Solid state forms of iptacopan hydrochloride

Abstract

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

Description

SOLID STATE FORMS OF IPTACOPANCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Application No. 202411050026 filed on June 29, 2024. The entire contents of the foregoing application are incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Iptacopan, in embodiments crystalline polymorphs or salts of Ipatcopan, particularly Iptacopan hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0003] Iptacopan hydrochloride, 4-((2S,4S)-(4-ethoxy-l-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride, has the following chemical structure:

[0004] Iptacopan hydrochloride is a complement Factor B inhibitor, and it is approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). Iptacopan is also under investigation for the treatment of Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Atypical Hemolytic Uremic Syndrome (aHUS), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD), Membranoproliferative Glomerulonephritis, Age-related Macular Degeneration, Lupus nephritis and Membranous Glomerulonephritis

[0005] The compound is described in U.S. Patent No. 9,682,968. Crystalline hydrate form of Iptacopan hydrochloride is described in U.S. Patent No. 11,603,363. The entire contents of the foregoing applications are incorporated by reference herein.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (“XRD”) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0008] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Iptacopan hydrochloride.SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline of Iptacopan hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof. These crystallinepolymorphs can be used to prepare other solid state forms of Iptacopan hydrochloride, other salts and their solid state forms.

[0010] The present disclosure also provides uses of the said solid state forms of Iptacopan hydrochloride in the preparation of other solid state forms of Iptacopan hydrochloride.

[0011] The present disclosure provides crystalline polymorphs of Iptacopan hydrochloride for use in medicine, including for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or for the treatment of Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).

[0012] The present disclosure also encompasses the use of crystalline polymorphs of Iptacopan hydrochloride of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Iptacopan hydrochloride according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Iptacopan hydrochloride with at least one pharmaceutically acceptable excipient.

[0015] The crystalline polymorph of Iptacopan hydrochloride as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Iptacopan hydrochloride may be used as medicaments, such as for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or for the treatment of Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).

[0016] The present disclosure also provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or methods of treating Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD), by administering a therapeutically effective amount of any one or acombination of the crystalline polymorphs of Iptacopan hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD) or otherwise in need of the treatment.

[0017] The present disclosure also provides uses of crystalline polymorphs of Iptacopan hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g. paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or for the manufacture of medicaments for treating Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a characteristic X-ray powder diffraction (“XRPD”) pattern of Iptacopan hydrochloride Form IP1;

[0019] Figure 2 shows a characteristic XRPD pattern of Iptacopan hydrochloride Form IP2; and

[0020] Figure 3 shows a characteristic XRPD pattern of Iptacopan hydrochloride Amorphous form.

[0021] Figure 4a shows solid state13C NMR spectrum of Iptacopan hydrochloride Form IP1 (full scan).

[0022] Figure 4b shows solid state13C NMR spectrum of Iptacopan hydrochloride Form IP1 (at the range of 0-90 ppm).

[0023] Figure 4c shows solid state13C NMR spectrum of Iptacopan hydrochloride Form IP1 (at the range of 90-200 ppm).DETAILED DESCRIPTION OF THE DISCLOSURE

[0024] The present disclosure encompasses solid state forms of Iptacopan hydrochloride, including crystalline polymorphs of Iptacopan hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof. In embodiments, the present disclosureprovides crystalline form of Iptacopan hydrochloride designated as Form IP1 and Form IP2 (defined herein).

[0025] Solid state properties of Iptacopan hydrochloride and crystalline polymorphs thereof can be influenced by controlling the conditions under which Iptacopan hydrochloride and crystalline polymorphs thereof are obtained in solid form.

[0026] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Iptacopan hydrochloride described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Iptacopan hydrochloride. In some embodiments of the disclosure, the described crystalline polymorph of Iptacopan hydrochloride may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Iptacopan hydrochloride.

[0027] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Iptacopan hydrochloride of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. The disclosed forms of Iptacopan hydrochloride may be especially stable. The disclosed forms of Iptacopan hydrochloride may have advantageous powder properties (such as a higher bulk density), which enables improved handling and processing.

[0028] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additionaltechnical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Iptacopan hydrochloride referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Iptacopan hydrochloride characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0029] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w / w) or less, about 5% (w / w) or less, about 4% (w / w) or less, about 3% (w / w) or less, about 2% (w / w) or less, about 1.5% (w / w) or less, about 1% (w / w), about 0.8% (w / w) or less, about 0.6% (w / w) or less, about 0.4% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent, or less about 0.2% area percent or less,, about 0.1% area percent or less or about 0% of any other compound as measured by HPLC. Thus, pure or purified Iptacopan hydrochloride described herein as substantially free of any compounds would be understood to contain greater than about 90% (w / w), greater than about 95% (w / w), greater than about 96% (w / w), greater than about 97% (w / w), greater than about 98% (w / w), greater than about 98.5% (w / w), greater than about 99% (w / w), greater than about 99.2%, (w / w) greater than about 99.4% (w / w), greaterthan about 99.6% (w / w), greater than about 99.8% (w / w), greater than about 99.9% (w / w), or about 100% of the subject Iptacopan hydrochloride. Alternatively, pure or purified Iptacopan hydrochloride described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2%, area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% (area percent, greater than about 99.9% area percent, or about 100% of the subject Iptacopan hydrochloride.

[0030] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Iptacopan hydrochloride, relates to a crystalline form of Iptacopan hydrochloride which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0031] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0032] As used herein, the term "isolated" in reference to crystalline polymorph of Iptacopan hydrochloride of the present disclosure corresponds to a crystalline polymorph of Iptacopan hydrochloride that is physically separated from the reaction mixture in which it is formed.

[0033] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuKa radiation, X = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0034] As used herein, unless stated otherwise,13C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency <z>r / 27t = 11 kHz, preferably at a temperature of at 293 K ± 3°C.

[0035] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT ” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., theroom or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0036] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mb of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mb of solvent X was added.

[0037] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0038] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0039] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0040] The present disclosure includes a crystalline polymorph of Iptacopan hydrochloride, designated IP1. The crystalline Form IP1 of Iptacopan hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 13.2, 14.5, 15.6, 18.1 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 166.9, 153.1, 140.4, 128.8 and 104.4 ppm ± 0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 63.8 ppm ± 2 ppm of 103.1, 89.3, 76.6, 65.0 and 40.2 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 4a, 4b or 4c and combinations of these data.

[0041] Crystalline Form IP1 of Iptacopan hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 13.2, 14.5, 15.6, 18.1 and 23.7 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 27.0, 27.7, 30.7, 31.6 and 33.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0042] Crystalline Form IP 1 of Iptacopan hydrochloride may be characterized by an X-ray powder diffraction pattern having the peaks as described in aspect or embodiment of the present disclosure, and further characterized an X-ray powder diffraction pattern having an absence of peaks at any one, two or three of the following (a), (b) and (c): (a) 3.8 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta, (b) either: (i) 5.7 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta, or (ii)5.4 to 9.5; and (c) 10.6 to 11.2 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form IP1 of Iptacopan hydrochloride may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a), (b- i) alone, or (b-ii) alone; or (c) alone; or (a) and (b-i), or (a) and (b-ii) in combination; or (b-i) and (c) in combination; or (b-ii) and (c) in combination, or (a), (b-i) and (c) in combination; or (a), (b-ii) and (c) in combination.

[0043] In one embodiment of the present disclosure, crystalline Form IP 1 of Iptacopan hydrochloride is isolated. Thus, crystalline Form IP1 of Iptacopan hydrochloride according any aspect or embodiment of the disclosure may be isolated.

[0044] Crystalline Form IP1 of Iptacopan hydrochloride may be hydrate, more preferably monohydrate.

[0045] Crystalline Form IP1 of Iptacopan hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 13.2, 14.5, 15.6, 18.1 and 23.7 degrees 2-theta± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0046] The disclosure further provides a process for preparing Iptacopan hydrochloride Form IP1 as defined in any aspect or embodiment herein, wherein the process comprises crystallising Iptacopan hydrochloride from a mixture of water and acetonitrile. Preferably the process comprises cooling a solution of Iptacopan hydrochloride in water and acetonitrile. According to any aspect or embodiment the water and acetonitrile are in a v / v ratio of: about 1:2 to about 1:25, about 1:4 to about 1:20, about 1:5 to about 1:22, about 1:6 to about 1: 15, about l:7 to about 1: 13, about l:8 to about 1: 12, about l:9 to about 1: 11, or about 1:9.5 to about 1: 11.5, or about 1: 10. The solution of Iptacopan hydrochloride in water and acetonitrile is preferably at a temperature of: about 18°C to about 50°C, about 19°C to about 40°C, about 20°C to about 35°C, about 21°C to about 32°C, about 22°C to about 30°C, about 23°C° to about 28°C, or about 24°C to about 26°C, or about 25°C. Preferably the cooling is to a temperature of: about -I0°C to about 10°C, about -7°C to about 7°C, about -5°C to about 5°C, about -4°C to about 2°C, about -2°C to about I °C, or about 0°C. The cooling may be carriedout at a rate of about 0.5 to about 2.0°C / minute, about 0.7 to about 1.8°C / minute, about 1 to about 1.5°C / min, or about 1.2 to about 1.3°C / min., or about 1.25°C / min. The crystalline Iptacopan hydrochloride may be isolated, preferably by fdtration, centrifuge or decantation, preferably by fdtration. The product may be dried, preferably under vacuum, and preferably at a temperature of: about 20°C to about 35°C, about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C. The drying may be for a period of about 10 minutes to about 2 hours, about 10 minutes to about 1 hour, about 10 minutes to about 30 minutes, or about 10 to about 15 minutes. The product may be further dried, preferably under vacuum, preferably in a vacuum tray dryer, preferably at a temperature of about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 55°C, or about 50°C. The further drying may be for any suitable period of time, preferably: about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, about 45 minutes to about 2 hours, or about 1 hour. According to any aspect or embodiment of the disclosed process, the process for preparing Form IP1 of Iptacopan hydrochloride may comprise:(i) dissolving Iptacopan hydrochloride in 10%v / v water in acetonitrile;(ii) cooling;(iii) filtering; and(iv) optionally drying

[0047] According to any aspect or embodiment of the disclosed processes for preparing Form IP1 of Iptacopan hydrochloride, 10%v / v water in acetonitrile may be used in in an amount of: about 15 ml to about 30 ml, about 20 ml to about 28 ml, or about 25 ml, per gram of Iptacopan hydrochloride. Iptacopan hydrochloride may be dissolved in 10% v / v water in acetonitrile at temperature of about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. The solution may be cooled to temperature of about -10°C to 5°C, or about 0°C in period of about 20 minutes and maintained at temperature of about -10°C to 5°C, or about 0°C for 1 hour. The process may further include isolating the obtained Form IP1 of Iptacopan hydrochloride, by any suitable procedure, such as fdtration with micron fdter. Particularly the product may be dried under vacuum at temperature of: about 35°C to about 40°C, about 30°C to about 35°C, or about 25°C for period of about 30 minutes to about 1 hour, or 15 minutes. The product may be further dried under vacuum tray dryer (VTD) at temperature of: about 35°C to about 60°C, about 40°C to about 55°C, or about 50°C for a period of about 2 hours to about 0.5 hour, or about 1 hour.

[0048] The disclosure further provides an alternative process for preparing Iptacopan hydrochloride Form IP1 as defined in any aspect or embodiment herein, wherein the processcomprises suspending amorphous Iptacopan hydrochloride in a mixture of water and dimethyl carbonate. According to any aspect or embodiment the water and dimethyl carbonate are in a v / v ratio of: about 1:2 to about 1:25, about 1:4 to about 1:20, about 1:5 to about 1:22, about 1:6 to about 1: 15, about l:7 to about 1: 13, about l:8 to about 1: 12, about l:9 to about 1: 11, or about 1:9.5 to about 1: 11.5, or about 1: 10. The solution of Iptacopan hydrochloride in water and dimethyl carbonate is preferably at a temperature of: about 18°C to about 50°C, about 19°C to about 40°C, about 20°C to about 35°C, about 21°C to about 32°C, about 22°C to about 30°C, about 23°C° to about 28°C, or about 24°C to about 26°C, or about 25°C. Preferably the cooling is to atemperature of: about -10°C to about 10°C, about -7°C to about 7°C, about -5°C to about 5 °C, about -4°C to about 2°C, about -2°C to about I °C, or about 0°C. The cooling may be carried out at a rate of about 0.5 to about 2.0°C / minute, about 0.7 to about 1.8°C / minute, about 1 to about 1.5°C / min, or about 1.2 to about 1.3°C / min., or about 1 ,25°C / min. The mixture may be stirred at the cooled temperature for: about 15 minutes to about 4 hours, about 30 minutes to about 3 hours, about 45 minutes to about 2 hours, or about 1 hour. The crystalline Iptacopan hydrochloride may be isolated, preferably by filtration, centrifuge or decantation, more preferably by filtration. The product may be dried, preferably under vacuum, and preferably at a temperature of: about 20°C to about 35°C, about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C. The drying may be for a period of about 10 minutes to about 2 hours, about 10 minutes to about 1 hour, about 10 minutes to about 30 minutes, or about 10 to about 15 minutes. The product may be further dried, preferably under vacuum, preferably in a vacuum tray dryer, preferably at a temperature of about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 55°C, or about 50°C. The further drying may be for any suitable period of time, preferably: about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, about 45 minutes to about 2 hours, or about 1 hour. According to any aspect or embodiment of the disclosed process, the process for preparing Form IP1 of Iptacopan hydrochloride may comprise:(i) suspending Iptacopan hydrochloride (amorphous) in 10%v / v water in dimethyl carbonate;(ii) cooling;(iii) filtering; and(iv) optionally drying

[0049] According to any aspect or embodiment of the disclosed processes for preparing Form IP1 of Iptacopan hydrochloride, 10% v / v water in dimethyl carbonate may be used in in an amount of: about 15 ml to about 30 ml, about 20 ml to about 28 ml, or about 25 ml, pergram of Iptacopan hydrochloride. Iptacopan hydrochloride may be dissolved in 10% v / v water in dimethyl carbonate at temperature of about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. The slurry mass may be cooled to temperature of about -10°C to 5°C, or about 0°C in period of about 20 minutes and maintained at temperature of about -10°C to 5°C, or about 0°C for 1 hour. The process may further include isolating the obtained Form IP1 of Iptacopan hydrochloride, by any suitable procedure, such as fdtration with micron filter. Particularly the product may be dried under vacuum at temperature of: about 35 °C to about 40°C, about 30°C to about 35°C, or about 25°C for period of about 30 minutes to about 1 hour, or 15 minutes. The product may be further dried under vacuum tray dryer (VTD) at temperature of: about 35 °C to about 60°C, about 40°C to about 55 °C, or about 50°C for period of about 2 hours to about 0.5 hour, or about 1 hour.

[0050] The present disclosure includes a crystalline polymorph of Iptacopan hydrochloride, designated IP2. The crystalline Form IP2 of Iptacopan hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 8.7, 9.6, 15.7, 18.5, and 19.5 degrees 2-theta± 0.2 degrees 2-theta; and combinations ofthese data.

[0051] Crystalline Form IP2 of Iptacopan hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 8.7, 9.6, 15.7, 18.5, and 19.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 23.5, 25.6 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0052] Crystalline Form IP2 of Iptacopan hydrochloride may be characterized by an X- ray powder diffraction pattern having the peaks as described in aspect or embodiment of the present disclosure, and further characterized an X-ray powder diffraction pattern having an absence of peaks at any one, two or three of the following (a), (b) and (c): (a) 3.8 to 8.1 degrees 2-theta ± 0.2 degrees 2-theta, (b) 12.2 to 12.8 degrees 2-theta ± 0.2 degrees 2-theta, or (c) 13.5 to 14.8 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form IP2 of Iptacopan hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0053] In one embodiment of the present disclosure, crystalline Form IP2 of Iptacopan hydrochloride is isolated. Thus, crystalline Form IP2 of Iptacopan hydrochloride according any aspect or embodiment of the disclosure may be isolated.

[0054] Crystalline Form IP2 of Iptacopan hydrochloride may be 1 -Propanol solvate.

[0055] Crystalline Form IP2 of Iptacopan hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 8.7, 9.6, 15.7, 18.5, and 19.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0056] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Iptacopan hydrochloride, and their solid state forms.

[0057] The present disclosure encompasses a process for preparing other solid state forms of Iptacopan hydrochloride and their solid state forms thereof.

[0058] The present disclosure provides the above described crystalline polymorphs of Iptacopan hydrochloride for use in the preparation of pharmaceutical compositions comprising Iptacopan hydrochloride and / or crystalline polymorphs thereof.

[0059] The present disclosure also encompasses the use of crystalline polymorphs of Iptacopan hydrochloride of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Iptacopan hydrochloride and / or crystalline polymorphs thereof.

[0060] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Iptacopan hydrochloride of the present disclosure with at least one pharmaceutically acceptable excipient.

[0061] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Iptacopan hydrochloride of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0062] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0063] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0064] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[0065] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0066] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0067] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0068] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0069] In liquid pharmaceutical compositions of the present invention, Iptacopan hydrochloride and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0070] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0071] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0072] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0073] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0074] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0075] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the routeof administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0076] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0077] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0078] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0079] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and then screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0080] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0081] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0082] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0083] A pharmaceutical formulation of Iptacopan hydrochloride can be administered. Iptacopan hydrochloride may be formulated for administration to a mammal, in embodiments to a human, by injection. Iptacopan hydrochloride can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation cancontain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0084] The crystalline polymorphs of Iptacopan hydrochloride and the pharmaceutical compositions and / or formulations of Iptacopan hydrochloride of the present disclosure can be used as medicaments, in embodiments in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis .

[0085] The present disclosure also provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or methods of treating Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).

[0086] by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Iptacopan hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0087] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.X-ray Powder Diffraction ("XRPD") method

[0088] X-ray diffraction was performed on X-Ray powder diffractometer:

[0089] Bruker D8 Advance; Copper Ka radiation (X = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.Measurement parameters:Scan range: 2 - 40 degrees 2-theta;Scan mode: continuous;Step size: 0.05 degrees;Time per step: 0.5 s;Sample spin: 30 rpm;Sample holder: PMMA specimen holder ring.

[0090] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.SSNMR method:13C CP / MAS NMR Method:

[0091] The solid-state NMR spectra were acquired at 11.7 T using a Bruker Avance III HD500 US / WB NMR spectrometer (Bruker, Karlsruhe, Germany, 2013) equipped with a 3.2 mm probehead.

[0092] The13C CP / MAS NMR spectra were recorded using a standard cross-polarization pulse sequence at a spinning frequency of 20 kHz. The cross-polarization contact time was set to 2 ms, and SPINAL64 dipolar decoupling was applied during signal acquisition. The spectral width was 300 ppm with a resonance offset of 100 ppm. The number of scans was adjusted to achieve a signal-to-noise ratio (S / N) at least 50. The13C chemical shifts were referenced to a- glycine (176.03 ppm for carbonyl carbon). The experiments were conducted under active cooling to maintain the sample temperature at a constant 295 K (room temperature).EXAMPLESPreparation of starting materials

[0093] Iptacopan and Iptacopan hydrochloride can be prepared according to methods known from the literature, for example US patent publication 9,682,968.Example 1: Preparation of Iptacopan hydrochloride Form IP1

[0094] Iptacopan hydrochloride (0.02 g) taken in 2 mL glass vial and was dissolved in 10%v / v water in acetonitrile (0.5 ml) at temperature of about 25°C. The clear solution was cooled to temperature of about 0°C in 20 minutes and precipitation started and maintained at 0°C for 1 hour. The obtained solid was filtered with micron filter and dried under vacuum at temperature of about 25 °C for 10-15 minutes. The obtained solid was further dried under vacuum tray Drier (VTD) at temperature of about 50°C for 1 hour. The obtained solid wasanalyzed by XRPD. Iptacopan hydrochloride Form IP1 was obtained. An XRPD pattern is shown in Figure 1.Example 2: Preparation of Iptacopan hydrochloride Form IP1

[0095] Iptacopan hydrochloride (Amorphous, 0.02g) was taken in 2 m glass vial and suspended in 0.5 ml of 10%v / v water in dimethyl carbonate at temperature of about 25°C. The slurry mass was cooled to temperature of about 0°C in 20 minutes, maintained at 0°C for 1 hour and was fdtered with micron fdter and dried under vacuum at temperature of about 25 °C for period of about 10 minutes to 15 minutes. The obtained solid was further dried under vacuum tray Drier (VTD) at temperature of about 50°C for period of about 1 hour. The obtained solid was analyzed by XRPD. Iptacopan hydrochloride. Form IP1 was obtained.Example 3: Preparation of Iptacopan hydrochloride Form IP2

[0096] Iptacopan hydrochloride (0.02g) was taken in 5 mb glass vial and dissolved in 1- propanol (0. 1 ml) at 25°C. The clear solution was fdtered with micron fdter. The clear solution was subjected to evaporation under reduced pressure of about ~50 mbar in the centrifugal evaporator at 40°C. After 4 hours, the solid obtained was isolated. The obtained solid was analyzed by XRPD. Iptacopan hydrochloride Form IP2 was obtained. An XRPD pattern is shown in Figure 2.Example 4: Preparation of Iptacopan hydrochloride amorphous form

[0097] Iptacopan (10 g) was dissolved in 161 ml of water and 48 ml of acetonitrile at temperature of about 25°C. To the clear solution, 8 ml of 5M aqueous hydrochloric acid solution was added. The solution was fdtered, and the clear solution was frozen and solidified under liquid nitrogen at about 100K. The frozen mass subjected to lyophillization on a virtis lyophillizer (Condenser temperature -76°C and vacuum 300 mtorr) for about 72 hours. The white fluffy solid mass was isolated and was analyzed by XRPD. Iptacopan hydrochloride amorphous form was obtained. An XRPD pattern is shown in Figure 3.Example 5: Stability ExperimentsStorage stability at different relative humidities

[0098] Samples of Form IP1 of Iptacopan hydrochloride were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:Table ]

[0099] These results demonstrate that Form IP1 of Iptacopan hydrochloride is stable after exposure to high and low relative humidity for at least 7 days.

[0100] Samples of Form IP1 of Iptacopan hydrochloride were subjected to conditions of different relative humidities at different temperatures. XRPD analysis was performed on the samples after 6 months. The results are shown in Table 2 below:Table 2

[0101] The results demonstrate that Form IP 1 of Iptacopan hydrochloride is stable after exposure to high and low relative humidity at different temperatures for at least 6 months, indicating that this crystalline form has good storage stability.Grinding experiments

[0102] Samples of Form IP1 of Iptacopan hydrochloride were subjected to strong grinding, and to solvent drop grinding in water, ethanol and isopropanol. Grinding was carried out on the samples alone, or in the presence of ethanol, isopropanol or water. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microlitres. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 3):Table 3

[0103] The results demonstrate that Form IP1 of Iptacopan hydrochloride is resistant to polymorphic changes and is highly suitable for preparing pharmaceutical formulations.Thermal stability

[0104] A sample of Form IP1 of Iptacopan hydrochloride was subjected to heating up to 100°C for 30 minutes. XRPD analysis of the sample confirmed no change in the starting material (Table 4):Table 4

Claims

CLAIMS1. A crystalline Form IP 1 of Iptacopan hydrochloride characterized by data selected from one or more of the following: a) an X-ray Powder Diffraction (“XRPD”) pattern having peaks at 13.2, 14.5, 15.6,18.1 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 1; c) a solid state 13C NMR spectrum having peaks at 166.9, 153.1, 140.4, 128.8 and 104.4 ppm ± 0.2 ppm; d) a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 63.8 ppm ± 2 ppm of 103.1, 89.3, 76.6, 65.0 and40.2 ppm ± 0.1 ppm; e) a solid-state 13C NMR spectrum substantially as depicted in Figures 4a, 4b or 4c; and f) combinations of two or more of: a, b, c, d, and e.

2. The crystalline Form IP1 of Iptacopan hydrochloride according to Claim 1, which is characterized by an XRPD pattern having peaks at 13.2, 14.5, 15.6, 18. land 23.7 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 27.0, 27.7, 30.7, 31.6 and 33.3 degrees 2-theta ± 0.2 degrees two theta.

3. The crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1 or2, which is characterized by an XRPD pattern having peaks at: 13.2, 14.5, 15.6, 18.1, 23.7, 27.0, 27.7, 30.7, 31.6 and 33.3 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1, 2, or 3, which is isolated.

5. The crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1 to 4, which is a hydrate form, more preferably monohydrate form.

6. The crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1, 2,3, 4, or 5, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Iptacopan hydrochloride.

7. The crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1, 2, 3, 4, 5, or 6, which contains: no more than about 20%, no more than about 10%, no more thanabout 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Iptacopan hydrochloride.

8. A pharmaceutical composition comprising the crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1 to 7.

9. A pharmaceutical formulation comprising the crystalline Form IP1 of Iptacopan hydrochloride according to any of Claims 1 to 7 or a pharmaceutical composition of Claim 8, and at least one pharmaceutically acceptable excipient.

10. A process for preparing a pharmaceutical formulation according to Claim 9, comprising combining the crystalline Form IP 1 of Iptacopan hydrochloride according to any of Claims 1 to 7 or a pharmaceutical composition of Claim 8, with at least one pharmaceutically acceptable excipient.

11. The crystalline Form IP1 of Iptacopan hydrochloride according to any one of Claims 1 to 7, the pharmaceutical composition according to Claim 8, or the pharmaceutical formulation according to Claim 9, for use as a medicament.

12. The crystalline Form IP1 of Iptacopan hydrochloride according to any one of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulation according to Claim 9, for use in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age- related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).

13. A method of treating paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis in patients on hemodialysis, or Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD), comprising administering a therapeutically effective amount of the crystalline Form IP1 of Iptacopan hydrochloride according to any one of Claims 1 to 7, the pharmaceutical composition according to Claim 8, or the pharmaceutical formulation according to Claim 9, to a subject in need of the treatment.

14. The crystalline Form IP1 of Iptacopan hydrochloride, according to any one of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulationaccording to Claim 9, for the manufacture of a medicament for treating paroxysmal nocturnal hemoglobinuria (PNH), Atypical Haemolytic Uraemic Syndrome, Membranoproliferative glomerulonephritis, Age-related macular degeneration, Lupus nephritis and Membranous glomerulonephritis, or Complement 3 Glomerulopathy (C3G), IgA nephropathy (IgAN, Berger’s disease), Immune Thrombocytopenia (ITP) and Cold Agglutinin Disease CAD).

15. Use of the crystalline Form IP1 of Iptacopan hydrochloride according to any one of Claims 1 to 7, in the preparation of another solid state form of Iptacopan hydrochloride, or another Iptacopan salt or solid state form thereof.

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