Polymorphs

Abstract

The present disclosure relates to crystalline polymorphs of the compound of Formula (I), namely N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide: [Refer to original abst

Description

[0001] The present invention relates to crystalline forms of a compound of Formula (I): BACKGROUND

[0002] G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors in the cell. They transduce extracellular signals to intracellular effector systems and are involved in a large variety of physiological phenomena, therefore representing the most common targets of pharmaceutical drugs although only a small percentage of GPCRs are targeted by current therapies.

[0003] GPCRs respond to a wide range of ligands. Due to the progress in human genome sequencing, for about 25% out of the more than 400 GPCRs (not including the olfactory GPCRs) that have been identified, a defined physiologically relevant ligand is still lacking. These receptors are known as "orphan GPCRs". "Deorphanization" and identification of their in vivo roles is expected to clarify novel regulatory mechanisms and, therefore, to disclose novel drug targets. Whether GPR17 is such an orphan receptor is still a matter of debate. Phylogenetically, GPR17 is closely related to the nucleotide P2Y receptors and the cysteinylleukotriene (Cysl T1, Cysl T2) receptors, with an amino acid sequence identity of between about 30 and about 35%, respectively.

[0004] Multiple-tissue Northern blot and RT-PCR analyses indicate a predominant expression of GPR17 in the central nervous system (CNS) (Giana et al., 2006, EMBO J 25(19): 4615; Blasius et al., 1998, J Neurochem 70(4 ): 1357) and additionally in heart and kidney, i.e. organs typically undergoing ischemic damage. Two human GPR17 isoforms have been identified differing only by the length of their N-terminus. The short GPR 17 isoform encodes a 339 amino acid-residue protein with typical rhodopsin type-seven transmembrane motifs. The long isoform encodes a receptor with a 28 amino acid longer N-terminus (Blasius et al., 1998). GPR17 is highly conserved among vertebrate species (-90% identity of amino acid sequence to both mouse and rat orthologs), which may constitute an advantageous feature for development of small molecule ligands and animal models in a drug discovery context.

[0005] In the original deorphanising report, GPR17 was identified as a dual receptor for uracil nucleotides and cysteinyl-leukotrienes (cysl Ts) L TC4 and L TD4, respectively based on 3SGTPyS binding and cAMP inhibition assays as well as single cell calcium imaging (Giana et al., 2006, ibid). Evidence for GPR17 functionality was provided in different cellular backgrounds such as 1321 N1, COS7, CHO, and HEK293 cells (Giana et al., 2006, ibid). Subsequently, an independent study confirmed activation of GPR 17 by uracil nucleotides but failed to recapitulate activation by Cysl Ts (Benned-Jensen and Rosenkilde, 2010, Br J Pharmacol , 159(5): 1092). Yet recent independent reports (Maekawa et al., 2009, PNAS 106(28), 11685; Qi et al., 2013, J Pharmacol Ther 347,1, 38; Hennen et al.,2013, Sci Signal 6, 298) suggested lack of GPR17 responsiveness to both uracil nucleotides and Cysl Ts across different cellular backgrounds stably expressing GPR17 (1321 N1, CHO, HEK293 cells). A novel regulatory role for GPR17 has also been proposed: GPR17 - upon coexpression with the Cysl T1 receptor- rendered the Cysl T1 receptor unresponsive to its endogenous lipid mediators L TC4 and L TD4. Clearly, additional in vitro investigations are required to probe GPR17 pharmacology and function in more depth.

[0006] Drugs modulating the GPR17 activity may have neuroprotective, anti-inflammatory and anti-ischemic effects and may thus be useful for the treatment of cerebral, cardiac and renal ischemia, and stroke (WO 2006 / 045476), and / or for improving the recovery from these events (Bonfanti et al, Cell Death and Disease, 2017, 8, e2871).

[0007] GPR17 modulators are also thought to be involved in food uptake, insulin and leptin responses and are thus claimed to have a role in obesity treatment (WO 2013 / 113032). Administration of an agent that reduces GPR17 expression or reduces GPR17 activity such as a GPR17 antagonist is expected to increase glucose tolerance / insulin sensitivity via inhibition of intestinal GPR17 activity (Yan, S. et al., Cell Reports 38(1), 110179, 2022). Administration of a GPR17 antagonist is expected to block hypothalamic GPR17 receptors and modulate the oligodendrocytic GPR17-cAMP-lactate axis which regulates neuronal activity and contributes to whole body metabolic regulation promoting decreased body weight by reducing food intake (Ou, S. et al., Cell Reports 26(11), 2984-2997, 2019). Administration of a GPR17 antagonist is expected to block FoxO1 activation of Agrp neurons, thus resulting in reduced food intake and hepatic glucose production (Ren, H. et al., Cell 149(6), 1314-1326, 2012; Ren, H. etal., Cell 153(5), 1166, 2013). Administration of a GPR17 antagonist is expected to increase POMC neuronal activity and promote better energy homeostasis which could curtail weight gain (Reilly, A. M. et al., Nutrition and Diabetes 9:29, 2019).

[0008] Moreover, there is strong evidence that GPR17 is involved in myelination processes and that negative GPR17 modulators (antagonists or inverse agonists) can be valuable drugs for the treatment or alleviation of myelination disorders such as multiple sclerosis or spinal cord injury (Chen et al, Nature neuroscience 2009, 12(11 ):1398-406; Ceruti et al; Brain: a journal of neurology 2009 132(Pt 8):2206-18; Hennenetal, Sci Signal, 6, 2013,298; Simon et al J Biol Chern 291, 2016, 705; Fumagalli et al, Neuropharmacology 104, 2016, 82). Activation of GPR17 has been shown to inhibit oligodendrocyte precursor cells (OPCs) maturation thus preventing effective myelination (Simon et al, supra). The identification of potent and selective GPR17 antagonists or inverse agonists would thus be of significant relevance in the treatment of myelination disorders.

[0009] Several serious myelination diseases are known to be caused by disturbances in myelination, either by a loss of myelin (usually called demyelination), and / or by a failure of the body to properly form myelin (sometimes called dysmyelination). The myelination diseases may be idiopathic or secondary to certain trigger events like e.g. traumatic brain injury or viral infection. Myelination diseases may primarily affect the central nervous system (CNS) but may also concern the peripheral nervous system. Myelination diseases include, inter alia, multiple sclerosis, neuromyelitis optica (also known as Devic's disease), leukodystrophies, Guillain-Barr~ syndrome, and many other diseases as described in more detail further below (see also e.g. Love, J Clin Pathol, 59, 2006,1151, Fumagalli etal, supra). Neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotropic lateral sclerosis (ALS) and multiple system atrophy (MSA) have been also strongly associated with decreased myelination recently (see e.g. Ettie et al, Mol Neurobiol 53, 2016, 3046; Jellingerand Welling, Movement Disorders, 31, 2016; 1767; Kang etal, Nature Neurosci 6, 2013, 571; Bartzokis, Neurochem Res (2007) 32:1655).

[0010] Multiple Sclerosis (MS) is a chronic progressive disorder. It is an inflammatory autoimmune disease causing oligodendrocyte damage, demyelination and ultimately axonal loss, thus leading to a broad spectrum of signs and symptoms of a severe neurological disease, like e.g. fatigue, dizziness, mobility and walking issues, speech and swallowing difficulties, pain and others. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). While certain symptoms may disappear completely between isolated attacks, severe neurological problems often remain, especially as the disease advances to a more progressive form. According to the Multiple Sclerosis Association of America, approximately 400,000 individuals have been diagnosed with MS in the United States and as many as 2.5 million worldwide, with an estimated 10,000 new cases diagnosed in the United States annually. Multiple sclerosis is two to three times more common in women than in men.

[0011] There is no known causal treatment or cure for multiple sclerosis, or many other myelination diseases. Treatments are usually symptomatic and try to improve function after an attack and prevent new attacks, by addressing the inflammatory component of the disease. Such immunomodulatory drugs are usually only modestly effective, in particular if the disease is progressed, but can have side effects and be poorly tolerated. Moreover, most of the available drugs, like -interferons, glatiramer acetate, or therapeutic antibodies are only available in injectable form and / or only address the inflammatory component of the disease but not demyelination directly. Other drugs, like corticosteroids, show rather unspecific antiinflammatory and immunosuppressive effects thus potentially leading to chronic side effects, such as manifested in Cushing's syndrome, for example.

[0012] A strong need therefore exists for a safe and effective drug for the treatment of myelination diseases, like MS, preferably for a drug that is suitable for oral administration. Ideally such a drug would reverse the demyelination process by decreasing demyelination and / or by promoting remyelination of the impacted neurons. A chemical compound which effectively decreases the GPR 17 receptor activity could fulfil these requirements.

[0013] However, only few chemical compounds are known that effectively modulate GPR 17 activity.

[0014] WO 2005 / 103291 suggests the endogenous molecules 5 amino levulinic acid (5-ALA) and porphobilinogen (PBG) as activating ligands for GPR17, discloses analgesic effects of a GPR17 agonist and proposes the use of GPR17 agonists for treating neuropathic pain and as tools in GPR17 screening assays. However, the reported affinity of 5-ALA and PBG is quite low and the amounts needed in the assays are significant, namely in the three digit micromolar range for 5-ALA or even in the mM range for PBG, which make both compounds not well suited for use in routine screening assays or even for therapy. Moreover, PBG is a chemically unstable, reactive compound which rapidly decomposes after exposure to air and light, making it impractical to handle on a routine basis. Hence, these compounds do not offer a promising starting point to develop therapeutically effective negative GPR17 modulators.

[0015] Montelukast and pranlukast were originally developed as leukotriene receptor antagonists and were recently found to act on the GPR17 receptor as well (Giana et al, EMBO J. 2006, 25, 4615-4627). However, subsequent results in a functional assay were contradictory for montekulast (Hennen et al, 2013, ibid), while pharmacological inhibition of GPR17 with pranlukast promotes differentiation of primary mouse (Hennen etal., 2013, ibid) and rat (Ou et al., J. Neurosci. 36, 2016, 10560-10573) oligodendrocytes. Pranlukast even phenocopies the effect of GPR17 depression in a lysolecithin model of focal demyelination because both GPR17 knock-out and pranlukast-treated wild-type mice show an earlier onset of remyelination (Ou, ibid). These results strongly support the hypothesis that GPR17 inhibitors offer potential for the treatment of human demyelinating diseases.

[0016] However, the affinity of montelukast and pranlukast to GPR17 is only in the high micromolar range (Kase et al, ACS Med. Chern. Lett. 2014, 5, 326-330). Given the high protein binding of both compounds and their poor brain penetration, it is unlikely that they could reach high enough free concentrations to bind to GPR17 receptors in amounts suitable for human therapy. In addition, results obtained in vivo with these compounds are difficult to interpret due to their confounding high affinity for CYSL T1 receptors.

[0017] US 8,623,593 discloses certain indole-2-carboxylic acids as GPR 17 agonists and their use in screening assays. However, these derivatives are all potent agonists and are not suited to down-regulate GPR 17 activity as needed in the treatment of myelination disorders such as MS. Moreover, this class of GPR17 activators does not sufficiently pass the blood-brain barrier due to their easily ionizable carboxyl groups, and were thus no suitable lead compounds to develop negative GPR17 modulators. See also Baqi et al, Med. Chern. Commun., 2014, 5, 86 and K~se et al, 2014, ibid.

[0018] WO 2013 / 167177 suggests certain phenyltriazole and benzodiazepine compounds as GPR17 antagonists. However, the disclosed compounds were selected solely based on in- silica screening results and no biological data at all was provided. The inventors of the present application were unable to confirm the GPR17 antagonist modulating activity of any of purported ligands proposed by the authors of this former patent application so far.

[0019] A need therefore exists to identify potent modulators, preferably negative modulators, of GPR17 which are capable of effectively decreasing the GPR17 activity, preferably upon oral administration.

[0020] Mehra et al (Eur J Med Chern, 92, 2015, 78-90) disclose a variety of compounds with EColi acetyltransferase inhibiting activity, including four phenyl-substituted pyrrolo[2,3-b]pyridine-3-sulfonamides (compounds 20 [N-(3,4-difluorophenyl 1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide], 32 [N-(3,5-dimethoxyphenyl 1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide],37 [N-(2,5-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide] and 43 [N-(3,5- difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide] of Table S7). These four azaindole compounds distinguish structurally from the presently disclosed compounds in that the azaindole core in Mehra is not further substituted. Moreover, Mehra et al do not suggest any GPR17 inhibiting property of these compounds and / or any utility of their compounds for treating a myelination disorder. Instead, Mehra et al disclose compounds as potential antibiotics.

[0021] WO2018 / 122232 discloses the compound , its preparation and its activity. WO2018 / 122232 discloses only the amorphous form of the compound above and does not disclose a method for preparing a crystalline form of this compound. 5 BRIEF SUMMARY OF THE DISCLOSURE

[0022] In accordance with a first aspect, the present invention provides a crystalline form of a compound of Formula (I): (N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide), 10 or a solvate or hydrate thereof.

[0023] In an embodiment, the present invention provides a crystalline form of a compound of Formula (I): F wherein the crystalline form is form F1 and exhibits an X-ray powder diffraction 15 pattern comprising at least one characteristic peak at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0024] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least two characteristic peaks at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0025] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8,19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0026] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0027] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least five characteristic peaks at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0028] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least six, seven, eight, or nine characteristic peaks at 29 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0029] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising the characteristic peaks at 29 of 7.3, 7.8, 8.1,12.9, 16.8, 19.8,25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

[0030] In an embodiment, the crystalline form F1 exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 15.

[0031] In an embodiment, the present invention provides a crystalline form of a compound of Formula (I): wherein the crystalline form is form F2 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 29 selected from the group consisting of 8.1, 14.8,16.6, 18.8, 19.5,21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0032] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least two characteristic peaks at 29 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0033] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks at 29 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0034] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 29 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0035] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least five characteristic peaks at 29 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0036] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least six, seven, eight, or nine characteristic peaks at 29 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5,21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0037] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising the characteristic peaks at 29 of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

[0038] In an embodiment, the crystalline form F2 exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 25.

[0039] In an embodiment, the present invention provides a crystalline form of a compound of Formula (I): F wherein the crystalline form is form F3 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0040] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least two characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0041] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0042] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0043] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least five characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0044] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least six, seven, eight, or nine characteristic peaks at 20 selected from the group consisting of 11.8, 15.2,15.4, 17.9, 23.8, 24.4,26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0045] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising the characteristic peaks at 20 of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

[0046] In an embodiment, the crystalline form F3 exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 32.

[0047] In an embodiment, the crystalline form is selected from the group consisting of S1, S2, S3, S5, S6, S8, S9, S10, S11, S12, S13, and S15, as defined herein.

[0048] In an embodiment, the crystalline form is selected from the group consisting of P3, P4, P5, P6, P7, P9, P13, P17, P18, P19, P20, P21, P22, P23, and P24, as defined herein.

[0049] In accordance with a second aspect, the present invention provides a pharmaceutical composition comprising a crystalline form according to the first aspect, and a pharmaceutically acceptable excipient.

[0050] In accordance with a third aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use as a medicament.

[0051] In accordance with a fourth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for the manufacture of a medicament.

[0052] In accordance with a fifth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a GPR17-associated disease.

[0053] In accordance with a sixth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disease of the central nervous system (CNS).

[0054] In accordance with a seventh aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a diseases associated with a myelination disorder, in particular a demyelination disorder, such as of the central nervous system.

[0055] In accordance with an eighth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disease selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuritis, acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis (AHL), periventricular leukomalacia, e.g. periventricular leukomalacia demyelination due to viral infections, such as by HIV or progressive multifocal leucoencephalopathy, central pontine and extrapontine myelinolysis, demyelination due to traumatic brain injury and / or traumatic brain tissue damage, including compression-induced demyelination, e.g. by tumours, demyelination in response to hypoxia, e.g. polycythemia vera, demyelination in response to stroke or ischaemia or other cardiovascular diseases, demyelination due to exposure to carbon dioxide, cyanide, or other CNS toxins, Schilder’s disease, Balo concentric sclerosis, Perinatal encephalopathy; Neurodegenerative Diseases including: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Multiple system atrophy, Parkinson’s Disease, Spinocerebellar ataxia (SCA), Huntington’s Disease; psychiatric disorders such as schizophrenia and bipolar disorder; and peripheral myelination diseases such as leukodystrophies (e.g. Pelizaeus-Merzbacher disease), peripheral demyelinating neuropathies, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease.

[0056] In accordance with a ninth aspect, the present invention provides a method for the treatment or prophylaxis of a GPR17-associated disease, comprising administering to a subject in need thereof, a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0057] In accordance with a tenth aspect, the present invention provides a method for the treatment or prophylaxis of a disease of the central nervous system (CNS), comprising administering to a subject in need thereof, a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0058] In accordance with an eleventh aspect, the present invention provides a method for the treatment or prophylaxis of a diseases associated with a myelination disorder, in particular a demyelination disorder, such as of the central nervous system, comprising administering to a subject in need thereof, a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0059] In accordance with a twelfth aspect, the present invention provides a method for the treatment or prophylaxis of a disease, comprising administering to a subject in need thereof, a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, wherein the disease is selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuritis, acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis (AHL), periventricular leukomalacia, e.g. periventricular leukomalacia demyelination due to viral infections, such as by HIV or progressive multifocal leucoencephalopathy, central pontine and extrapontine myelinolysis, demyelination due to traumatic brain injury and / or traumatic brain tissue damage, including compression-induced demyelination, e.g. by tumours, demyelination in response to hypoxia, e.g. polycythemia vera, demyelination in response to stroke or ischaemia or other cardiovascular diseases, demyelination due to exposure to carbon dioxide, cyanide, or other CNS toxins, Schilder’s disease, Balo concentric sclerosis, Perinatal encephalopathy; Neurodegenerative Diseases including: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Multiple system atrophy, Parkinson’s Disease, Spinocerebellar ataxia (SCA), Huntington’s Disease; psychiatric disorders such as schizophrenia and bipolar disorder; and peripheral myelination diseases such as leukodystrophies (e.g. Pelizaeus-Merzbacher disease), peripheral demyelinating neuropathies, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease.

[0060] In accordance with a thirteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with food uptake, insulin response and leptin response, for example obesity.

[0061] In accordance with a fourteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with intestinal GPR17 activity, for example obesity.

[0062] In accordance with a fifteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with glucose tolerance and / or insulin sensitivity, for example obesity.

[0063] In accordance with a sixteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with hypothalamic GPR17 receptors, for example obesity.

[0064] In accordance with a seventeenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with the oligodendrocytic GPR17-cAMP-lactate axis, for example obesity.

[0065] In accordance with an eighteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with FoxO1 activation of Agrp neurons, for example obesity.

[0066] In accordance with a nineteenth aspect, the present invention provides a crystalline form of a compound of Formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment or prophylaxis of a disorder associated with POMC neuronal activity, for example obesity.

[0067] In accordance with a twentieth aspect, the present invention provides a method of manufacturing a pharmaceutical formulation comprising combining a crystalline form of a compound of Formula (I) according to the first aspect and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: Figure 1: a typical HPLC chromatogram for the compound of Formula (I). Figure 2: XRPD of confirmed F1 (black), F2 (blue) and F3 (green). Figure 3: DSC of confirmed forms F1 black thermogram, F2 blue thermogram and F3 green thermogram. Figure 4: XRPD of unconfirmed forms P3 (black), P4 (blue), P6 (green) and P13 (red). Figure 5: XRPD of unconfirmed forms P5 (black), P7 (blue) and P19 (green) Figure 6: XRPD of unconfirmed forms P17 (black), P18 (blue), P20 (green) and P21 (red). Figure 7: XRPD of unconfirmed forms P22 (black), P23 (blue) and P24 (green). Figure 8: DSC of unconfirmed form P13. Figure 9: XRPD of F1, F2 and F3 competitive slurry at 5 °C in EtOH isolated after 24 hours - reference pattern for F3 (black) and pattern obtained from experiment-wet (blue) and dry (green) Figure 10: XRPD of F1, F2 and F3 competitive slurry at 25 °C in EtOH isolated after 24 hours - reference pattern for F3 (black) and pattern obtained from experiment-wet (blue) and dry (green). Figure 11: XRPD of F1, F2 and F3 competitive slurry at 50 °C in EtOH isolated after 24 hours - reference pattern for F3 (black) and pattern obtained from experiment -wet (blue) and dry (green). Figure 12: XRPD of F1, F2 and F3 competitive slurry at 5 °C in 50% v / v water in MeOH isolated after 24 hours - reference pattern for F3 (black), reference pattern for F2 (grey) and pattern obtained from experiment - wet (blue) and dry (green). Figure 13: XRPD of F1, F2 and F3 competitive slurry at 25 °C in 50% v / v water in MeOH isolated after 24 hours - reference pattern for F3 (black) and pattern obtained from experiment - wet (blue) and dry (green). Figure 14: XRPD of F1, F2 and F3 competitive slurry at 50 °C in 50% v / v water in MeOH isolated after 24 hours - reference pattern for F3 (black) and pattern obtained from experiment - wet (blue) and dry (green). Figure 15: XRPD of F1. Figure 16: Micrograph of F1, 10* objectives Figure 17: Micrograph of F1, 20x objectives Figure 18: 1H NMRof F1. Figure 19: 19FNMRofF1. Figure 20: TGA of F1. Figure 21: DSC of F1. Figure 22: DVS of F1. Figure 23: XRPD of the F1 a) before (black) and b) after DVS (red). Figure 24: Isotherm plot for F1. Figure 25: XRPD of F2. Figure 26: Micrograph of F2, 20x objectives Figure 27: Micrograph of F2, 20x objectives Figure 28: 1H NMRof F2. Figure 29: 19F NMRof F2. Figure 30: TGA of F2. Figure 31: DSC of F2. Figure 32: XRPD of F3. Figure 33: Micrograph of F3, 50x objective. Figure 34: Micrograph of F3, 50x objective. Figure 35: 1H NMR of F3. Figure 36: 19F NMR of F3. Figure 37: TGA of F3. Figure 38: DSC of F3. Figure 39: DVS of F3. Figure 40: XRPD of the F3 before (black) and after DVS (blue). Figure 41: Isotherm plot of F3. Figure 42: XRPD of S1 Figure 43: DSC (green) and TGA to 110 °C of S1 (blue). Figure 44: XRPD of S2. Figure 45: DSC (green) and TGA to 160 °C of S2 (blue). Figure 46: XRPD of S3. Figure 47: DSC (green) and TGA to 110 °C of S3 (blue). Figure 48: XRPD of S5. Figure 49: DSC (green) and TGA to 110 °C of S5 (blue). Figure 50: XRPD of S6. Figure 51: DSC (green) and TGA to 120 °C of S6 (blue). Figure 52: XRPD of S8. Figure 53: DSC (green) and TGA to 140 °C of S8 (blue). Figure 54: XRPD of S9. Figure 55: DSC (green) and TGA to 140 °C of S9 (blue). Figure 56: XRPD of S10. Figure 57: DSC (green) and TGA to 170 °C of S10 (blue). Figure 58: XRPD of S11. Figure 59: DSC (green) and TGA to 140 °C of S11 (blue). Figure 60: XRPD of S12. Figure 61: DSC (green) and TGA to 160 °C of S12 (blue). Figure 62: XRPD ofS13. Figure 63: DSC (green) and TGA to 170 °C of S13 (blue). Figure 64: XRPD of S15. Figure 65: DSC of S15. Figure 66: XRPD of P3 with characteristic 20 reflections. Figure 67: XRPD of P4 with characteristic 20 reflections. Figure 68: XRPD of P5 (obtained through Slow Evaporative Crystallisation with 1,4-Dioxane) with characteristic 20 reflections. Figure 69: XRPD of P5 (obtained through Fast Evaporative Crystallisation with 1,4-Dioxane) with characteristic 20 reflections. Figure 70: XRPD of P5 (obtained through Slow Evaporative Crystallisation with CPME) with characteristic 20 reflections. Figure 71: XRPD of P5 (obtained through Fast Evaporative Crystallisation with CPME) with characteristic 20 reflections. Figure 72: XRPD of P6 with characteristic 20 reflections. Figure 73: XRPD of P7 (obtained through Slow Evaporative Crystallisation with 2-Me-THF) with characteristic 20 reflections. Figure 74: XRPD of P7 (obtained through Fast Evaporative Crystallisation with 2-Me-THF) with characteristic 20 reflections. Figure 75: XRPD of P9 (obtained through Single Solvent Slurry with 50% water in acetone) with characteristic 20 reflections. Figure 76: DSC (green) and TGA to 150 °C of P9 (obtained through Single Solvent Slurry with 50% water in acetone). Figure 77: XRPD of P9 (obtained through Single Solvent Slurry with DMC) with characteristic 20 reflections. Figure 78: DSC (green) and TGA to 160 °C of P9 (obtained through Single Solvent Slurry with DMC). Figure 79: XRPD of P9 (obtained through Single Solvent Slurry with 2-Me-THF) with characteristic 20 reflections. Figure 80: DSC (green) and TGA to 110 °C of P9 (obtained through Single Solvent Slurry with 2 Me-THF). Figure 81: XRPD of P13. Figure 82: DSC of P13. Figure 83: XRPD of P17. Figure 84: XRPD of P18. Figure 85: XRPD of P19 (obtained through Single Solvent Slurry - Temperature Cycling with 2% H2O in EtOH) with characteristic 20 reflections. Figure 86: XRPD of P19 (obtained through Single Solvent Slurry - Temperature Cycling with ACN) with characteristic 20 reflections. Figure 87: XRPD of P20. Figure 88: XRPD of P21. Figure 89: XRPD of P22. Figure 90: XRPD of P23. Figure 91: XRPD of P24. Figure 92: The asymmetric unit of F1 with non-hydrogen atom labels. All atoms are displayed with arbitrary radii. Figure 93: The first hydrogen bond present in F1 (dotted line) which occurs between N1 and 02. Figure 94: The second hydrogen bond present in F1 (dotted line) which occurs between N2 and N3. Figure 95: Packing of F1 viewed down the a-axis. Figure 96: Packing of F1 viewed down the b-axis. Figure 97: Packing of F1 viewed down the c-axis. Figure 98: Packing of F1 viewed down the a-axis showing the potential slip plane on

[001] , Figure 99: Experimental XRPD diffractogram of F1 (top, 298 K) and simulated XRPD diffractogram of F1 (bottom, 100 K) Figure 100: The asymmetric unit of F3 with non-hydrogen atom labels. Figure 101: The first hydrogen bond present in F3 which occurs between N1 and 02. Figure 102: Packing of F3 viewed down the a-axis. Figure 103: Packing of F3 viewed down the b-axis. Figure 104: Packing of F3 viewed down the c-axis. Figure 105: Packing of F3 viewed down the c-axis showing the potential slip plane on

[100] , Figure 106: Experimental XRPD diffractogram of F3 (top, 298 K) and simulated XRPD diffractogram of F3 (bottom, 100 K). Figure 107: Biorelevant solubility in FaSSIF (pH 6.5) at 37 °C and at 300 RPM bottom stirring of F1, F2, F3, amorphous. Figure 108: F2 non-micronised suspension vs micronised F2 suspension two stage dissolution (% drug dissolved vs time) in FaSSGF (pH 1.6) followed by FaSSIF (pH 5.6, 6.0 and 6.5) at 50 RPM and 37±0.5 °C) Figure 109: F2 non-micronised suspension vs micronised F2 suspension two stage dissolution (concentration vs time) in FaSSGF (pH 1.6) followed by FaSSIF (pH 5.6, 6.0 and 6.5) at 50 RPM and 37±0.5 °C). Figure 110: F3 non-micronised suspension vs micronised F3 suspension two stage dissolution (% drug dissolved vs time) in FaSSGF (pH 1.6) followed by FaSSIF (pH 5.6, 6.0 and 6.5) at 50 RPM and 37±0.5 °C). Figure 111: F3 non-micronised suspension vs micronised F3 suspension two stage dissolution (concentration vs time) in FaSSGF (pH 1.6) followed by FaSSIF (pH 5.6, 6.0 and 6.5) at 50 RPM and 37±0.5 °C). Figure 112: Comparison of two-stage dissolution profiles of F2 (non-micronised and micronised) vs F3 (non-micronised and micronised) suspension. Figure 113: Comparison of two-stage dissolution profiles of F2 (non-micronised and micronised) vs F3 (non-micronised and micronised) suspension. DETAILED DESCRIPTION

[0069] For the avoidance of doubt, the term ‘a crystalline form of a compound of Formula (I) according to the first aspect’, includes all embodiments of the first aspect described herein.

[0070] For the avoidance of doubt, any one of the embodiments described herein relating to the first aspect, such as those described in paragraphs

[0023] -

[0048] , may apply equally to any one of the second to twentieth aspects.

[0071] Unless otherwise stated, the X-ray powder diffraction data provided herein was determined using a Cu Ka radiation source.

[0072] It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure (for further information see Jenkins, R &Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley &Sons, 1996). PHARMACEUTICAL COMPOSITIONS

[0073] In accordance with another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of the invention, or solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0074] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0075] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for sublingual use, for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intraperitoneal dosing or as a suppository for rectal dosing).

[0076] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0077] An effective amount of a crystalline form of the invention, or solvate or hydrate thereof, for use in therapy of a condition is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of the condition or to slow the progression of the condition.

[0078] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.1 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0079] The size of the dose for therapeutic or prophylactic purposes of a crystalline form of the invention, or solvate or hydrate thereof, will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well- known principles of medicine.

[0080] In using a crystalline form of the invention, or solvate or hydrate thereof, for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, a daily dose selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg or 5 mg / kg to 10 mg / kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous, subcutaneous, intramuscular or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight may be suitable. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight may be suitable. When administered orally a total daily dose of a crystalline form of the invention, or solvate or hydrate thereof, may be, for example, selected from: 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg or 25 mg to 500 mg. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of the invention. In a particular embodiment the crystalline form of the invention, or solvate or hydrate thereof, is administered parenterally, for example by intravenous administration. In another particular embodiment the crystalline form of the invention, or solvate or hydrate thereof, is administered orally. THERAPEUTIC USES AND APPLICATIONS

[0081] In this section describing therapeutic uses, applications and methods of treatment reference to “a crystalline form of the invention, or solvate or hydrate thereof’ includes crystalline forms of the invention, according those of formula (I), or solvates or hydrates thereof.

[0082] In accordance with another aspect, the present invention provides a crystalline form of the invention, or solvate or hydrate thereof, of the invention, for use as a medicament.

[0083] A further aspect of the invention provides a crystalline form of the invention, or solvate or hydrate thereof, for use in the treatment or prophylaxis of a GPR17-associated disease.

[0084] Also provided is a method of the treatment or prophylaxis of a GPR17-associated disease in a subject, the method comprising administering to the subject an effective amount of a crystalline form of the invention, or solvate or hydrate thereof.

[0085] Also provided is the use of a crystalline form of the invention, or solvate or hydrate thereof, for the manufacture of a medicament.

[0086] Also provided is the use of a crystalline form of the invention, or solvate or hydrate thereof, for the manufacture of a medicament for the treatment or prophylaxis of a GPR17-associated disease.

[0087] In the following sections of the application, reference is made to a crystalline form of the invention, or solvate or hydrate thereof, for use in the treatment of certain diseases or medical disorders. It is to be understood that any reference herein to a crystalline form of the invention, or solvate or hydrate thereof, for a particular use is also intended to be a reference to (i) the use of the crystalline form of the invention, or solvate or hydrate thereof, in the manufacture of a medicament for the treatment of that disease or disorder; and (ii) a method for the treatment of the disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of the invention, or solvate or hydrate thereof.

[0088] In certain embodiments the GPR17-associated disease is selected from: a disease of the central nervous system (CNS), diseases associated with a myelination disorder, multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuritis, acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis (AHL), periventricular leukomalacia, e.g. periventricular leukomalacia demyelination due to viral infections, such as by HIV or progressive multifocal leucoencephalopathy, central pontine and extrapontine myelinolysis, demyelination due to traumatic brain injury and / or traumatic brain tissue damage, including compression-induced demyelination, e.g. by tumours, demyelination in response to hypoxia, e.g. polycythemia vera, demyelination in response to stroke or ischaemia or other cardiovascular diseases, demyelination due to exposure to carbon dioxide, cyanide, or other CNS toxins, Schilder’s disease, Balo concentric sclerosis, Perinatal encephalopathy; Neurodegenerative Diseases (such as Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Multiple system atrophy, Parkinson’s Disease, Spinocerebellar ataxia (SCA), and Huntington’s Disease); psychiatric disorders (such as schizophrenia and bipolar disorder), and peripheral myelination diseases (such as leukodystrophies (e.g. Pelizaeus-Merzbacher disease), peripheral demyelinating neuropathies, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease).

[0089] In certain embodiments the GPR17-associated disease is selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s Disease, stroke, traumatic brain injury, Pelizaeus-Merzbacher disease, Polycythemia vera, and schizophrenia.

[0090] In certain embodiments the GPR17-associated disease is selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s Disease (PD).

[0091] In certain embodiments the GPR17-associated disease is multiple sclerosis (MS).

[0092] In certain embodiments the GPR17-associated disease is obesity.

[0093] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0094] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0095] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. Experimental Abbreviations DSC Differential scanning calorimetry mDSC Modulated DSC DVS Dynamic vapour sorption RH Relative humidity TGA Thermogravimetric analysis XRPD X-ray powder diffraction NMR Nuclear magnetic resonance ACN Acetonitrile CPME Cyclopentyl methyl ether DCM Dichloromethane DMC Dimethyl carbonate DMSO Dimethyl sulfoxide ED Electron diffraction EtOH Ethanol EtOAc Ethyl acetate I PA Isopropyl alcohol I PAC Isopropyl acetate MeOH Methanol MTBE Methyl tert-butyl ether SXRD Single crystal x-ray diffraction THF Tetrahydrofuran 2-MeTHF 2-Methyl tetrahydrofuran HCOOH Formic Acid PLM Polarised Light Microscopy Naming Convention

[0096] Crystalline forms were categorised into one of the five groups as follows: Unconfirmed forms: (1) Pattern 1 (P1, P2, etc.) Distinct XRPD pattern whose identity is unconfirmed. Could consist of multiple phases. Water and solvent content unconfirmed. Confirmed forms: (2) Form (F1, F2, etc.) Single phase that has been demonstrated to be anhydrous and non-solvated. (3) Solvate (S1, S2, etc.) Single phase that has been demonstrated to be anhydrous and contain a stoichiometric or non-stoichiometric amount of organic solvent.

[0097] The crystallisation methods that were included in this polymorph screen were Fast and Slow Evaporative Crystallisation, Single Solvent Slurry and Single Solvent Slurry -Temperature Cycling methods. Materials Synthesis

[0098] The compound of Formula (I), i.e. N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide, was prepared according to Scheme 1. Scheme 1:

[0099] A 500 ml double-jacket reactor equipped with a mechanical stirrer was successively charged under nitrogen at 20°C with 6-chloro-1H-pyrrolo[2,3-b]pyridine A (30.4 g; 195.3 mmol; 1 eq.) and 230 ml of acetonitrile. The suspension was heated to 30°C before the dropwise addition of chlorosulfonic acid (20.1 ml; 299 mmol; 1.5 eq.) over 15 minutes (caution: strongly exothermic addition). Stirring was pursued at 30°C for 2.5 hours and at 35°C for 1.5 hours, HPLC of the mixture at that time showed 0.7% of A and 99% of B (at 210 nm). The suspension was heated to 70°C before the dropwise addition of phosphorus oxychloride (40.5 ml; 430 mmol; 2.2 eq.) over 10 minutes. Stirring of the mixture was pursued over the night at 75°C, HPLC at that time showed 0.9% of B and 99% of C (at 210 nm). The mixture was cooled down to 30°C before the dropwise addition of 80 ml of water over 1 hour (caution: strongly exothermic during the first quarter of the addition). Stirring of the suspension was pursued at 20°C for 1 hour and then at 5°C for 2 hours before filtration. The wet cake was rinsed with 80 ml of a mixture of acetonitrile and water (50 / 50, v / v) and dried under vacuum at 45°C until constant weight, 46.2 g of compound C was obtained as an off-white solid (yield: 94%; HPLC at 210 nm: 98.6% yield); 1H NMR in CD3CN: 96% w / w).

[00100] A 250 ml three-necked round bottom flask equipped with a mechanical stirrer was successively charged under nitrogen at20°C with compound C (25.1 g; 100 mmol; 1 eq.), dichloromethane (100 ml) and 4-bromo-2,5-difluoroaniline D (20.1 g; 94.7 mmol; 0.95 eq.). Dry pyridine (12.3 ml; 151 mmol; 1.5 eq.) was added at once to the suspension (note: mass temperature rise from 10 to 30°C is observed within half-an-hour). Stirring was pursued at room temperature overnight, HPLC of the suspension at that time showed traces of C, 2% of D and 92% of the compound of formula (I). The mixture was filtered, the wet cake was rinsed with 25 ml of dichloromethane and dried under vacuum at 45°C until constant weight, 27.7 g of crude N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide was obtained as a white solid (crude yield: 65%; HPLC at 210 nm: 98.0%).

[00101] A second crop accounting for 21% yield was obtained through addition of 10 ml of water to the mother liquors; after stirring the suspension at room temperature for 1.5 hours, filtration gave 9.0 g of crude N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide as a white solid (HPLC at 210 nm: 96.6%). Instruments and Methods Physicochemical Characterisation X-Ray Powder Diffraction (XRPD) - D8 Discover (Transmission mode)

[00102] X-ray powder diffraction data in transmission mode was collected on a Bruker D8 Discover using Cu Ka radiation (40 kV, 40 mA), X-ray focusing Gobel mirror, 0-0 goniometer, divergence slit (1.0 mm), Collimator (6 x 1.5 mm) and the SSD160-2 Detector with a 4.5 °20 to 5.0 °201 opening without Nickel filter. The software used for data collection was DIFFRAC.COMMANDER version 6.5.0.1 and the data was presented using DIFFRAC.EVA version 4.2.1.11. XRPD diffractograms were acquired under ambient conditions via transmission on a 96 well plate. The data collection range was 3.0 - 40.0 °20 with a step size of 0.020 °20 and a collection time of 0.10 seconds per step. Samples were prepared by placing powder or slurry onto a 96 well plate. Differential Scanning Calorimetry (DSC)

[00103] DSC data was collected on a TA Instruments Q2000 DSC. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in an aluminium pan and heated at 10 °C / minute from 40 °C to 300 °C. A purge of dry nitrogen at 100 mL / minute was maintained over the sample. The instrument control and data acquisition were acquired using Q Advantage software release version 5.5.23. The data was processed and presented using the TA Universal Analysis 2000 software version 4.5A build 4.5.0.5. Nuclear Magnetic Resonance (NMR)

[00104] 1H and 19F NMR measurements were performed by dissolving the sample at approximately 14 mg / mL in 600 pL volume of deuterated DMSO before analysing by Bruker 400 MHz NMR Spectrometer using the parameters shown in Table 1 below. The sample was analysed using the MestreNova software 14.3.1. Table 1: Parameters used for NMR spectrometry. Method Name Parameters Value Proton, icon (identity determination) Pulse angle 30° Spectral Width (SW) 30 ppm T ransmitter offset (01P) 5 ppm Digitisation (TD) 64 K Number of scans (NS) > 32 Pulse repetition time (D1) > 3s F19.icon Pulse angle 30° Spectral Width (SW) 270 ppm T ransmitter offset (01P) -100 ppm Digitisation (TD) 262 K Number of scans (NS) > 16 Pulse repetition time (D1) > 1 s Dynamic Vapour Sorption (DVS)

[00105] Dynamic Vapour Sorption (DVS) was carried out using the TA Instruments 10 Discovery-SA. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in a platinum pan. The sample was allowed to equilibrate at 50 °C at 0% RH for a period of 60 minutes. The sample was then equilibrated at 25 °C before ramping the humidity from 0 to 95% RH at 5% increments every hour. A similar ramp profile was used for desorption cycle. XRPD analysis was also performed on post DVS sample. 15 Thermal Gravimetric Analysis (TGA)

[00106] TGA data was collected on a TA Instruments Q5000 TGA. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in an aluminium pan and heated at 10 °C / minute from 40 °C to 300 °C, or varied as experimentation dictated. A purge of dry nitrogen at 25 mL I minute was maintained over the sample. The instrument control and data acquisition were acquired using Q Advantage software release version 5.5.23. The data was processed and presented using the TA Universal Analysis 2000 software version 4.5A build 4.5.0.5. Optical Microscopy

[00107] Optical Microscopy was performed using the Nikon Eclipse LV100ND Optical Microscope equipped with 5, 10, 20, 50 and 100* objective lens. The microscope was coupled with a PROMICRA, PROMICAM 3-5CP digital camera. The camera was controlled by the QuickPHOTO MICRO 3.2 software. The camera software measurement tool was calibrated using a transmitted Illumination slide (76 x26 mm, crossed scale-20 mm divided into 0.1 mm divisions, 200 divisions of 0.1 mm (100 pm)). Samples were prepared by distributing a powder over a microscope slide. High Performance Liquid Chromatography (HPLC)

[00108] HPLC system Agilent 1260 equipped with DAD detector was used in this work. The samples were placed in HPLC vials and stored at room temperature throughout the experiments. HPLC familiarisation was performed with the method shown in Table 2. A typical HPLC chromatogram is shown in Figure 1. Samples were made to the concentration of 0.25 mg / mL to obtain LCAP. UV-HPLC method and parameters are listed in Table 2 below. Table 2: HPLC method details. Analytical column Ascentis Express C18 4.6 x 150 mm, 2.7 pm Column temperature (°C) 40 °C Diluent ACN:H2O = 1:1 Mobile phase A 0.1% HCOOH in Water Mobile phase B 0.1% HCOOH in ACN Flow rate (mL / min) 1.0 Injection volume (pL) 5 Detector DAD Detection wavelength (nm) 210 Run time (min) 22 Gradient Time (min) %B 0.0 5 14.0 90 17.0 90 17.1 5 22.0 5 Crystallisation system - Crystal 16

[00109] Temperature cycling was performed on the crystallisation system Crystal 16 using the Crystallisation Systems software, version 1.14.0. Samples were prepared in 2 mL vials charged with overhead stirrers (for Single Solvent Slurry - Temperature Cycling) and bottom magnetic stirring bars (for Competitive Slurry). For Single Solvent Slurry - Temperature Cycling, cycling was between 0 - 55 °C with a heating ramp rate of 0.2 - 0.5 °C / min and a cooling rate of 0.2 - 0.5 °C / min and stirred at 650 RPM. An isotherm for 10 minutes at 0 and 55 °C was performed during each cycle.). For Competitive slurry, vials were cooled / heated to 5 °C, 25 °C and 50 °C and stirred for 24 hours at 650 RPM. Polymorph Identification Table 3: List of 26 solvent systems used. ID Solvent ID Solvent 1 Acetone 14 2-Butanol 2 ACN 15 DMC 3 2-Butanone 16 DMSO 4 DCM 17 n-heptane 5 1,4-Dioxane 18 2-Me-THF 6 EtOH 19 EtOAc 7 I PAC 20 I PA 8 MeOH 21 Nitromethane 9 MTBE 22 CPME 10 THF 23 2% v / v water in EtOH (~ 0.2 aw) 11 Toluene 24 8% v / v water in EtOH (~ 0.5 aw) 12 Water 25 30% v / v water in EtOH (~ 0.8 aw) 13 Anisole 26 50% v / v water in Acetone (~ 0.92 aw) Competitive slurry experiments

[00110] A competitive slurry experiment was performed to determine the most thermodynamically stable form. This was performed by adding EtOH to a 2 mL vial which was then saturated with appropriate amounts of F1, F2 and F3 to form a suspension. Slurries were cooled / heated to 5 °C, 25 °C and 50 °C and stirred for 1 day at 650 RPM using a magnetic bottom stirrer. Competitive slurry was repeated using 50% v / v water in MeOH as solvent. 50% v / v water in MeOH was added to a 2 mL vial which was then saturated with appropriate amounts of F1, F2 and F3 to form a suspension. Slurries were cooled / heated to 5 °C, 25 °C and 50 °C and stirred for 1 day at 650 RPM using a magnetic bottom stirrer. Upscaling methods for forms F1 • Input material: the compound of Formula (I), in form F1 • Solids were analysed by XRPD, TGA, DSC, DVS, NMR, PLM and HPLC. F2 • Input material: the compound of Formula (I), in form F1 (approximately 200 mg) was added to a 7 mL vial. • 1 mL of EtOAc was added to form a slurry and the vial capped and stirred at room temperature at 500 RPM for 24 hours. • Solids were left under vacuum at 40 °C in vacuum oven for 24 hours to form EtOAc solvate (S8). • Solids were heated to 150 °C on TGA. • Solids were collected and analysed by XRPD, TGA, DSC, NMR and PLM. F3 • Input material: the compound of Formula (I), in form F1 (approximately 200 mg) was added to a 7 mL vial. • 4 mL of 2% v / v water in EtOH was added to form a slurry and the vial capped and stirred at room temperature at 500 RPM for 24 hours. • Solids were left under vacuum at 40 °C in vacuum oven for 24 hours. • Solids were collected and analysed by XRPD, TGA, DSC, DVS, NMR and PLM.

[00111] Example 1

[00112] Crystalline form 1 was obtained according to the following method, where the crude N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide, i.e. the compound of formula (I), was obtained as set out in the synthesis section described herein.

[00113] A 500 ml three-necked round bottom flask equipped with a mechanical stirrer was successively charged at 20°C with crude N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide (35.0 g) and acetonitrile (385 ml). The mixture was heated to reflux (full dissolution was observed). The solution was allowed to cool down naturally to room temperature. Spontaneous crystallization was observed at about 58°C. Stirring was pursued at room temperature for 3 hours before filtration. The wet cake was rinsed with 25 ml of acetonitrile and dried under vacuum at 45°C until constant weight, 28.5 g of N-(4-bromo-2,5-difluorophenyl)-6-chloro-1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide was obtained as a white solid (yield: 81%; HPLC at 210 nm: 99.7%), as crystalline form 1.

[00114] XRPD showed that the material was crystalline with characteristic 20 reflections for F1 at 6.9, 7.3, 7,7, 7.8, 8.1, 12.9, 13.1, 13.2, 14.5, 14.6, 14.9, 16.8, 18.9, 19.4, 19.8, 20.2, 20.3, 21.3, 21.8, 22.7, 22.9, 23.9, 25.1, 25.5, 25.9, 26.2, 27.3, 28.6, 29.0, 31.4, 32.3, 32.7, 33.8, 33.9, 34.3, 34.6, 36.2, 36.5, 37.0, 38.8, 39.3 (Figure 15).

[00115] NMR confirmed that the material was consistent with chemical structure of the compound of Formula (I) (Figure 18). TGA showed an initial weight loss of 0.5% for residual adsorbed solvent, followed by a thermal decomposition onset at 251 °C confirmed that F1 was an anhydrate (Figure 20). DSC analysis showed a small broad exothermic event at 132 °C attributed to F1 to F2 transition. A small sharp endothermic event is seen at onset temperature at 221 °C (onset) attributed to an F2 to F3 transition, followed by an endothermic melt with onset temperature at 238 °C (onset) and heat fusion of 105.8 J / g (Figure 21), attributed to F3 melt. DVS showed F1 had 0.2% water uptake between 0-80% RH which showed that the material was non-hygroscopic (Figure 22). The isotherm plot showed there was no hysteresis (Figure 24). The XRPD data demonstrated that physical formed was retained after DVS (Figure 23). PLM showed plate like crystals with size between 120-150 pm (Figure 16 and Figure 17).

[00116] Example 2 Estimation of Solubility (by visual inspection)

[00117] An estimation of solubility for the compound of Formula (I), in form F1, was carried out in 26 solvents, as set out in the table below.

[00118] For each solvent, approximately 15 mg of the compound of Formula (I), in form F1, was added to a 2 mL glass vial followed by 50 pL of a solvent. If a clear point for a solution was visually observed, then solubility was estimated. If solids remained out of solution, solvent was added in increments of 50 pL up to 200 pL to dissolve the residual solids. Solvent was then added in increments of 100 pL up to 500 pL to dissolve the residual solids. If solid remained undissolved, solvent was added in increments of 250 pL until a maximum of 1 mL was added. Solvent Solubility at room temperature [mg / mL] Acetone 72-97 ACN « 16 2-Butanone 76-102 DCM « 16 1,4-Dioxane 52-79 EtOH 15-21 IPAC « 15 MeOH 20-32 MTBE « 15 TUI C I nr 99-150 Toluene « 15 Water « 15 Anisole « 15 2-Butanol « 15 DMC « 15 DMSO 152-304 n-heptane « 15 2-Me-THF 101 - 153 EtOAc 30-39 I PA « 16 Nitromethane « 15 CPME « 15 2% v / v water in EtOH « 15 8% v / v water in EtOH « 15 30% v / v water in EtOH « 16 50% v / v water in Acetone « 15

[00119] The results showed that Form F1 had the highest solubility in DMSO. Solubility was significantly greater than 50 mg / mL in Acetone, 2-butanone, THF, DMSO and 2-Me-THF. Poor solubility was observed in I, DCM, IPAC, MTBE, toluene, water, anisole, 2-butanol, 5 DMC, n-heptane, I PA, nitromethane, CPME, 2% v / v water in EtOH, 8% v / v water in EtOH, 30% v / v water in EtOH and 50% v / v water in acetone.

[00120] Example 3 Ambient (Slow) Evaporative Crystallisation

[00121] All solutions prepared for the estimation of solubility in the 26 solvent systems 10 described above were subsequently used for evaporative crystallisation assessment. The 2 mL glass vials were uncapped and solvents were allowed to evaporate under ambient conditions. Only solvent systems that resulted in clear solutions were used, as such all solutions were clear of solids before performing the evaporative crystallisation. Fast Evaporative Crystallisation

[00122] Half of each of the solutions prepared as described under the ‘Estimation of Solubility (by visual inspection)’ section was added to a 96 well plate and heated to 40 °C under vacuum, until the sample had evaporated. 5 Single Solvent Slurry

[00123] Single Solvent Slurry tests were performed to allow for the conversion of the compound of Formula (I), in form F1, to a more thermodynamically stable crystalline form. The solvents that were used are shown in Table 4. 500 - 1000 pL of solvent was added to a 2 mL vial, appropriate amounts of the compound of Formula (I), in form F1, were added 10 to the solvent to form a slurry. This was allowed to stir for 2 days using a bottom stirrer at 600 RPM. The crystalline material was then isolated for analysis by XRPD to confirm physical form. Table 4: Solvents used in single solvent slurry. ID Solvent 1 Acetone 2 ACN 3 2-Butanone 4 DCM 5 1,4-Dioxane 6 EtOH 7 I PAC 8 MeOH 9 MTBE 10 Tl-I C I nr 11 Toluene 12 Water 13 Anisole 14 2-Butanol 15 DMC 17 n-heptane 18 2-Me-THF 19 Ethyl Acetate 20 Isopropyl alcohol 21 Nitromethane 22 CPME 23 2% v / v water in EtOH 24 8% v / v water in EtOH 25 30% v / v water in EtOH 26 50% v / v water in Acetone Single Solvent Slurry (Temperature cycling)

[00124] Samples from the single solvent screen that yielded crystalline solids were temperature cycled (Table 5). This was performed by temperature cycling between 0-35 °C for solvents with ID 1, 2, 3 and 4 and a ramp rate of 0.2 °C / min whilst stirring with a hastelloy 5 hook at 600 RPM. A 10 minute isothermal hold was performed at 0 °C and 35 °C. For all other solvents, temperature cycling was between 0 - 55 °C and a ramp rate of 0.5 °C / min whilst stirring with a hastelloy hook at 600 RPM. A 10 minute isothermal hold was performed at 0°C and 55 °C. In total 10 cycles were performed. Upper temperature was set to at least 10 °C below solvent boiling point. 10 Table 5: Solvents used in Single Solvent Slurry - Temperature Cycling ID Solvent 1 DCM 2 MTBE 3 Acetone 4 50% v / v water in Acetone 5 MeOH 6 Tl-I C I nr 7 EtOAc 8 EtOH 9 2% v / v water in EtOH 10 8% v / v water in EtOH 11 30% v / v water in EtOH 12 2-Butanone 13 2-Me-THF 14 AON 15 I PA 16 I PAC

[00125] Example 3a

[00126] An overview of the forms identified is shown in Table 7a. The XRPD patterns for the assigned anhydrous forms are shown in Figure 2. 15 Table 7a: Overview of forms identified Form Assignment Notes F2 Anhydrous • First Isolated from Post-TGA heating at 150 °C compound of Formula (I). • Observed from drying / desolvating single solvent slurry from EtOAc. • TGA showed no weight loss prior to decomposition suggesting an anhydrous non-solvated form with thermal decomposition onset at 253 °C. • DSC showed a small sharp endothermic event at onset temperature 221 °C attributed to an F2 to F3 transition. DSC showed an endothermic event at onset temperature 239 °C attributed to F3 melt. F3 Anhydrous • First Isolated from drying / desolvating single solvent slurry from 2-Me-THF. • Observed from Single Solvent Slurry from EtOH, 2% v / v water in EtOH, 8% v / v water in EtOH and 30% v / v water in EtOH. • TGA showed no weight loss prior to decomposition suggesting an anhydrous non-solvate form with thermal decomposition onset at 265 °C. • DSC showed an endothermic event at onset temperature 238 °C attributed to F3 melt. • DVS showed material to be non hygroscopic with 0.1 % weight gain between 0-80% RH. Characterisation of form F2

[00127] F2 was isolated from Single Solvent Slurry, as described herein, followed by a heating to 150 °C on TGA. XRPD showed that the material was crystalline with characteristic 5 20 reflections for F2 at 6.4, 7.1, 8.1, 11.5, 13.4, 14.8, 15.9, 16.6, 17.1, 18.0, 18.3, 18.8, 19.5, 20.0, 20.5, 21.1, 21.5, 21.9, 22.6, 23.6, 24.1, 24.9, 25.5, 26.0, 26.7, 27.0, 27.7, 28.8, 30.0, 30.7, 31.5, 31.9, 32.7, 33.5, 34.3, 35.7, 36.5, 37.1, 37.5, 39.7 (Figure 25).

[00128] NMR confirmed that the material was consistent with chemical structure of the compound of Formula (I) (Figure 28 and Figure 29). TGA showed that the decomposition 10 temperature is at 253 °C. In addition to this, no significant mass loss associated with solvent loss was observed between 20-100 °C which suggested that F2 is anhydrous (Figure 30). DSC corroborates with the TGA data, no solvent loss was observed in the DSC trace between 20-100 °C. The endothermic event was observed at 221 °C (onset) with the heat of fusion of 0.04402 J / g. This is followed by second endothermic event at 238 °C (onset) with the heat of fusion of 105.4 J / g (Figure 31). PLM showed needle like crystals around 45-64 pm (Figure 26 and Figure 27). Characterisation of F3

[00129] F3 was isolated from Single Solvent Slurry, as described herein, XRPD showed that the material was crystalline with characteristic 20 reflections for F3 at 6.8, 7.0, 11.6, 11.8, 12.2, 12.5, 14.1, 14.2, 15.3, 15.4, 17.1, 18.0, 19.0 20.3, 20.7, 20.9, 21.1, 21.3, 21.8, 22.7, 23.1,23.4, 23.9, 24.5, 26.2, 26.7, 27.1, 28.2, 28.4, 28.6, 28.8, 30.0, 30.5, 31.3, 31.7, 32.2, 32.8, 33.3, 34.4, 35.9, 36.3, 36.5, 37.0, 37.2, 37.6, 37.9, 38.6, 39.7 (Figure 32).

[00130] NMR confirmed that the material was consistent with chemical structure of the compound of Formula (I) Figure 35 and Figure 36). TGA showed that the decomposition temperature is at 264.7 °C. In addition to this, no significant mass loss associated with solvent loss was observed between 20-100 °C which suggested that F3 is anhydrous (Figure 37). DSC corroborates with the TGA data, no solvent loss was observed in the DSC trace between 20-100 °C. The thermal decomposition endothermic melt was observed at 238 °C (onset) with the heat of fusion of 102.6 J / g (Figure 38). F3 had 0.05% water uptake between 0-80% RH which showed that the material was non-hygroscopic (Figure 39). The isotherm plot showed there was no hysteresis (Figure 41). The XRPD data demonstrated that physical formed was retained after DVS (Figure 40). PLM showed irregular plate like crystals with size between 15-25 pm (Figure 33 and Figure 34).

[00131] Example 3b

[00132] An overview of the solvate forms identified is shown in Table 7b. Table 7b: Overview of forms identified Form Assignment Notes S1 Solvate • First isolated from a Single Solvent Slurry from MTBE. • XRPD showed that the material was crystalline (see Figure 42). • TGA showed a weight loss of 16.9%, corresponding to 1 eq. MTBE. (see Figure 43). • DSC showed an endothermic event at 81.5 °C (onset), attributed to desolvation. A small unknown endothermic event was observed at 146 °C (onset). The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 43). S2 Solvate • First isolated from a Single Solvent Slurry from CPME. • XRPD showed that the material was crystalline, (see Figure 44) • TGA showed a weight loss of 10.1%, corresponding to 0.5 eq. CPME. (see Figure 45) • DSC showed a broad endothermic event at 109.9 °C (onset), attributed to desolvation, followed by a small unknown endothermic event at 194 °C (onset). A small endo / exothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C, attributed to an F3 melt, (see Figure 45) S3 Solvate • First isolated from a Single Solvent Slurry from I PAC. • XRPD showed that the material was crystalline, (see Figure 46) • TGA showed a weight loss of 10.1%, corresponding to 1 eq. I PAC. (see Figure 47) • DSC showed a broad endothermic event at 65.0 °C (onset), attributed to desolvation, followed by an unknown small endothermic event at 182 °C (onset). A small endothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition, however no exothermic event observed which typically proceeds an endothermic event The thermal decomposition endothermic melt was observed at 239 °C (onset), attributed to an F3 melt, (see Figure 47) S5 Solvate • First isolated from a Single Solvent Slurry from IPA. • XRPD showed that the material was crystalline, (see Figure 48) • TGA showed a weight loss of 11.2%, corresponding to 1 eq. IPA. (see Figure 49) • DSC showed a broad endothermic event at 75.0 °C (onset), attributed to desolvation. A number of unknown endothermic events follow at 102 °C (onset), 118 °C (onset), 130 °C (onset), 141.2 °C (onset) and 200.6 °C (onset). A small endothermic event at 221 °C (onset) is attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 239 °C (onset), attributed to an F3 melt, (see Figure 49) S6 Solvate • First isolated from a Single Solvent Slurry from THF. • XRPD showed that the material was crystalline, (see Figure 50) • TGA showed a weight loss of 13.7%, corresponding to 1 eq. THF. (see Figure 51) • DSC showed a broad endothermic event at 70.6 °C (onset), attributed to desolvation, followed by an unknown small endothermic event at 193 °C (onset). A small endo / exothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt (see Figure 51) S8 Solvate • First isolated from a Single Solvent Slurry from EtOAc. • XRPD showed that the material was crystalline, (see Figure 52) • TGA showed a weight loss of 9.0%, corresponding to 0.5 eq. EtOAc. (see Figure 53) • DSC showed an endothermic event at 102 °C (onset), attributed to desolvation, followed by a small endo / exothermic event at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 53) S9 Solvate • First isolated from a Single Solvent Slurry from 2-Butanol. • XRPD showed that the material was amorphous, (see Figure 54) • TGA showed a weight loss of 7.2%, corresponding to 0.5 eq. 2-Butanol. (see Figure 55) • DSC showed an endothermic event at 108 °C (onset), attributed to desolvation, followed by an unknown small endothermic event at 188 °C (onset). A small endo / exothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 55) S10 Solvate • First isolated from a Single Solvent Slurry from n-heptane. • XRPD showed that the material was weakly crystalline, (see Figure 56) • TGA showed a weight loss of 3.2%, corresponding to 0.2 eq. n-heptane. (see Figure 57) • DSC showed a small endothermic event at 76.0 °C (onset) followed by an exothermic event at 120 °C (onset), then another endothermic event at 126 °C (onset), which may be attributed to desolvation. An unknown endothermic event follows at 173 °C (onset). The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 57) S11 Solvate • First isolated from a Single Solvent Slurry from 2-Butanone. • XRPD showed that the material was crystalline, (see Figure 58) • TGA showed a weight loss of 7.3%, corresponding to 0.5 eq. 2-Butanone. (see Figure 59) • DSC showed an endothermic event at 69 °C (onset), followed by an endothermic event at 109 °C (onset), attributed to desolvation. A small unknown endothermic event was observed at 172 °C (onset). The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 59) S12 Solvate • First isolated from a Single Solvent Slurry from 1,4-Dioxane. • XRPD showed that the material was crystalline, (see Figure 60) • TGA showed a weight loss of 16.6%, corresponding to 1 eq. 1,4-Dioxane. (see Figure 61) • DSC showed a broad endothermic event at 67.0 °C (onset), followed by another endothermic event at 109 °C (onset), attributed to a two-step desolvation. An unknown endothermic event was observed at 190 °C (onset). A small endothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 61) S13 Solvate • First isolated from a Single Solvent Slurry from Toluene. • XRPD showed that the material was crystalline, (see Figure 62) • TGA showed a weight loss of 9.61%, corresponding to 0.5 eq. Toluene, (see Figure 63) • DSC showed a broad endothermic event at 121 °C (onset), attributed to desolvation. An unknown endothermic event was observed at 199 °C (onset). A small endothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 63) S15 Solvate • First isolated from a Single Solvent Slurry from Anisole. • XRPD showed that the material was crystalline, (see Figure 64) • DSC showed a broad endothermic event at 141.3 °C (onset), attributed to desolvation. A broad unknown endothermic event was observed at 194 °C (onset). A small endothermic event was observed at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 238 °C (onset), attributed to an F3 melt, (see Figure 65) Defining the form landscape (unconfirmed forms)

[00133] An overview of the unassigned forms is shown in Table 8. The XRPD patterns for the unassigned forms are shown in Figure 4, Figure 5, Figure 6, and Figure 7. For patterns 5 isolated from multiple solvents, only the most crystalline profile is displayed. Table 8: Overview of the fifteen unconfirmed forms. Form Notes Characterisation (XRPD / TGA / DSC) P3 • First Isolated from ACN in Slow Evaporative Crystallization. Figure 66 P4 • First Isolated from 2-Butanone in Slow Evaporative Crystallization. Figure 67 P5 • First Isolated from 1,4-Dioxane and CPME in Slow Evaporative Crystallization and Fast Evaporative Crystallization. Figure 68 Figure 69 Figure 70 Figure 71 P6 • First Isolated from THF in Slow Evaporative Crystallization. Figure 72 P7 • First Isolated from 2-Me-THF in Slow Evaporative Crystallization and Fast Evaporative Crystallization. Figure 73 Figure 74 P9 • First Isolated from a Single Solvent Slurry from CPME, IPAC, DMC, IPA, Anisole, Water, 50% water in Acetone, Figure 75 Figure 76 Figure 77 Figure 78 MTBE, 2-Me-THF, 2-Butanone and Acetone. • For SSS 50% v / v water in Acetone: o TGA showed a weight loss of 1.17%, attributed to low non-stoichiometric amount of Water and / or Acetone (< 0.3 eq.). o DSC showed a broad endothermic event at 80.0 °C (onset) with the heat of fusion of 24.9 J / g, attributed to a potential desolvation. A broad unknown exothermic event was observed at 163 °C (onset) with the heat of fusion of 8.07 J / . The thermal decomposition endothermic melt was observed at 238 °C (onset) with the heat of fusion of 91.9 J / g, attributed to an F3 melt. • For SSS DMC: o TGA showed a weight loss of 4.02%, potentially corresponding to 0.2 eq. DMC. o DSC showed a broad endothermic event at 72.4 °C (onset) followed by an endothermic event at 122 °C (onset) potentially attributed to a two-step desolvation. An unknown endothermic event at 193 °C (onset) follows. A small endothermic event at 221 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 239 °C (onset), attributed to an F3 melt. . For SSS 2-Me-THF: Figure 79 Figure 80 o TGA showed a weight loss of 5.3%, potentially corresponding to 0.3 eq. 2-Me-THF. o DSC showed a broad endothermic event at 45.3 °C (onset), potentially attributed to desolvation, followed by an endo / exothermic event at 201 °C (onset), attributed to an F2 to F3 transition. The thermal decomposition endothermic melt was observed at 239 °C (onset), attributed to an F3 melt. P13 • First Isolated from ACN in Single Solvent Slurry. • DSC showed an endothermic event at 203.8 °C (onset) with a heat of fusion of 1.59 J / g followed by an endothermic event at 218.9 °C (onset) with a heat of fusion of 0.09 J / g. An endothermic thermal decomposition event at 239.3 °C (onset) with a heat of fusion of 104.1 J / g. No endotherm is seen below 200 °C indicated no solvent or water present in form. • Potential anhydrous form as transition to F2 at high temperature had very small enthalpy. Figure 81 Figure 82 P17 • First Isolated from IPAC in Single Solvent Slurry - Temperature Cycling. Figure 83 P18 • First Isolated from IPA in Single Solvent Slurry - Temperature Cycling. Figure 84 P19 • First Isolated from ACN and 2% v / v water in EtOH in Single Solvent Slurry -Temperature Cycling. Figure 85 Figure 86 P20 • First Isolated from 2-Me-THF in Single Solvent Slurry - Temperature Cycling. Figure 87 P21 • First Isolated from 2-Butanone in Single Solvent Slurry - Temperature Cycling. Figure 88 P22 • First Isolated from 30% v / v water in EtOH in Single Solvent Slurry -Temperature Cycling. Figure 89 P23 • First Isolated from EtOH in Single Solvent Slurry - Temperature Cycling. Figure 90 P24 • First Isolated from DCM in Single Solvent Slurry - Temperature Cycling. Figure 91

[00134] Example 4 Competitive slurries to identify the most thermodynamically stable anhydrous form

[00135] Competitive slurry experiments were performed with F1, F2 and F3 at 5, 25 and 50 °C in EtOH and 50% v / v water in MeOH. The results showed that solids converted to F3 at 5 °C, 25 °C and 50 °C in EtOH. Solids converted to F3 at 25 °C and 50 °C in 50% v / v water in MeOH. Solids remained as a mixture of F2 and F3 at 5 °C in 50% v / v water in MeOH indicating form conversion was not complete at 5 °C. This was likely due to kinetic effects causing slow conversion at lower temperature. However, results from competitive slurry in EtOH suggested that F3 was the most stable form at 5 °C. Therefore, F3 was determined as the most stable form between 5 °C and 50 °C. On drying, solids remained the same pattern. The XRPD results are summarised in Table 9 and Table 10. The XPRD patterns for experiments performed at 5 C, 25 °C and 50 C in EtOH are shown in Figure 9, Figure 10 and Figure 11 respectively. The XPRD patterns for experiments performed at 5 C, 25 C and 50 C in 50% v / v water in MeOH are shown in Figure 12, Figure 13 and Figure 14, respectively. Table 9: Competitive slurry experiments using F1, F2 and F3 at temperature range of 5 - 50 °C in EtOH. Temperature (°C) XRPD assignment 5 F3 25 F3 50 F3 Table 10: Competitive slurry experiments using F1, F2 and F3 at temperature range of 5 -50 °C in 50% v / v water in MeOH. Temperature (°C) XRPD assignment 5 F2 + F3 25 F3 50 F3

[00136] Example 5 Single crystal X-ray diffraction of Fl and F3

[00137] X-Ray powder diffraction (XRPD)

[00138] Single crystal X-Ray diffraction (SXRD)

[00139] Suitable crystals were selected and mounted on a MITIGEN holder in perfluoroether oil. Data was collected on a Rigaku 007HF diffractometer with HF Varimax confocal mirrors, an UG2 goniometer and HyPix 6000HE detector at 100(2) K using Cu-Ka radiation (1.54178 A). Crystals were kept at a steady T = 100(2) K during data collection. Single Crystal XRD Analysis of F1:

[00140] Data Refinement of F1

[00141] The structure was solved in the space group P-1 (no. 2) with the SheIXT 2014 / 5 (Sheldrick, 2014) solution program using dual space methods and using Olex2 1.5 (Dolomanov et al., 2009) as the graphical interface. The model was refined with ShelXL 2014 / 7 (Sheldrick, 2015) using full matrix least squares minimisation on F2. All nonhydrogen atoms were refined anisotropically. The positions of the N-H atoms H1 and H2 were located from the electron difference map and refined with their thermal parameters linked to their parent atoms. The positions of the remaining H atoms were calculated geometrically and refined using the riding model.

[00142] Crystal Data (F1)

[00143] Ci3H7BrCIF2N3O2S (M =422.64 g / mol): triclinic, space group P-1 (no. 2), a = 5.41500(10) A, b = 12.4868(4) A, c = 13.6139(4) A, a = 113.900(3)°, p = 96.835(2)°, y = 98.614(2)°, V = 815.49(4) A3, Z = 2, T= 100(2) K, p(Cu Ka) = 6.452 mm\ Dcalc= 1.721 g / cm3, 15315 reflections measured (7.246° <20 <140.304°), 3051 unique (Rint = 0.0321, Rsigma = 0.0261) which were used in all calculations. The final Ri was 0.0336 (I >2o(l)) and WR2 was 0.0809 (all data).

[00144] Structural Analysis (F1)

[00145] The structure of F1 was solved and refined into the triclinic space group P-1. The asymmetric unit comprised 1 molecule of F1 (Figure 92) and there were 2 asymmetric units in the unit cell. No solvent molecules were refined into the asymmetric unit and there were no regions of unrefined electron density in the Fourier map. a = 5.41500(10) A b = 12.4868(4) A c= 13.6139(4) A a = 113.900(3) 0 / 3 = 96.835(2) 0 Ri (I >2a(l)) = 3.36% wR2 (all data) = 4.11% S (Goodness of fit) = 1.054 Rint = 3.21% y= 98.614(2) 0 The refinement statistics indicated that the model was sufficient to confirm the connectivity of F1.

[00146] Hydrogen bonding

[00147] The structure was stabilised by a pair of cooperative hydrogen bonds. The first hydrogen bonding interaction was between a hydrogen atom (H1) on the sulfonamide nitrogen (N1) to a sulfonamide oxygen atom (02) of a neighbouring molecule [N1-O2_$1 = 2.934(3) A with an (NH-O) angle of 165(4) °, where $1 = 2-X,1-Y,2-Z] (Figure 93). The second hydrogen bonding interaction was between a hydrogen atom (H2) on the pyrrole nitrogen (N2) to a pyridine nitrogen atom (N3) of a neighbouring molecule [N2 - N3_$2 = 2.912(3) A with an (NH-N) angle of 166(4) °, where $2 = 1-X,-Y,1-Z] (Figure 94).

[00148] Further Bonding Features

[00149] There are no observable tt---tt or halogen-- halogen interactions present in the structure.

[00150] Packing

[00151] The unit cell when viewed down the a, b, and c -axis is shown in Figure 95, Figure 96, and 97, respectively. There is a potential slip plane on

[001] shown in Figure 98, however, the presence of the hydrogen bonds across this plane may inhibit the free movement of the layers.

[00152] Simulated XRPD diffractogram

[00153] An overlay of the simulated (100 K) and experimental (298 K) XRPD 20 diffractograms is presented in Figure 99. Due to the thermal expansion effects caused by the difference in temperature between the two measurements, some shifting of the diffraction peaks is to be expected. 5

[00154] The simulated and experimental diffractograms are generally consistent with each other, confirming that the model accurately represents the major component the experimental data. The experimental data may show the presence of a small impurity leading to additional peaks that do not confirm the predicted XRPD pattern.

[00155] Crystallographic parameters (F1) Empirical formula Ci3H7BrCIF2N3O2S Formula weight 422.64 Temperature / K 100(2) Crystal system triclinic Space group P-1 a / A 5.41500(10) b / A 12.4868(4) c / A 13.6139(4) a / ° 113.900(3) p / ° 96.835(2) Y / ° 98.614(2) Volume / A3 815.49(4) Z 2 pcaic g / cm3 1.721 p / mm'1 6.452 F(000) 416 Crystal size / mm3 0.09 x 0.04 x 0.02 Radiation Cu Ka (A= 1.54184) 20 range for data collection / 0 7.246 to 140.304 Index ranges -6<h<6,-15<k<12,-16<l<16 Reflections collected 15315 Independent reflections 3051 [Rint = 0.0321, Rsigma = 0.0261] Data / restra i nts / pa ram eters 3051 / 0 / 214 Goodness-of-fit on F2 1.054 Final R indexes [l>=2o (I)] Ri = 0.0336, wR2 = 0.0780 Final R indexes [all data] Ri = 0.0411, wR2 = 0.0809 Largest diff, peak / hole / e A’3 0.43 / -0.71 10 Single Crystal XRD Analysis of F3:

[00156] Data Refinement of (F3)

[00157] The structure was solved in the space group P2i / c (No. 14) with the SheIXT 2015 (Sheldrick, 2015) solution program using dual space methods and using Olex2 1.5 (Dolomanov et al., 2009) as the graphical interface. The model was refined with ShelXL 2014 / 7 (Sheldrick, 2015) using full matrix least squares minimisation on / =2. All non-hydrogen atoms were refined anisotropically. The positions of the N-H atoms H1 and H2 were located from the electron difference map and refined with their thermal parameters linked to their parent atoms. The N-H distances were restrained in order to maintain reasonable bond lengths. The positions of the remaining H atoms were calculated geometrically and refined using the riding model.

[00158] Twinning was observed, the high data quality allowed for easy resolution of the twinned components. A second component was observed where component 2 was rotated by -179.9903° around [-0.37 0.00 0.93] (reciprocal) or [0.00 -0.00 1.00] (direct). Rint is not available as all the reflections were used for the refinement and no equivalent reflection were recorded, this is likely due to the twinning observed.

[00159] Crystal Data (F3)

[00160] Ci3H7BrCIF2N3O2S (M = 422.64 g / mol): monoclininc, P2i / c, (No. 14), a = 13.4504(5) A, b = 9.2281(3) A, c = 12.4087(4) A, a = y = 90°, / 3= 111.678(4)°, V = 1431.26(9) A3, Z = 4, T= 100(2) K, p(Cu Ka) = 7.352 mm'1, Deale = 1.961 g / cm3, 5194 reflections measured (7.072° <20 <147.676°), 5194 unique (Rint = N / A, RSigma = 0.0154) which were used in all calculations. The final Ri was 0.0269 (I >2o(l)) and WR2 was 0.0728 (all data).

[00161] Structural Analysis (F3)

[00162] The structure of Form 3 was solved and refined into the monoclinic space group P2i / c. The asymmetric unit comprised of 1 molecule of F3 (Figure 100) and there were 4 asymmetric units in the unit cell. No solvent molecules were refined into the asymmetric unit and there were no regions of unrefined electron density in the Fourier map. a = 13.4504(5) A 6 = 9.2281(3) A c= 12.4087(4) A a = 90° Ri (I >2a(l)) = 2.69% wR2 (all data) = 7.28% S (Goodness of fit) = 1.075 Rint = N / A / 3 = 111.678(4) y = 90° The refinement statistics indicated that the model was sufficient to confirm the connectivity of F3.

[00163] Hydrogen bonding

[00164] There is a single cooperative hydrogen bond in the crystal structure of F3. This hydrogen bond appears as a cooperative pair forming a dimer-like interaction between two molecules (Figure 101). This forms between a hydrogen atom (H2) on the pyrrole nitrogen (N2) to a pyridine nitrogen atom (N3) of a neighbouring molecule [N2---N3_$1 = 2.913(3) A with an (NH-N) angle of 171 (3)°, where $1 = -X,1-Y,-Z],

[00165] Further Bonding Features

[00166] There are no observable tt -tt or halogen- -halogen interactions present in the structure.

[00167] Packing

[00168] The unit cell when viewed down the a, b, and c -axis is shown in Figure 102, Figure 103, and Figure 104, respectively. There is a potential slip plane on

[100] shown in Figure 105, however, the presence of the hydrogen bonds across this plane may inhibit the free movement of the layers.

[00169] Simulated XRPD diffractogram

[00170] An overlay of the simulated (100 K) and experimental (298 K) XRPD 20 diffractograms is presented in Figure 106. Due to the thermal expansion effects caused by the difference in temperature between the two measurements, some shifting of the diffraction peaks is to be expected.

[00171] The simulated and experimental diffractograms are consistent with each other, confirming that the model accurately represents the data.

[00172] Crystallographic parameters (F3) Empirical formula Ci3H7N3O2F2SCIBr Formula weight 422.64 Temperature / K 100(2) Crystal system monoclinic Space group P2i / c a / A 13.4504(5) b / A 9.2281(3) c / A 12.4087(4) a / ° 90 p / ° 111.678(4) y / ° 90 Volume / A3 1431.26(9) Z 4 Pcaicg / cm3 1.961 p / mm'1 7.352 F(000) 832.0 Crystal size / mm3 0.09x0.09x0.02 Radiation Cu Ka (A = 1.54184) 20 range for data collection / 0 7.02 to 147.676 Index ranges -16 <h <16, -11 <k <11, -11 <I <15 Reflections collected 5194 Independent reflections 5194 [Rint = N / A, Rsigma = 0.0154] Data / restra i nts / pa ram eters 5194 / 2 / 215 Goodness-of-fit on F2 1.075 Final R indexes [l>=2o (I)] Ri = 0.0269, wR2 = 0.0715 Final R indexes [all data] Ri = 0.0299, wR2 = 0.0728 Largest diff, peak / hole / e A-3 0.45 / -0.45

[00173] Example6 Biorelevant solubility of F1, F2, F3, amorphous

[00174] Biorelevant solubility of was determined in FaSSIF (pH 6.5) at 37 °C and at 300 RPM bottom stirring. About 8 mg of each API (F1, F2, F3, amorphous) was weighed into two different 4 mL clear glass vial and 4 mL of media was added (2 mg / mL). Three (n=3) such vials were prepared.

[00175] To prepare 100 mL of FaSSIF media, 4.2 mL of FaSSIF buffer concentrate (containing water sodium hydroxide, monobasic sodium phosphate) and 96.2 mL of water were combined in a 100 mL Duran bottle. Approximately 0.2 g of FaSSIF powder was weighed and transferred to the bottle followed by stirring until complete dissolution of powder was achieved. The final pH of the solution was adjusted to pH 6.5 using 1M HCI or 1M NaOH under ambient conditions. The media was allowed to equilibrate for 2 hours at ambient conditions before using it with 48 hours. When mentioned double strength it suggests twice the quantity of solids mentioned in the above recipe was used to prepare the final buffer media. The composition of FaSSIF pH 6.5 is: Taurocholate (mM) Lecithin (mM) Sodium (mM) Chloride (mM) Phosphate (mM) FaSSIF (pH 6.5) 3 0.75 148 106 29

[00176] Samples were collected at 1 hr, 4 hr and 24 hr time points. At each time point 500 pL of sample was withdrawn into a syringe. Sample was filtered using 0.2 pm PTFE syringe filter, before diluting the filtrate with diluent and analysing by HPLC.

[00177] HPLC data was collected using an Agilent 1260 / 1290 system equipped with diode array detector (DAD), using the parameters shown below. The samples were stored in clear HPLC vials at 25 °C temperature throughout the experiments. Analytical column Ascentis Express C18, 150 x 4.6 mm, 2.7 pm Column temperature 40 °C Diluent 50: 50 (v / v) Acetonitrile : water Mobile phase A: 0.1% Formic acid in water B: 0.1% Formic acid in MeCN Flow rate 1.0 mL / min Injection volume 5 pL Detection wavelength 210 nm Run time 22 minutes Gradient Time (mins) %A %B 0.0 95 5 14.0 10 90 17.0 10 90 17.1 95 5 22.0 95 5 5

[00178] After 24 hours solids were collected and analysed by XRPD. The results were as follows: Solubility in FaSSIF pH 6.5 (mg / mL) Time point (hrs) Amorphous F1 F2 F3 1 0.053 0.032 0.044 0.028 4 0.05 0.026 0.042 0.025 24 0.02 0.02 0.018 0.019

[00179] A plot of the results is presented in Figure 107. That figure shows that amorphous material has the highest dissolution rate. F2 has the highest dissolution rate of the three 10 crystalline polymorphs tested. F1 and F3 exhibited slower dissolution rates than F2.

[00180] Example? Particle size reduction of F2 and F3

[00181] To achieve API particle size of <5pm, the API and the milling media (1.0 mm zirconia silica beads) were weighed in a clear glass vial at 1:20 API: beads ratio. The required volume of decafluoropentane (suspending vehicle) was added to the same glass vial. Milling was performed using the planetary mill (Fritsch PULVERISETTE 6 Mono Mill) for up to 6 hours at 520 rpm. Initially, API was milled for 90 minutes followed by additional 90 minutes milling. Post each 90 minute interval, micronisation progress was monitored by optical microscopy.

[00182] Optical Microscopy was performed using the Nikon Eclipse LV100ND Optical Microscope equipped with 5, 10, 20, 50 and 100* objective lens. The microscope is coupled with a PROMICRA, PROMICAM 3-5CP digital camera. The camera is controlled by the QuickPHOTO MICRO 3.2 software. The camera software measurement tool is calibrated using a transmitted Illumination slide (76 x 26 mm, crossed scale - 20 mm divided into 0.1 mm divisions, 200 divisions of 0.1 mm (100 pm)). Samples were prepared by distributing a powder over a microscope slide.

[00183] Micronisation process was continued further until sufficient particle size reduction was observed. At the end of milling the suspension was separated from the milling media and the decafluoropentane evaporated at 30 °C overnight to isolate solids.

[00184] The micronised F2 and F3 was characterised by optical microscopy. This was to determine physicochemical properties of the micronised F2 / F3 and confirm the particle size requirement of <5pm.

[00185] Results for F2

[00186] The below results show that 6 hours of milling at 520 RPM, 1:20 API:bead ratio was required to obtain majority of particles <5 pm. Longer milling time could potentially be attributed to a rod-like morphology of the input material (F2). Optical microscopy images of the milling trials were used to measure particle size. Milling cnond w|Jt£v»U Milling Time API: milling media Microscopy 520 RPM 90 min 1:20 Particles up to 26 pm were observed. 520 RPM 180 min 1:20 Majority of particles observed <5 pm Some particles up to 15 pm were observed. 520 RPM 240 min 1:20 Majority of particles observed <5 pm Some particles up to 19 pm were observed. 520 RPM 300 min 1:20 Majority of particles observed <5 pm Some particles up to 11 pm were observed. 520 RPM 360 min 1:20 Majority of particles observed <5 pm

[00187] XRPD of the API showed no form change upon milling.

[00188] Results for F3

[00189] The below results show that 210 minutes of milling at 520 RPM, 1:20 APkbead ratio 5 was required to obtain majority of particles <5 pm.

[00190] It was observed that shorter milling time was required for F3 as compared to F2. This was potentially due to differences in morphology - non-micronised F3 consisted of wide, irregular shaped particles whereas non-micronised F2 showed a thin needle morphology which tend to be more difficult to mill. Additionally, the presence of slip planes 10 in F3 (which are not present in F2) could also make it easier to mill and therefore reduce the milling time for F3 vs F2. Milling speed Milling Time API: milling media Microscopy 520 RPM 90 min 1:20 Potential particles up to 54 pm were observed. 520 RPM 150 min 1:20 Potential particles up to 19 pm were observed. 520 RPM 210 min 1:20 Majority of particles <5 pm were observed.

[00191] XRPD of the API showed no form change upon milling.

[00192] Example 8 15 Micronised F2 / F3 in biorelevant dissolution study

[00193] A two stage dissolution study on F2 / F3 micronised and non-micronised suspension was performed to investigate the effect on the particle size on dissolution in biorelevant media.

[00194] The dissolution media were prepared as follows: Taurocholate (mM) Lecithin (mM) Sodium (mM) Chloride (mM) Phosphate (mM) Acetic Acid (mM) FaSSGF (pH 1.6) 0.08 0.02 34 59 - - FaSSIF (pH 6.5) 3 0.75 148 106 29 - FeSSIF (pH 5.0) 15 3.75 319 203 - 144

[00195] Preparation of Fasted state simulated gastric fluid at pH 1.6 (FaSSGF):

[00196] To prepare 100 mL of FaSSGF media, 3.7 g of FaSSGF buffer concentrate (containing water sodium chloride and HCI) and 96.2 mL of water were combined in a 100 mL Duran bottle. Approximately 6 mg of FaSSIF / FeSSIF / FaSSGF powder was weighed and transferred to the bottle followed by stirring until complete dissolution of powder was achieved. The final pH of the solution was adjusted to pH 1.6 using 1M HCI or 1M NaOH under ambient conditions. The media was used within 48 hours. The composition of FaSSGF pH 1.6 can be found above.

[00197] Preparation of Fasted state stimulated intestinal fluid at pH 6.5 (FaSSIF)

[00198] To prepare 100 mL of FaSSIF media, 4.2 mL of FaSSIF buffer concentrate (containing water sodium hydroxide, monobasic sodium phosphate) and 96.2 mL of water were combined in a 100 mL Duran bottle. Approximately 0.2 g of FaSSIF / FeSSIF / FaSSGF powder was weighed and transferred to the bottle followed by stirring until complete dissolution of powder was achieved. The final pH of the solution was adjusted to pH 6.5 using 1M HCI or 1M NaOH under ambient conditions. The media was allowed to equilibrate for 2 hours at ambient conditions before using it with 48 hours. When mentioned double strength it suggests twice the quantity of solids mentioned in the above recipe was used to prepare the final buffer media. The composition of FaSSIF pH 6.5 can be found above.

[00199] Preparation of Fed state stimulated intestinal fluid at pH 5.0 (FeSSIF)

[00200] To prepare 100 mL of FeSSIF media, 8.1 mL of FeSSIF buffer concentrate (containing water, sodium hydroxide, sodium chloride and glacial acetic acid) and 92.0 mL of water were combined in a 100 mL Duran bottle. Approximately 1.1 g of FaSSIF / FeSSIF / FaSSGF powder was weighed and transferred to the beaker followed by stirring until complete dissolution of powder was achieved. The final volume of the solution was adjusted to pH 5.0 using 1M HCI or 1M NaOH under ambient conditions. The media was used within 48 hours. The composition of FeSSIF pH 5.0 can be found above.

[00201] Suspensions of F2 / F3 non-micronised and micronised F2 / F3 were initially prepared at 50 mg / mL concentration in aqueous vehicle consisting of 0.5% w / v Methylcellulose (400 cP) and 0.1% w / v Tween 80. Prior to the dissolution, samples were homogenised for an hour at room temperature and were maintained under constant stirring at ca. 600 RPM. About 1 mL volume of the pre-homogenised suspensions (equivalent to 50 mg dose) were added to the respective dissolution vessel containing 250 mL FaSSGF (pH 1.6) maintained at 37 °C at the start of dissolution. The suspensions were exposed for a total of 30 minutes in FaSSGF (pH 1.6) before addition of 250 mL of double concentrated FaSSIF (pre adjusted 5 to obtain pH 5.6 post dilution) media. The detailed method parameters can be found below. Two-stage biorelevant dissolution method parameters Dissolution apparatus USP II dissolution apparatus Media FaSSGF and FaSSIF (2* cone.) Equilibration temp (°C) 37 ± 0.5 Paddle speed (rpm) 50 Sample(s) F2 / F3 non-micronised suspension F2 / F3 micronised suspension Dose 50 mg (n=2) Sampling time points FaSSGF- 5, 15 and 30 minutes FaSSIF (pH 5.6)- 5 and 15 minutes FaSSIF (pH 6.0)- 5, 15 and 30 minutes FaSSIF (pH 6.5)- 5, 15, 30, 45 and 60 minutes Sampling volume 1 mL of sample volume was withdrawn with the help of a cannula attached with alm pore size cannula filter. Sample was then passed through a 0.2 pm PTFE filter, before diluting and analysing by HPLC.

[00202] F2 results

[00203] Results showed a negligible drug dissolution for the initial 30 minutes of gastric phase (FaSSGF, pH 1.6) for both non-micronised and micronised F2. Post pH switch, a 10 faster dissolution rate was observed for the micronised suspension (ca. 0.04 mg / mL, 35% dissolved) as compared to the suspension prepared using non-micronised API (ca. 0.02 mg / mL, 20% dissolved) (Figure 108). Overall, the results suggested that ca. 2-fold increase in solubility could potentially be achieved for the F2 by reducing the particle size (Figure 109). 15

[00204] F3 results

[00205] Results showed a negligible drug dissolution for the initial 30 minutes of gastric phase (FaSSGF, pH 1.6) for both non-micronised and micronised F3. Post pH switch, an increase in dissolution rate was observed for the micronised suspension (ca. 0.02 mg / mL, 20% dissolved) as compared to the suspension prepared using non-micronised API (ca. 0.01 mg / mL, 11% dissolved) (Figure 110). This suggested that a two-fold increase in dissolution rate could potentially be achieved by reducing particle size of F3 (Figure 111).

[00206] A similar trend in the rate of dissolution was observed for F3 and F2 (Figure 112), although F3 showed consistently lower solubility for both micronised and non-micronised 5 material than F2 (Figure 113).

Claims

1. A crystalline form of a compound of Formula (I):or a solvate or hydrate thereof.

2. The crystalline form of claim 1, wherein the crystalline form is form F1 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

3. The crystalline form of claim 2, wherein the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

4. The crystalline form of claim 3, wherein the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

5. The crystalline form of claim 1, wherein the crystalline form is F1 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 15.

6. The crystalline form of claim 1, wherein the crystalline form is form F2 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5,21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

7. The crystalline form of claim 6, wherein the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

8. The crystalline form of claim 7, wherein the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 8.1, 14.8, 16.6, 18.8,19.5, 21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

9. The crystalline form of claim 1, wherein the crystalline form is F2 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 25.

10. The crystalline form of claim 1, wherein the crystalline form is form F3 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 29 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

11. The crystalline form of claim 10, wherein the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

12. The crystalline form of claim 11, wherein the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

13. The crystalline form of claim 1, wherein the crystalline form is F3 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 32.

14. A pharmaceutical composition comprising a crystalline form of any one of claims 1 to 13, and a pharmaceutically acceptable excipient.

15. A crystalline form of any one of claims 1 to 13, or a pharmaceutical composition of claim 14, for use in the treatment or prophylaxis of a disease selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuritis, acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis (AHL), periventricular leukomalacia, e.g. periventricular leukomalacia demyelination due to viral infections, such as by HIV or progressive multifocal leucoencephalopathy, central pontine and extrapontine myelinolysis, demyelination due to traumatic brain injury and / or traumatic brain tissue damage, including compression-induced demyelination, e.g. by tumours, demyelination in response to hypoxia, e.g. polycythemia vera, demyelination in response to stroke or ischaemia or other cardiovascular diseases, demyelination due to exposure to carbon dioxide, cyanide, or other CNS toxins, Schilder’s disease, Balo concentric sclerosis, Perinatal encephalopathy; Neurodegenerative Diseases including: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Multiple system atrophy, Parkinson’s Disease, Spinocerebellar ataxia (SCA), Huntington’s Disease; psychiatric disorders such asschizophrenia and bipolar disorder; peripheral myelination diseases such as leukodystrophies (e.g. Pelizaeus-Merzbacher disease), peripheral demyelinating neuropathies, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease; and obesity.

16. A method of manufacturing a pharmaceutical formulation comprising combining a5 crystalline form of a compound of Formula (I) of any one of claims 1 to 13, and at least one pharmaceutically acceptable excipient.AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS:Claims1. A crystalline form of a compound of Formula (I):wherein the crystalline form is form F3 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 11.8, 15.2,15.4,17.9,23.8, 24.4, 26.6,28.3,28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

2. The crystalline form of claim 1, wherein the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

3. The crystalline form of claim 2, wherein the crystalline form F3 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 11.8, 15.2, 15.4, 17.9, 23.8, 24.4, 26.6, 28.3, 28.8, and 30.5 degrees, wherein each peak is correct to ± 0.2 degrees.

4. The crystalline form of claim 1, wherein the crystalline form is F3 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 32.

5. A crystalline form of a compound of Formula (I):wherein the crystalline form is form F1 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

6. The crystalline form of claim 5, wherein the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

7. The crystalline form of claim 6, wherein the crystalline form F1 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 7.3, 7.8, 8.1, 12.9, 16.8, 19.8, 25.5, 25.9, 26.2, and 32.3 degrees, wherein each peak is correct to ± 0.2 degrees.

8. The crystalline form of claim 5, wherein the crystalline form is F1 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 15.

9. A crystalline form of a compound of Formula (I):wherein the crystalline form is form F2 and exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak at 20 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

10. The crystalline form of claim 9, wherein the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising at least four characteristic peaks at 20 selected from the group consisting of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1, 22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to ± 0.2 degrees.

11. The crystalline form of claim 10, wherein the crystalline form F2 exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 20 of 8.1, 14.8, 16.6, 18.8, 19.5, 21.1,22.6, 26.0, 26.7, and 28.8 degrees, wherein each peak is correct to + 0.2 degrees.

12. The crystalline form of claim 9, wherein the crystalline form is F2 and exhibits an X-ray powder diffraction pattern substantially as shown in the XRPD of Figure 25.

13. A pharmaceutical composition comprising a crystalline form of any one of claims 1 to 12, and a pharmaceutically acceptable excipient.

14. A crystalline form of any one of claims 1 to 12, or a pharmaceutical composition of claim 13, for use in the treatment or prophylaxis of a disease selected from: multiple sclerosis (MS), neuromyelitis optica (Devic’s disease), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuritis, acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis (AHL), periventricular leukomalacia, e.g. periventricular leukomalacia demyelination due to viral infections, such as by HIV or progressive multifocal leucoencephalopathy, central pontine and extrapontine myelinolysis, demyelination due to traumatic brain injury and / or traumatic brain tissue damage, including compression-induced demyelination, e.g. by tumours, demyelination in response to hypoxia, e.g. polycythemia vera, demyelination in response to stroke or ischaemia or other cardiovascular diseases, demyelination due to exposure to carbon dioxide, cyanide, or other CNS toxins, Schilder’s disease, Balo concentric sclerosis, Perinatal encephalopathy; Neurodegenerative Diseases including: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Multiple system atrophy, Parkinson’s Disease, Spinocerebellar ataxia (SCA), Huntington’s Disease; psychiatric disorders such as schizophrenia and bipolar disorder; peripheral myelination diseases such as leukodystrophies (e.g. Pelizaeus-Merzbacher disease), peripheral demyelinating neuropathies, Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease; and obesity.

15. A method of manufacturing a pharmaceutical formulation comprising combining a crystalline form of a compound of Formula (I) of any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.