, 16.0, 17.1, 19.1, 20.5, 21.1, 22.7, and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

31. Crystalline Buntanetap L-tartrate according to any of Claims 28, 29 or 30, which is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4.

32. Crystalline Buntanetap L-tartrate according to any of Claims 28, 29, 30, or 31, which is isolated.

33. Crystalline Buntanetap L-tartrate according to any of Claims 28, 29, 30, 31, or 32, which is an anhydrous form.34 Crystalline Buntanetap L-tartrate according to any of Claims 28, 29, 30, 31, 32, or 33, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Buntanetap L-tartrate.

35. Crystalline Buntanetap L-tartrate according to any of Claims 28, 29, 30, 31, 32, 33, or 34, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Buntanetap L-tartrate.

36. Crystalline Buntanetap D-tartrate according to any of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Buntanetap D- tartrate.

37. Crystalline Buntanetap D-tartrate according to any of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 36, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Buntanetap D- tartrate.

38. A pharmaceutical composition comprising a crystalline product according to any of Claims 1 to 37.

39. Use of a crystalline product according to any of Claims 1 to 37 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is oral formulation.

40. A pharmaceutical formulation comprising a crystalline product according to any of Claims 1 to 37, or a pharmaceutical composition of Claim 38, with at least one pharmaceutically acceptable excipient.

41. A process for preparing a pharmaceutical formulation according to Claim 40, comprising combining a crystalline product according to any of Claims 1 to 37, or a pharmaceutical composition of Claim 38, with at least one pharmaceutically acceptable excipient.

42. A crystalline product according to any of Claims 1 to 37, a pharmaceutical composition according to Claim 38, or a pharmaceutical formulation according to Claim 40, for use as a medicament.

43. A crystalline product according to any of Claims 1 to 37, a pharmaceutical composition according to Claim 38, or a pharmaceutical formulation according to Claim 40, for use in the treatment of Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

44. A method of treating Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries, comprising administering a therapeutically effective amount of a crystalline product according to any of Claims 1 to 37, a pharmaceutical composition according to Claim 38, or a pharmaceutical formulation according to Claim 40, to a subject in need of the treatment.

45. A crystalline product according to any of Claims 1 to 37, a pharmaceutical composition according to Claim 38, or a pharmaceutical formulation according to Claim 40, for the manufacture of a medicament for Parkinson’s Disease, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, Down syndrome, Frontotemporal dementia, Stroke and Traumatic brain injuries.

6. Use of a crystalline product according to any of Claims 1 to 37, in the preparation of another solid state form of Buntanetap D-tartrate or Buntanetap L-tartrate, or another salt or solid state form thereof.

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