Crystalline forms of LNP023

Abstract

Crystalline hydrate forms of LNP023 hydrochloride and processes for their preparation are described herein. In addition, described herein are pharmaceutical compositions comprising a crystalline hydrate form of LNP023 hydrochloride and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions described herein are useful for the treatment of diseases and disorders mediated by complement activation.

Description

[0001] This application is a divisional application of the patent application with the application date of May 17, 2021, application number 202180035091.0, and invention title "Crystalline Forms of LNP023". Technical Field

[0002] Described herein are crystalline forms of LNP023 hydrochloride and processes for their preparation. Also described herein are pharmaceutical compositions comprising a crystalline form of LNP023 hydrochloride and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be used to treat diseases or disorders mediated by complement activation. Background Art

[0003] LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or repressing the amplification of the complement system caused by C3 activation, independent of the initial mechanism of activation. LNP023 is currently in development for the treatment or prevention of paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN), and membranous nephropathy (MN). LNP023 hydrochloride is chemically designated as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the chemical structure according to the following formula (A)

[0004]

[0005] LNP023 hydrochloride and its preparation method are disclosed in WO 2015 / 009616, which is incorporated herein by reference in its entirety. In Example 26d of WO 2015 / 009616, LNP023 hydrochloride in the form of a crystalline solid was obtained by recrystallization of the obtained amorphous material and was characterized by X-ray powder diffraction. This crystalline form is referred to herein as Form A.

[0006] Different solid forms of an active pharmaceutical ingredient generally have different properties. Differences in the physicochemical properties of the solid form can play a key role in the improvement of pharmaceutical compositions. For example, due to the improvement of the solid form of the active pharmaceutical ingredient, pharmaceutical formulations with improved dissolution profiles or improved stability or shelf life can become readily available. Moreover, the processing or handling of the active pharmaceutical ingredient during formulation and manufacturing can be improved. Thus, new solid forms of an active pharmaceutical ingredient can have desirable processing characteristics. Compared with previously known solid forms, they are easier to handle, more suitable for storage, or allow better purification.

[0007] The crystalline "Form A" of LNP023 HCl of WO 2015 / 009616 has certain properties that make it less suitable for large-scale manufacturing processes. Therefore, a more stable form of LNP023 HCl is needed.

[0008] Accordingly, there is a need to provide a solid-state form of LNP023 hydrochloride that has physicochemical properties that permit the reliable production of a safe and effective pharmaceutical product comprising LNP023 hydrochloride. SUMMARY OF THE INVENTION

[0009] The present disclosure provides a crystalline hydrate form of LNP023 hydrochloride, which is also referred to hereinafter as "Form HB". The "Form HB" of LNP023 hydrochloride has good physicochemical properties for an active pharmaceutical ingredient intended for use in oral solid dosage forms.

[0010] Advantageous properties of Form HB of LNP023 include chemical stability, physical stability, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, compressibility, and wettability. Accordingly, these properties render Form HB suitable for large-scale manufacturing processes.

[0011] In one embodiment, Form HB is a phase-pure, highly crystalline form of LNP023 hydrochloride that is physically and chemically stable during pharmaceutical processing and storage. Form HB is the thermodynamically more stable form and can minimize the likelihood of conversion to other forms. Form A can convert to Form HB under certain conditions. The use of the thermodynamically stable form of a compound is highly desirable because when the most stable form is used, conversions such as from Form A to Form HB or polymorphic conversions that may occur during the manufacture and storage of the active pharmaceutical ingredient can be precluded. This ensures reliable bioavailability and thus consistent efficacy of the pharmaceutical product.

[0012] ABBREVIATIONS

[0013] PXRD Powder X-ray Diffraction

[0014] SXRD Single Crystal X-ray Diffraction

[0015] FTIR Fourier Transform Infrared

[0016] ATR Attenuated Total Reflection

[0017] DSC Differential Scanning Calorimetry

[0018] DVS Dynamic Vapor Sorption

[0019] TGA Thermogravimetric Analysis

[0020] MS Mass Spectrometry

[0021] NMR Nuclear Magnetic Resonance

[0022] GC Gas chromatography

[0023] KF Karl Fischer

[0024] RH Relative humidity

[0025] RT Room temperature

[0026] w-% Weight percentage

[0027] vol-% Volume percentage

[0028] Definitions

[0029] In the context of this disclosure, unless otherwise expressly stated, the following definitions have the indicated meanings:

[0030] As used herein, the term "room temperature" refers to a temperature in the range of 20 °C to 30 °C.

[0031] As used herein, the term "measured at a temperature in the range of 20 °C to 30 °C" refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of 20 °C to 30 °C, i.e., at room temperature. Standard conditions can mean a temperature of about 22 °C.

[0032] As used herein, when describing the solid form of LNP023 hydrochloride, the term "Form HB" refers to a specific crystalline hydrate form of LNP023 hydrochloride, e.g., the monohydrate form. This form is further defined herein and in the claims.

[0033] As used herein, when describing the solid form of LNP023 hydrochloride, the term "Form A" refers to a specific crystalline form of LNP023 hydrochloride as disclosed in WO 2015 / 009616. Form A of LNP023 hydrochloride is characterized by having a powder X-ray diffraction pattern that contains peaks at 2-θ angles of (11.6 ± 0.1)°, (15.3 ± 0.1)°, (16.5 ± 0.1)°, (20.1 ± 0.1)° and (23.3 ± 0.1)° when measured with Cu-Kα 1,2 radiation having a wavelength of 0.15419 nm.

[0034] Form A is prepared as follows according to WO 2015 / 009616 (see Example 26d):

[0035] To a solution of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid (620 mg, 1.467 mmol) in H2O / CH3CN (10 / 3 mL) was added 5 M aqueous HCl solution (500 μL, 2.500 mmol). The reaction mixture was then lyophilized to afford an amorphous compound, which was then suspended in iPrOH (300 mL). The suspension was heated to 70 °C. After 1.5 h, the suspension became a solution. The solution was then cooled to room temperature with stirring for about 5 h to afford a solid. The resulting solid was collected by filtration and dried at 50 °C under high vacuum to give the title compound as a crystalline solid. 1 1H NMR (HCl salt, 400 MHz, CD3OD) δ 10.73 (br.s., 1H), 8.23 (d, J = 8.44 Hz, 2H), 7.74 (d, J = 8.44 Hz, 2H), 7.31 - 7.36 (m, 1H), 6.77 (s, 1H), 6.37 (dd, J = 1.77, 3.12 Hz, 1H), 4.33 (d, J = 12.72 Hz, 1H), 4.25 (d, J = 12.72 Hz, 1H), 3.79 - 3.85 (m, 1H), 3.76 (s, 3H), 3.51 - 3.67 (m, 4H), 3.37 - 3.44 (m, 1H), 2.51 (s, 3H), 2.21 - 2.29 (m, 2H), 1.90 - 2.15 (m, 2H), 1.31 (t, J = 6.97 Hz, 3H).

[0036] The X-ray powder diffraction pattern is described in Table 1 below.

[0037] Table 1

[0038]

[0039] As used herein, the term "reflection" with respect to powder X-ray diffraction means a peak in an X-ray diffraction pattern that is caused by constructive interference of X-rays scattered by parallel planes of atoms in a solid material, where the solid material is distributed in a sequential and repeating pattern of long-range positional order. Such a solid material is classified as a crystalline material, while an amorphous material is defined as a solid material that lacks long-range order and only exhibits short-range order, thus resulting in broad scattering. According to the literature, long-range order extends, for example, over about 100 to 1000 atoms, while short-range order extends only over a few atoms (see Fundamentals of Powder Diffraction and Structural Characterization of Materials by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

[0040] The term "substantially the same" with respect to powder X-ray diffraction means considering the variability of peak positions and the relative intensities of the peaks. For example, the typical precision of 2-θ values is in the range of ±0.2° 2-θ, for example, in the range of ±0.1° 2-θ. Thus, on most X-ray diffractometers under standard conditions, a peak that typically appears at 9.2° 2-θ can, for example, appear between (9.2 - 0.2)° and (9.2 + 0.2)° 2-θ, for example, between (9.2 - 0.1)° and (9.2 + 0.1)° 2-θ. In addition, those skilled in the art will understand that relative peak intensities will show variability between instruments as well as variability due to crystallinity, preferred orientation, particle size, sample preparation, and other factors known to those skilled in the art, and should be considered only as a qualitative measurement.

[0041] The term "substantially the same" with respect to infrared spectroscopy means considering the variability of peak positions and the relative intensities of the peaks. For example, the typical precision of wavenumber values is in the range of ±4 cm -1 -1, for example, in the range of ±2 cm -1 -1. Thus, on most infrared spectrometers under standard conditions, a peak at 1692 cm -1 -1 can, for example, appear between (1692 - 4) and (1692 + 4) cm -1 -1, for example, between (1692 - 2) and (1692 + 2) cm -1 -1. Peak intensities can be determined from the accompanying figures, but those skilled in the art will understand that differences in peak intensities due to crystallinity, sample preparation, measurement methods, and other factors can also occur in infrared spectroscopy. Thus, peak intensities should be considered only as a qualitative measurement.

[0042] Form HB of LNP023 hydrochloride as described herein can be referred to herein as being characterized by graphical data "as shown in the figures". Such data includes, for example, powder X-ray diffraction and FTIR. Those skilled in the art understand that when presented in graphical form, factors such as changes in instrument type, response and variation in sample orientation, sample concentration, and sample purity may result in minor variations in such data, such as variations related to precise peak positions and intensities. However, comparison of the graphical data in the figures herein with graphical data generated for another or unknown solid form and confirmation that the two sets of graphical data pertain to the same crystal form are well within the knowledge of those skilled in the art.

[0043] The terms "solid form" or "solid state form", which are used interchangeably herein, refer to any crystalline or amorphous phase of a compound.

[0044] As used herein, the term "amorphous" refers to a solid form of a compound that is non-crystalline. An amorphous compound does not have long-range order and does not exhibit a definitive X-ray diffraction pattern with peaks.

[0045] As used herein, the term "polymorph" refers to a crystalline form having the same chemical composition but a different spatial arrangement of the molecules, atoms, or ions that form the crystal.

[0046] As used herein, the term "cocrystal" refers to a crystalline material that contains two or more different molecular or ionic compounds in the same crystal lattice, where the two or more different molecular or ionic compounds are bound by non-ionic and non-covalent bonds, and at least two of these individual molecular or ionic compounds are solids at room temperature.

[0047] The term "hydrate" as used herein refers to a crystalline solid in which water is incorporated into or accommodated by the crystal structure (e.g., as part of the crystal structure) or trapped within the crystal (water inclusion). Thus, water can be present in stoichiometric or non-stoichiometric amounts. When water is present in stoichiometric amounts, the hydrate can be referred to by adding Greek numerical prefixes. For example, depending on the stoichiometry of water / compound, the hydrate can be called a hemihydrate or a monohydrate. The water content can be measured, for example, by Karl-Fischer-Coulometry.

[0048] The term "dehydrating" or "dehydration" as used herein describes the at least partial removal of water from the crystal structure of a host molecule.

[0049] As used herein, the term "solvate" refers to a crystalline solid in which one or more organic solvents are incorporated into or entrapped by (e.g., as part of) the crystal structure (solvent inclusions). Thus, one or more organic solvents can be present in stoichiometric or non-stoichiometric amounts. When one or more organic solvents are present in one or more stoichiometric amounts, the solvate can be designated by adding a Greek numerical prefix. For example, depending on the stoichiometry of the one or more solvents / compounds, the solvate can be termed a hemisolvate or a monosolvate. The solvent content can be measured, for example, by GC, NMR, SXRD, or TGA / MS.

[0050] As used herein, the term "isomorphic solvate" refers to a solvate having the same space group (with only minor unit cell size distortions) and the same type of host molecule molecular network. Isomorphic solvates as defined herein differ in the type of one or more organic solvents present as one or more guest molecules.

[0051] As used herein, the term "desolvating" or "desolvation" describes the at least partial removal of organic solvents from the crystal structure of a host molecule.

[0052] As used herein, the term "anhydrous form" or "anhydrate" refers to a crystalline solid in which no water is incorporated into or entrapped by the crystal structure. The anhydrous form can still contain residual water that is not part of the crystal structure but may be adsorbed on the surface of the crystal or absorbed into disordered regions of the crystal. Typically, the anhydrous form contains no more than 3.0 w-% water, e.g., no more than 1.0 w-% based on the weight of the crystalline form.

[0053] When referring to a crystalline solid, the term "unsolvated" as used herein means a crystalline solid in which no organic solvent is incorporated into or entrapped by the crystal structure. The unsolvated form can still contain residual organic solvents that are not part of the crystal structure but can be adsorbed on the surface of the crystal or absorbed into disordered regions of the crystal. In one embodiment, the unsolvated form contains no more than 3.0 w-%, e.g., no more than 1.0 w-%. In one embodiment, the unsolvated form contains no more than 0.5 w-% organic solvent based on the weight of the crystalline form.

[0054] As used herein, the term "mother liquor" refers to the solution remaining after a solid has crystallized from said solution.

[0055] As used herein, the term "antisolvent" refers to a liquid that reduces the solubility of LNP023 hydrochloride in a solvent.

[0056] As used herein, "predetermined amount" with respect to LNP023 hydrochloride refers to the initial amount of LNP023 hydrochloride used to prepare a pharmaceutical composition having the desired dosage strength of LNP023 hydrochloride.

[0057] As used herein, the term "therapeutically effective amount" with respect to LNP023 hydrochloride encompasses the amount of LNP023 hydrochloride that elicits a desired therapeutic or prophylactic effect.

[0058] As used herein, the term "non-hygroscopic" means that, based on the weight of the compound, the mass increase (due to water absorption) at 25 °C and 80% RH is less than 0.2%.

[0059] As used herein, the term "equant" with respect to crystal shape refers to equidimensional crystals, such as cubes or spheres.

[0060] As used herein, the terms "plate" or "platy" with respect to crystal shape refer to flat, sheet-like crystals having a similar width and breadth and being thicker than flakes.

[0061] As used herein, the terms "flake" or "flaky" with respect to crystal shape refer to thin and flat crystals having a similar width and breadth and being thinner than plates.

[0062] As used herein, the terms "needle-like" or "acicular" with respect to crystal shape refer to needle-pointed, thin, and highly elongated crystals having a similar breadth and width.

[0063] As used herein, the terms "column-like" or "columnar" with respect to crystal shape, which may be used interchangeably herein, refer to elongated, prismatic crystals having a greater breadth and thickness than needle-like crystals.

[0064] Such definitions of crystal habits are consistent with those commonly used in the art; see, for example, "Polymorphism in the Pharmaceutical Industry" edited by Rolf Hilfiker (Wiley VCH, 2006); Chapter 7, Optical Microscopy (Gary Nichols).

[0065] As used herein, the term "about" means approximately, within its range, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the values shown above. In general, the term "about" is used herein to modify a value by a variation of 10% above and below the stated value.

[0066] As used herein, the term "substantially free of any other solid form" with respect to a composition comprising a particular solid form of LNP023 hydrochloride means that the composition comprises up to 20 w-% (weight percent), up to 15 w-%, up to 10 w-%, up to 9 w-%, up to 8 w-%, up to 7 w-%, up to 6 w-%, up to 5 w-%, up to 4 w-%, up to 3 w-%, up to 2 w-%, up to 1 w-%, up to 0.5 w-%, or up to 0.1 w-%, or any weight percentage between 80 and 100 w-% of any other solid form of LNP023 hydrochloride, based on the weight of the composition.

[0067] As used herein, when used with respect to a form, "substantially pure" means a compound having a purity of greater than 90 w-%, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 w-%, and also including a purity of approximately 100 w-% of a particular solid form of LNP023 hydrochloride, based on the weight of the compound. The remaining material comprises one or more other forms of the compound, or reaction impurities, or processing impurities resulting from its preparation. For example, a crystalline form of LNP023 hydrochloride can be considered substantially pure because it has a purity of greater than 90 w-% as measured by means known and generally accepted in the art at this time, where the remaining material less than 10 w-% comprises one or more other forms of LNP023 hydrochloride, reaction impurities, or processing impurities.

[0068] As used herein, the term "subject" is intended to mean a human. Exemplary human subjects include human patients (referred to as patients) or normal subjects suffering from a disorder, such as the disorders described herein.

[0069] As used herein, the term "physically stable" means that when subjected to specific conditions (e.g., room temperature ambient humidity or 40 °C / 75% relative humidity) for a specified period of time (e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or longer), a particular free base or salt form does not change into one or more different physical forms (e.g., different solid forms as measured by XRPD, DSC, etc.). In some embodiments, when subjected to specific conditions, less than 25% of the form of the compound changes into one or more different physical forms. In some embodiments, when subjected to specific conditions, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% of the form of a particular compound changes into one or more different physical forms of that particular compound. In some embodiments, no detectable amount of the particular form of the compound changes into one or more different physical forms of that compound.

[0070] As used herein, the term "chemically stable" means that when subjected to specific conditions (e.g., room temperature ambient humidity or 40 °C / 75% relative humidity) for a specified period of time (e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or longer), the chemical structure of a specific compound does not change into another compound (e.g., decompose). In some embodiments, when subjected to specific conditions, less than 25% of the form of the specific compound changes into one or more other compounds. In some embodiments, when subjected to specific conditions, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% of the form of the specific compound changes into one or more other compounds. In some embodiments, no detectable amount of the form of the specific compound changes into one or more different physical forms of the specific compound.

[0071] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that does not exhibit significant pharmacological activity at a given dosage and is added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients can function as vehicles, diluents, release agents, disintegrants, dissolution modifiers, absorption promoters, stabilizers or manufacturing aids, etc. Excipients can include fillers (diluents), binders, disintegrants, lubricants and glidants.

[0072] As used herein, the term "filler" or "diluent" refers to a substance used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also function as stabilizers.

[0073] As used herein, the term "binder" refers to a substance that binds the active pharmaceutical ingredient and the pharmaceutically acceptable excipients together to maintain cohesive and discrete portions.

[0074] As used herein, the term "disintegrant (disintegrant or disintegrating agent)" refers to a substance that, after being added to a solid pharmaceutical composition, promotes the decomposition or disintegration of the active pharmaceutical ingredient after administration and allows its release as effectively as possible to enable rapid dissolution.

[0075] As used herein, the term "lubricant" refers to a substance that is added to a powder blend to prevent the compacted powder mass from adhering to the equipment during tableting or encapsulation processes. They assist in ejecting the tablets from the dies and can improve powder flowability.

[0076] As used herein, the term "glidant" refers to a substance used in tablet and capsule formulations to improve the flow characteristics during tablet compression and to produce an anti-caking effect. Description of the Drawings

[0077] Figure 1 : Illustrates the representative PXRD of Form HB of LNP023 hydrochloride described herein. The x-axis shows the scattering angle (in °2-θ), and the y-axis shows the intensity of the scattered X-ray beam (in counts / second of detected photons).

[0078] Figure 2 : Illustrates the comparison of the representative PXRD of Form HB of LNP023 hydrochloride described herein (bottom) with the representative PXRD of Form A of LNP023 hydrochloride of WO 2015 / 009616 (top). The x-axis shows the scattering angle (in °2-θ). For clarity, the powder X-ray diffraction pattern of Form A is shifted along the y-axis to separate the diffraction patterns. Thus, the y-axis is arbitrary and not labeled.

[0079] Figure 3 : Illustrates the representative FTIR spectrum of Form HB of LNP023 hydrochloride described herein. The x-axis shows the wave number (in cm -1 ), and the y-axis shows the relative intensity (in percent transmittance).

[0080] Figure 4 : Illustrates the representative DSC curve of Form HB of LNP023 hydrochloride described herein. The x-axis shows the temperature (in degrees Celsius (°C)), and the y-axis shows the heat flow rate (in watts / gram (W / g)) rising with the endothermic peak.

[0081] Figure 5 : Illustrates the representative TGA curve of Form HB of LNP023 hydrochloride described herein. The x-axis shows the temperature (in degrees Celsius (°C)), and the y-axis shows the mass (loss) of the sample (in weight percent (w-% )).

[0082] Figure 6 : Illustrates the representative DVS isotherm of Form HB of LNP023 hydrochloride described herein in the range of 0 to 95% relative humidity. The x-axis shows the relative humidity (in percent (%)) measured at a temperature of (25.0 ± 1.0) °C, and the y-axis shows the equilibrium mass change with respect to the sample weight at 0% RH (in weight percent (w-% )). The adsorption cycle is marked with triangles, while the desorption cycle is marked with squares.

[0083] Figure 7a and 7b : Illustrates the scanning electron microscope image of Form HB of LNP023 hydrochloride described herein when prepared according to Example 3 (scale total size: 50 microns). Detailed Description

[0084] Crystalline Forms

[0085] Examples of embodiments:

[0086] In one embodiment, the present invention relates to a crystalline hydrate form of LNP023 hydrochloride, also referred to herein as "Form HB".

[0087] LNP023 hydrochloride can be represented by the chemical structure according to the following formula (A)

[0088]

[0089] The Form HB of LNP023 hydrochloride described herein can be characterized by analytical methods well-known in the pharmaceutical industry for characterizing solids. Such methods include, but are not limited to, PXRD, SXRD, FTIR, DSC, DVS, TGA, and SEM. It can be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the Form HB of LNP023 hydrochloride described herein can be characterized by any one of the following examples or by combining two or more of the following examples.

[0090] Examples of PXRD embodiments:

[0091] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (9.2 ± 0.2)°, and (19.1 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2

[0092] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, and (19.1 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2

[0093] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (19.1 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2

[0094] ​​​In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm. 1,2 radiation.

[0095] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation.

[0096] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation.

[0097] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation.

[0098] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized by PXRD peaks identified at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα having a wavelength of 0.15419 nm.1,2 Upon radiation measurement, PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

[0099] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 Upon radiation measurement, the crystalline form (Form HB) of LNP023 hydrochloride can be characterized by PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

[0100] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 Upon radiation measurement, PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

[0101] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)° during radiation measurement.

[0102] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (24.0 ± 0.2)°, and (24.6 ± 0.2)° during radiation measurement.

[0103] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)°, and (24.6 ± 0.2)° during radiation measurement.

[0104] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)°, (24.6 ± 0.2)° and (28.0 ± 0.2)° during radiation measurement.

[0105] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 PXRD peaks identified at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)° and (24.6 ± 0.2)°, and at least one or more peaks selected from the group consisting of: (10.0 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)° and (28.0 ± 0.2)°.

[0106] In another embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 PXRD peaks identified at the following 2-θ angles during radiation measurement:

[0107] (4.6 ± 0.1)°, (9.2 ± 0.1)° and (19.1 ± 0.1)°; or

[0108] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)° and (19.1 ± 0.1)°; or

[0109] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (19.1 ± 0.1)° and (24.6 ± 0.1)°; or

[0110] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (12.2 ± 0.1)°, (19.1 ± 0.1)°, and (24.6 ± 0.1)°; or

[0111] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (12.2 ± 0.1)°, (19.1 ± 0.1)°, (21.3 ± 0.1)°, and (24.6 ± 0.1)°; or

[0112] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (12.2 ± 0.1)°, (12.6 ± 0.1)°, (16.6 ± 0.1)°, (19.1 ± 0.1)°, (21.3 ± 0.1)°, and (24.6 ± 0.1)°; or

[0113] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.1)°, (12.6 ± 0.1)°, (16.6 ± 0.1)°, (19.1 ± 0.1)°, (21.3 ± 0.1)°, and (24.6 ± 0.1)°; or

[0114] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.1)°, (12.6 ± 0.1)°, (16.6 ± 0.1)°, (19.1 ± 0.1)°, (21.3 ± 0.1)°, and (24.6 ± 0.1)°; or

[0115] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.1)°, (12.6 ± 0.1)°, (15.3 ± 0.1)°, (16.6 ± 0.1)°, (19.1 ± 0.1)°, (21.3 ± 0.1)°, and (24.6 ± 0.1)°; or

[0116] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)°; or

[0117] (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)°; or

[0118] (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (24.0 ± 0.2)°, and (24.6 ± 0.1)°; or

[0119] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.1)°, (12.6 ± 0.1)°, (15.3 ± 0.1)°, (16.6 ± 0.1)°, (17.2 ± 0.1)°, (19.1 ± 0.1)°, (20.7 ± 0.1)°, (21.3 ± 0.1)°, (22.2 ± 0.1)°, (24.0 ± 0.1)°, and (24.6 ± 0.1)°; or

[0120] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (10.0 ± 0.1)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.1)°, (16.6 ± 0.1)°, (17.2 ± 0.1)°, (19.1 ± 0.1)°, (20.7 ± 0.1)°, (21.3 ± 0.1)°, (22.2 ± 0.1)°, (24.0 ± 0.1)°, (24.6 ± 0.1)°, and (28.0 ± 0.1)°.

[0121] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when at a temperature in the range of 20 °C to 30 °C and using Cu-Kα with a wavelength of 0.15419 nm 1,2Upon radiometric measurement, PXRD peaks identified at 2-θ angles of (4(4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (12.2 ± 0.1)°, (19.1 ± 0.1)°, and (24.6 ± 0.1)°, and at least one or more peaks selected from the group consisting of: (10.0 ± 0.1)°, (12.6 ± 0.1)°, (15.3 ± 0.1)°, (16.6 ± 0.1)°, (17.2 ± 0.1)°, (20.7 ± 0.1)°, (21.3 ± 0.1)°, (22.2 ± 0.1)°, (24.0 ± 0.1)°, and (28.0 ± 0.1)°.

[0122] The PXRD of Form HB described herein can be clearly distinguished from the PXRD of Form A of WO 2015 / 009616 (see also the PXRD overlay shown in Figure 2 herein). For example, Form HB shows characteristic peaks at 2-θ of (4.6 ± 0.1) and (9.2 ± 0.1)°, while Form A does not show peaks in the same range. According to page 176 of WO 2015 / 009616, among the four most characteristic peaks of Form A, one is the peak at 2-θ of 11.6°. In contrast, Form HB described herein does not show a peak in the same range.

[0123] In another embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a PXRD as described in one of the above embodiments, but does not include a peak at a 2-θ angle of (11.6 ± 0.2)°.

[0124] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a PXRD as described above, but does not include a peak at a 2-θ angle of (11.6 ± 0.1)° 2-θ.

[0125] In another embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), which is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a PXRD substantially the same as that shown in Figure 1 herein.

[0126] Due to the particulate morphology of Form HB, the relative intensities of the peaks (e.g., as shown in Figure 1 and listed in Table 2) can undergo a certain degree of variation. Generally, the morphology of many crystalline particles tends to cause the sample to exhibit a certain degree of preferred orientation in the sample holder. This is particularly evident for needle-shaped or plate-like crystals, as size reduction results in finer needle-like or small plate-like crystals. The preferred orientation in the sample affects the intensities of various peaks, such that some peaks are more intense and some are less intense compared to what would be expected for a completely random sample.

[0127] Examples of FTIR embodiments:

[0128] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized by having an FTIR spectrum that includes peaks at the following wave numbers: (3452 ± 4) cm -1 , (2875 ± 4) cm -1 and (1692 ± 4) cm -1 .

[0129] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized by having an FTIR spectrum that includes peaks at the following wave numbers: (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (1692 ± 4) cm -1 and (1439 ± 4) cm -1 .

[0130] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized by having an FTIR spectrum that includes peaks at wave numbers of (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (1692 ± 4) cm -1 , (1439 ± 4) cm -1 and (1243 ± 4) cm -1 .

[0131] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized by having an FTIR spectrum that includes peaks at wave numbers of (3452 ± 4) cm -1 , (2875 ± 4) cm -1, (1692 ± 4) cm -1 , (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks.

[0132] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that contains peaks at the following wave numbers when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C: (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1692 ± 4) cm -1 , (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 .

[0133] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that contains peaks at the following wave numbers when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C: (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1709 ± 4) cm -1 , (1692 ± 4) cm -1 , (1658 ± 4) cm -1 , (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 .

[0134] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that contains peaks at the following wave numbers when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C: (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1709 ± 4) cm -1 , (1692 ± 4) cm - 1, (1658 ± 4) cm -1 , (1615 ± 4) cm -1, (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 .

[0135] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes peaks at wavenumbers of (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1709 ± 4) cm -1 , (1692 ± 4) cm - 1, (1658 ± 4) cm -1 , (1615 ± 4) cm -1 , (1601 ± 4) cm -1 , (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 .

[0136] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes peaks at wavenumbers of (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1709 ± 4) cm -1 , (1692 ± 4) cm - 1, (1658 ± 4) cm -1 , (1615 ± 4) cm -1 , (1601 ± 4) cm -1 , (1515 ± 4) cm -1 , (1439 ± 4) cm -1 , (1243 ± 4) cm -1 and (767 ± 4) cm -1 .

[0137] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes peaks at wavenumbers of (3452 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm-1 、 (1709 ± 4) cm -1 、 (1692 ± 4) cm - 1. (1658 ± 4) cm -1 、 (1615 ± 4) cm -1 、 (1601 ± 4) cm -1 、 (1515 ± 4) cm -1 、 (1497 ± 4) cm -1 、 (1439 ± 4) cm -1 、 (1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks.

[0138] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has an FTIR spectrum that includes wavenumbers of (3452 ± 4) cm -1 、 (2875 ± 4) cm -1 、 (2732 ± 4) cm -1 、 (1709 ± 4) cm -1 、 (1692 ± 4) cm - 1. (1658 ± 4) cm -1 、 (1615 ± 4) cm -1 、 (1601 ± 4) cm -1 、 (1515 ± 4) cm -1 、 (1497 ± 4) cm -1 、 (1461 ± 4) cm -1 、 (1439 ± 4) cm -1 、 (1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks.

[0139] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has an FTIR spectrum that includes wavenumbers of (3452 ± 4) cm -1 、 (2875 ± 4) cm -1 、 (2732 ± 4) cm -1 、 (1709 ± 4) cm -1 、 (1692 ± 4) cm - 1. (1658 ± 4) cm -1 、 (1615 ± 4) cm -1 、 (1601 ± 4) cm-1 、(1515 ± 4) cm -1 、(1497 ± 4) cm -1 、(1461 ± 4) cm -1 、(1439 ± 4) cm -1 、(1425 ± 4) cm -1 、(1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks.

[0140] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes, when measured at a temperature in the range of 20 °C to 30 °C using a diamond ATR cell, at wavenumbers of (3452 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm -1 、(1709 ± 4) cm -1 、(1692 ± 4) cm - 1、(1658 ± 4) cm -1 、(1615 ± 4) cm -1 、(1601 ± 4) cm -1 、(1515 ± 4) cm -1 、(1497 ± 4) cm -1 、(1461 ± 4) cm -1 、(1439 ± 4) cm -1 、(1425 ± 4) cm -1 、(1384 ± 4) cm -1 、(1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks.

[0141] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes, when measured at a temperature in the range of 20 °C to 30 °C using a diamond ATR cell, at wavenumbers of (3452 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm -1 、(1709 ± 4) cm -1 、(1692 ± 4) cm - 1、(1658 ± 4) cm -1 、(1615 ± 4) cm -1 、(1601 ± 4) cm -1 、(1515 ± 4) cm-1 、(1497 ± 4) cm -1 、(1461 ± 4) cm -1 、(1439 ± 4) cm -1 、(1425 ± 4) cm -1 、(1384 ± 4) cm -1 、(1243 ± 4) cm -1 、(1184 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks at.

[0142] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has an FTIR spectrum that includes wave numbers at (3452 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm -1 、(1709 ± 4) cm -1 、(1692 ± 4) cm - 1、(1658 ± 4) cm -1 、(1615 ± 4) cm -1 、(1601 ± 4) cm -1 、(1515 ± 4) cm -1 、(1497 ± 4) cm -1 、(1461 ± 4) cm -1 、(1439 ± 4) cm -1 、(1425 ± 4) cm -1 、(1384 ± 4) cm -1 、(1243 ± 4) cm -1 、(1184 ± 4) cm -1 、(1069 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks at.

[0143] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized in that when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has an FTIR spectrum that includes wave numbers at (3452 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm -1 、(1709 ± 4) cm -1 、(1692 ± 4) cm - 1、(1658 ± 4) cm-1 、 (1615 ± 4) cm -1 、 (1601 ± 4) cm -1 、 (1515 ± 4) cm -1 、 (1497 ± 4) cm -1 、 (1461 ± 4) cm -1 、 (1439 ± 4) cm -1 、 (1425 ± 4) cm -1 、 (1384 ± 4) cm -1 、 (1243 ± 4) cm -1 、 (1184 ± 4) cm -1 、 (1069 ± 4) cm -1 、 (767 ± 4) cm -1 and (739 ± 4) cm -1 at the peaks.

[0144] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes wavenumbers of (3452 ± 4) cm -1 、 (3274 ± 4) cm -1 、 (2875 ± 4) cm -1 、 (2732 ± 4) cm -1 、 (1709 ± 4) cm - 1、 (1692 ± 4) cm - 1、 (1658 ± 4) cm -1 、 (1615 ± 4) cm -1 、 (1601 ± 4) cm -1 、 (1515 ± 4) cm -1 、 (1497 ± 4) cm -1 、 (1461 ± 4) cm -1 、 (1439 ± 4) cm -1 、 (1425 ± 4) cm -1 、 (1384 ± 4) cm -1 、 (1243 ± 4) cm -1 、 (1184 ± 4) cm -1 、 (1069 ± 4) cm -1 、 (767 ± 4) cm -1 and (739 ± 4) cm -1 at the peaks.

[0145] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, the spectrum comprising at a wavenumber of (3452 ± 4) cm -1 、(3274 ± 4) cm -1 、(2933 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm - 1、(1709 ± 4) cm - 1、(1692 ± 4) cm - 1、(1658 ± 4) cm -1 、(1615 ± 4) cm -1 、(1601 ± 4) cm -1 、(1515 ± 4) cm -1 、(1497 ± 4) cm -1 、(1461 ± 4) cm -1 、(1439 ± 4) cm -1 、(1425 ± 4) cm -1 、(1384 ± 4) cm -1 、(1243 ± 4) cm -1 、(1184 ± 4) cm -1 、(1069 ± 4) cm -1 、(767 ± 4) cm -1 and (739 ± 4) cm -1 at the peaks.

[0146] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, the spectrum comprising at a wavenumber of (3452 ± 4) cm -1 、(2875 ± 4) cm -1 、(2732 ± 4) cm -1 、(1692 ± 4) cm -1 、(1439 ± 4) cm -1 、(1243 ± 4) cm -1 and (767 ± 4) cm -1 at the peaks, and at least one plurality of peaks selected from the group consisting of: (3274 ± 4) cm -1 、(2933 ± 4) cm -1 、(1709 ± 4) cm -1 、(1658 ± 4) cm -1 、(1615 ± 4) cm-1 、 (1601 ± 4) cm -1 、 (1515 ± 4) cm -1 、 (1497 ± 4) cm -1 、 (1461 ± 4) cm -1 、 (1425 ± 4) cm -1 、 (1384 ± 4) cm -1 、 (1184 ± 4) cm -1 、 (1069 ± 4) cm -1 and (739 ± 4) cm -1 。

[0147] In another embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that contains peaks at the following wave numbers when measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C:

[0148] (3452 ± 2) cm -1 、 (2875 ± 2) cm -1 and (1692 ± 2) cm -1 , or

[0149] (3452 ± 2) cm -1 、 (2875 ± 2) cm -1 、 (1692 ± 2) cm -1 and (1439 ± 2) cm -1 ; or

[0150] (3452 ± 2) cm -1 、 (2875 ± 2) cm -1 、 (1692 ± 2) cm -1 、 (1439 ± 2) cm -1 and (1243 ± 2) cm -1 ; or

[0151] (3452 ± 2) cm -1 、 (2875 ± 2) cm -1 、 (1692 ± 2) cm -1 、 (1439 ± 2) cm -1 、 (1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0152] (3452 ± 2) cm -1 、 (2875 ± 2) cm -1 、 (2732 ± 2) cm -1 、 (1692 ± 2) cm-1 、(1439±2)cm -1 、(1243±2)cm -1 and (767±2)cm -1 ;or

[0153] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm -1 、(1658±2)cm -1 、(1439±2)cm -1 、(1243±2)cm -1 and (767±2)cm -1 ;or

[0154] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1. (1658±2)cm -1 、(1615±2)cm -1 、(1439±2)cm -1 、(1243±2)cm -1 and (767±2)cm -1 ;or

[0155] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1. (1658±2)cm -1 、(1615±2)cm -1 、(1601±2)cm -1 、(1439±2)cm -1 、(1243±2)cm -1 and (767±2)cm -1 ;or

[0156] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm-1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1439 ± 2) cm -1 、(1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0157] (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(1439 ± 2) cm -1 、(1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0158] (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(1461 ± 2) cm -1 、(1439 ± 2) cm -1 、(1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0159] (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(2732 ± 2) cm-1 、(1709 ± 2) cm -1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(1461 ± 2) cm -1 、(1439 ± 2) cm -1 、(1425 ± 2) cm -1 、(1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0160] (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(1461 ± 2) cm -1 、(1439 ± 2) cm -1 、(1425 ± 2) cm -1 、(1384 ± 2) cm -1 、(1243 ± 2) cm -1 and (767 ± 2) cm -1 ; or

[0161] (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1692 ± 2) cm - 1、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(1461 ± 2) cm -1、(1439±2)cm -1 、(1425±2)cm -1 、(1384±2)cm -1 、(1243±2)cm -1 、(1184±2)cm -1 和(767±2)cm -1 ;或

[0162] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1、(1658±2)cm -1 、(1615±2)cm -1 、(1601±2)cm -1 、(1515±2)cm -1 、(1497±2)cm -1 、(1461±2)cm -1 、(1439±2)cm -1 、(1425±2)cm -1 、(1384±2)cm -1 、(1243±2)cm -1 、(1184±2)cm -1 、(1069±2)cm -1 和(767±2)cm -1 ;或

[0163] (3452±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1、(1658±2)cm -1 、(1615±2)cm -1 、(1601±2)cm -1 、(1515±2)cm -1 、(1497±2)cm -1 、(1461±2)cm -1 、(1439±2)cm -1 、(1425±2)cm -1 、(1384±2)cm -1 、(1243±2)cm -1 、(1184±2)cm-1 、(1069±2)cm -1 、(767±2)cm -1 和(739±2)cm -1 ;或

[0164] (3452±2)cm -1 、(3274±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1、(1658±2)cm -1 、(1615±2)cm -1 、(1601±2)cm -1 、(1515±2)cm -1 、(1497±2)cm -1 、(1461±2)cm -1 、(1439±2)cm -1 、(1425±2)cm -1 、(1384±2)cm -1 、(1243±2)cm -1 、(1184±2)cm -1 、(1069±2)cm -1 、(767±2)cm -1 和(739±2)cm -1 ;或

[0165] (3452±2)cm -1 、(3274±2)cm -1 、(2933±2)cm -1 、(2875±2)cm -1 、(2732±2)cm -1 、(1709±2)cm -1 、(1692±2)cm - 1、(1658±2)cm -1 、(1615±2)cm -1 、(1601±2)cm -1 、(1515±2)cm -1 、(1497±2)cm -1 、(1461±2)cm -1 、(1439±2)cm -1 、(1425±2)cm -1 、(1384±2)cm -1, (1243 ± 2) cm -1 , (1184 ± 2) cm -1 , (1069 ± 2) cm -1 , (767 ± 2) cm -1 and (739 ± 2) cm -1 .

[0166] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that includes peaks at wavenumbers (3452 ± 2) cm -1 , (2875 ± 2) cm -1 , (2732 ± 2) cm -1 , (1692 ± 2) cm -1 , (1439 ± 2) cm -1 , (1243 ± 2) cm -1 and (767 ± 2) cm -1 and at least one or more peaks selected from the group consisting of: (3274 ± 2) cm -1 , (2933 ± 2) cm -1 , (1709 ± 2) cm -1 , (1658 ± 2) cm -1 , (1615 ± 2) cm -1 , (1601 ± 2) cm -1 , (1515 ± 2) cm -1 , (1497 ± 2) cm -1 , (1461 ± 2) cm -1 , (1425 ± 2) cm -1 , (1384 ± 2) cm -1 , (1184 ± 2) cm -1 , (1069 ± 2) cm -1 and (739 ± 2) cm -1 .

[0167] In yet another embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having an FTIR spectrum that is substantially the same as that shown in Figure 3 described herein when measured at a temperature in the range of 20°C to 30°C using a diamond ATR cell.

[0168] Examples of DSC embodiments:

[0169] In one embodiment, LNP023 hydrochloride (Form HB) can be prepared by a process having the same as Figure 4Characterized by substantially the same DSC curves as shown. In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having a DSC curve showing a broad endothermic event that ends at about 170 °C and is followed by an exothermic decomposition at about 200 °C when measured at a heating rate of 10 K / min. In one embodiment, the broad endothermic event that ends at about 170 °C is an endothermic event in the range of 35 °C to 170 °C when measured at a heating rate of 10 K / min.

[0170] Examples of TGA embodiments:

[0171] In one embodiment, LNP023 hydrochloride (Form HB) can be characterized by Figure 5 substantially the same thermogravimetric analysis (TGA) as shown. In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by having a TGA curve showing a mass loss of no more than 4.5 w-% due to the loss of water and residual solvents when heated from 30 °C to 300 °C at a rate of 20 K / min, and at a temperature of about 220 °C, for example, in the temperature range of 200 °C to 220 °C, based on the weight of the crystalline form, for example, no more than 4.3 w-%, for example, no more than 4.0 w-%, for example, no more than 3.8 w-%, for example, no more than 3.4 w-%.

[0172] Examples of DVS embodiments:

[0173] In one embodiment, LNP023 hydrochloride (Form HB) can be characterized by Figure 6 substantially the same DVS as shown. In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by showing a mass change of no more than 4.5 w-%, for example, no more than 4.0 w-%, for example, no more than 3.0 w-%, for example, no more than 2.0 w-%, for example, no more than 1.8 w%, 1.6 w-%, 1.5 w-% or 1.4 w-% based on the weight of the crystalline form when measured with DVS at a relative humidity in the range of 0 to 95% and at a temperature of (25 ± 1.0) °C.

[0174] Examples of additional embodiments:

[0175] In another embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by being a non-solvated form. In one embodiment, the crystalline form of LNP023 hydrochloride is a hydrated form, for example, a monohydrate form.

[0176] Examples of morphology

[0177] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which is characterized by exhibiting a columnar or equant morphology.

[0178] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride, which has a substantially equant or columnar crystal habit, e.g., substantially equant in shape. As opposed to crystals in the shape of small needles or blades, this results in preferred volume and flow properties. Such preferred crystal shapes can be obtained by conducting the processes described herein, e.g., when conducting crystallization engineering techniques, including temperature cycling, followed by milling that results in particle size reduction.

[0179] The resulting particles are characterized by a suitable aspect ratio. The aspect ratio ψ A (0 < ψ A ≤ 1) is defined by the ratio ψA = x 费雷特最小值 / x 费雷特最大值 of the minimum to the maximum Feret diameter. It indicates the elongation of the particle, i.e., the smaller the value, the more elongated the particle. Thus, in a further embodiment, the equant-shaped particles of the crystalline form (Form HB) of LNP023 hydrochloride have an aspect ratio (a50) greater than about 0.4 (e.g., greater than about 0.45). In other embodiments, the equant-shaped particles of Form HB have an aspect ratio of about 0.4 to about 0.7 (e.g., about 0.45 to 0.6).

[0180] In a further embodiment, the particle size distribution X of the equant-shaped particles of the crystalline form (Form HB) of LNP023 hydrochloride 90 is less than about 300 μm, e.g., less than about 200 μm, e.g., less than about 150 μm. In a further embodiment, the particle size distribution X 90 is from about 30 to about 150 μm, e.g., from about 35 to about 130 μm, e.g., from about 40 to about 105 μm.

[0181] In a further embodiment, the particle size distribution X of the equant-shaped particles of Form HB 50 is from about 5 to about 100 μm, e.g., from about 10 to about 70 μm, e.g., from about 15 to about 55 μm.

[0182] In yet a further embodiment, the particle size distribution X of the equant-shaped particles of Form HB 10 is from about 0.1 to about 50 μm, e.g., from about 1 to about 30 μm, e.g., from about 2 to about 20 μm.

[0183] In another embodiment, the equidimensional shaped particles of Form HB have a compacted (15 kPa) bulk density of less than about 0.8 g / ml, such as less than about 0.7 g / ml. In other embodiments, the equidimensional shaped particles of Form HB have a compacted (15 kPa) bulk density of from about 0.4 to about 0.7 g / ml, such as from about 0.50 to about 0.65 g / ml, such as from about 0.55 to about 0.60 g / ml.

[0184] Composition

[0185] Examples of embodiments:

[0186] In another aspect, the present invention relates to a composition comprising Form HB of LNP023 hydrochloride as described herein, as defined in any of the above embodiments, said composition being substantially free of any other solid forms of LNP023 hydrochloride. For example, a composition comprising Form HB of LNP023 hydrochloride as described herein comprises, based on the weight of the composition, at most 20 w-%, such as at most 10 w-%, such as at most 5, 4, 3, 2 or 1 w-% of any other solid forms of LNP023 hydrochloride. In one embodiment, any other solid form of LNP023 hydrochloride is Form A of WO 2015 / 009616 or is amorphous. When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 Form A of LNP023 hydrochloride exhibits a PXRD that comprises a characteristic peak especially at a 2-θ angle of (11.6 ± 0.1)°. Thus, the absence of this peak at a 2-θ angle of (11.6 ± 0.1)° in the PXRD confirms the absence of Form A of LNP023 hydrochloride in the composition.

[0187] In one embodiment, the present invention relates to a composition comprising Form HB of LNP023 hydrochloride as described herein, as defined in any of the above embodiments, which, when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation, has a PXRD that does not comprise a peak at a 2-θ angle of (11.6 ± 0.1)°.

[0188] In one embodiment, the present invention relates to a composition comprising at least 90 w-% based on the total weight of the composition, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and further including equal to about 100 w-% of the crystalline form HB of LNP023 hydrochloride as defined in any one of the above embodiments. The remaining material may comprise one or more other solid forms of LNP023 hydrochloride, or reaction impurities, or processing impurities resulting from the preparation of the composition.

[0189] Process

[0190] Examples of embodiments:

[0191] In another aspect, the present invention relates to a process for preparing the form HB of LNP023 hydrochloride as described herein or a composition comprising the same as defined in any one of the above aspects and their corresponding embodiments, the process comprising:

[0192] (i) providing LNP023 hydrochloride in solid form;

[0193] (ii) suspending the LNP023 hydrochloride provided in step (i) in a first solvent comprising acetone and water and heating to dissolve the solid, thereby providing a solution;

[0194] (iii) cooling the solution obtained in step (ii) and adding a second solvent comprising acetone, or ethyl acetate or a combination thereof, to provide crystals in the mother liquor;

[0195] (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor;

[0196] (v) optionally washing the separated crystals obtained in step (iv); and

[0197] (vi) drying the crystals obtained in step (iv) or (v).

[0198] Examples of process descriptions:

[0199] The solid LNP023 hydrochloride starting material can be prepared according to the procedure disclosed in Example 26d of WO 2015 / 009616.

[0200] The solid starting material provided in step (i) can be suspended in a first solvent comprising acetone and water. The first solvent can comprise additional organic solvents. In one embodiment, acetone and water can be the only solvents present in the suspension. The concentration of LNP023 hydrochloride in the suspension is, for example, in the range of about 0.07 to 0.30 g / g, for example in the range of about 0.10 to 0.25 g / g, for example in the range of about 0.15 to 0.20 g / g, for example the concentration is about 0.20 g / g. In one embodiment, the ratio of acetone to water (g / g) is, for example, 60:40 to 90:10, for example 65:45 to 85:15, for example 75:25 to 80:20. In one embodiment, the heating in step (ii) can be carried out at an elevated temperature, for example at a temperature in the range of about 30°C to 56°C, for example in the range of about 45°C to 55°C. The heating can be accompanied by any type of movement of the solid material suspended in the solvent, including but not limited to, for example, agitation, stirring, mixing, shaking, vibration, sonication, wet milling, etc. Once the solid material has dissolved, the solution can be cooled to a temperature in the range of about 20°C to 50°C, for example in the range of about 35°C to 45°C, and a second solvent comprising acetone, ethyl acetate, or a combination thereof can be added. The second solvent can comprise additional organic solvents or water. In one embodiment, acetone and ethyl acetate can be the only solvents added in step (iii). If both acetone and ethyl acetate are used as the second solvent, they can be added as a solvent mixture of acetone and ethyl acetate or they can be added sequentially. In one embodiment, when added sequentially, acetone is added first, followed by ethyl acetate. The concentration of LNP023 hydrochloride is, for example, in the range of about 0.04 to 0.15 g / g, for example in the range of about 0.05 to 0.10 g / g, and for example in the range of about 0.05 to 0.07 g / g, for example the concentration is about 0.06 g / g. The ratio of acetone to ethyl acetate (g / g) is, for example, 0.5:3 to 1:1, for example 1:2. In one embodiment, the suspension can be further cooled to a temperature in the range of about 0°C to 25°C, for example in the range of about 5°C to 15°C (for example 10°C), to complete crystallization. Once form HB in a substantially pure form is obtained, at least a portion of the crystals can be separated from the mother liquor. In one embodiment, the crystals can be separated from their mother liquor by any conventional method, such as filtration, centrifugation, solvent evaporation, or decantation, for example by filtration or centrifugation. In one embodiment, the crystals can be separated from their mother liquor by filtration.

[0201] Optionally, in another step, the separated crystals can be washed with a suitable solvent, such as an organic solvent or water. Suitable organic solvents include but are not limited to acetone and ethyl acetate.

[0202] The obtained crystals can then be dried. The drying can be carried out at a temperature of about 70 °C or lower (e.g., about 60 °C or lower, e.g., about 50 °C). The drying can also be carried out at about room temperature. The drying can be carried out over a period of about 2 to 24 hours (e.g., about 4 to 16 hours, e.g., about 6 to 10 hours). In one embodiment, the drying can be carried out over a period of about 6 to 8 hours. The drying can be carried out at ambient pressure or under reduced pressure. In one embodiment, the drying is carried out at a pressure of about 200 mbar or less, e.g., at a pressure of about 150 mbar or less. In one embodiment, the drying is carried out at a pressure of about 80 mbar or less. In one embodiment, the drying is carried out, for example, under a vacuum of about 50 mbar or less.

[0203] In one embodiment, certain crystallization techniques can be applied to the process to obtain Form HB crystals with improved product processability. These techniques include but are not limited to temperature cycling or addition of a second solvent over an extended period (e.g., within 12 to 36 h). For example, it can be temperature cycling. The temperature cycling can be carried out as follows: in step (iii), before adding the second solvent, the solution can be cooled to a temperature in the range of about 0 °C to 25 °C, e.g., about 5 °C to 15 °C (e.g., 10 °C), and then heated to a temperature of up to about 30 °C to 45 °C, e.g., in the range of about 30 °C to 40 °C (e.g., 35 °C). This temperature cycling can be carried out at least 3 times, e.g., at least 6 times, e.g., at least 8 times, e.g., 6 to 12 times. After the temperature cycling, the second solvent can be added. In one embodiment, the second solvent can be ethyl acetate.

[0204] After being engineered, i.e., after applying certain crystallization techniques as described above, Form HB consists of crystals with a well-defined morphology that results in excellent powder properties and processability, allowing the formulation of pharmaceutical products containing Form HB via standard manufacturing processes and equipment. In one embodiment, compared to Form A which cannot be engineered in this way, Form HB is less brittle, so the problems of grinding and wide particle size distribution can be minimized. In addition, the flow properties of Form HB are superior to those of Form A. Therefore, Form HB (especially after being engineered) combines high physicochemical stability with excellent powder properties. Therefore, it is superior to Form A and is the ideal solid form of LNP023 hydrochloride for the standard manufacture of improved pharmaceutical compositions.

[0205] In one embodiment, the present invention relates to a process for preparing Form HB of LNP023 hydrochloride as described herein or a composition containing the same as defined in any one of the above aspects and their corresponding embodiments, the process comprising step (iii) of the above procedure:

[0206] a) Cool the solution obtained in step (ii), and then reheat the solution again;

[0207] b) Repeat step (a) at least 3 times; and

[0208] c) Add a second solvent comprising acetone, ethyl acetate, or a combination thereof.

[0209] Examples of grinding

[0210] Before filling the particles of Form HB of LNP023 hydrochloride described herein into capsules or otherwise further processing them, they are, for example, milled. Milling can be carried out to make the particles easy to fill directly into capsules, especially without additional excipients.

[0211] In one embodiment, the particle size of Form HB of LNP023 hydrochloride is reduced by using rotor impact milling. Rotor impact milling can be carried out by using different static and rotating tool elements, such as a rotor beater with a static screen, a rotor beater with a static screen and impact elements, a rotating pin disk with a static pin disk, or a rotating pin disk with a rotating pin disk. The Form HB of LNP023 hydrochloride to be milled is fed into the rotor impact mill through a suitable powder delivery system (e.g., a vibratory feeder or a twin-screw feeder) to fully control the relevant powder feed rate. The powder is further transported to the impact tool element by an air stream, which is generated by the rotating element of the rotor impact mill or by a blower connected to the rotor impact mill. The reduction of the particle size of the Form HB of LNP023 hydrochloride particles occurs by impact on the rotating element, by impact on the static element, or by impact between the Form HB particles in collision. For the customized Form HB of the physical properties of LNP023 hydrochloride, appropriate process parameters (such as rotor speed and feed rate) are related to the specific equipment parameters of the rotor impact mill. After separation from the conveying gas through, for example, a filter, a cyclone separator, the milled product with customized physical properties is collected in a product container. The milled product can be finally blended by an appropriate technique (e.g., a diffusion blender) to obtain the appropriate physical homogeneity of the manufactured batch.

[0212] Rotor impact grinding can be carried out, for example, by rotor impact grinding using a rotating pin disk with a static pin disk tool (commonly described in the art as a needle mill). The scale-independent parameters of the rotor speed and the feed rate can be described by the rotor tip speed and the specific feed rate. The rotor speed for a specific equipment scale is in principle associated with the pin disk diameter of the relevant equipment scale through the parameter rotor tip speed (for the scale-independent parameter). The feed rate for a specific equipment scale is in principle associated with the pin surface area of the relevant equipment scale through the parameter specific feed rate (for the scale-independent parameter). It is possible to obtain the form HB of the LNP023 hydrochloride product with customized physical properties using rotor impact grinding, which has the following scale-independent grinding parameters: the rotor tip speed is 10 to 60 m / s, and the diameter of the external rotating pins is considered for standardization, or the specific feed rate is up to about 4,000 kg / (h·m 2 ), and the cylindrical pin surface area of the rotating pins is considered for standardization.

[0213] In a scale-dependent example, the form HB of LNP023 hydrochloride can be ground by using a rotor impact mill (e.g., model 100UPZ of Hosokawa Alpine AG, Augsburg / Germany) and a rotating pin disk with a static pin disk tool (commonly described in the public domain as a needle mill). It can be obtained by operating the rotor speed at to rpm, for example 4,000 to 8,500 rpm, for example the rotor speed is rpm. A product with customized physical properties can be obtained by a process with a feed rate of, for example, 1 to 22 kg / h, for example 6 to 18 kg / h, for example at a feed rate of 15 kg / h.

[0214] Pharmaceutical compositions and uses

[0215] Examples of embodiments:

[0216] In another aspect, the present invention relates to the use of the form HB of LNP023 hydrochloride described herein as defined in any one of the above aspects and their corresponding embodiments or a composition comprising the form HB of LNP023 hydrochloride for the preparation of a pharmaceutical composition.

[0217] In yet another aspect, the present invention relates to a pharmaceutical composition comprising the form HB of LNP023 hydrochloride as defined in any one of the above aspects and their corresponding embodiments or a composition containing the form HB of LNP023 hydrochloride (e.g., in a predetermined amount or a therapeutically effective amount), and at least one pharmaceutically acceptable excipient.

[0218] In one embodiment, a pharmaceutical composition comprising LNP023 hydrochloride in Form HB as defined in any of the above aspects and their corresponding embodiments contains up to about 200 mg of LNP023 hydrochloride calculated as the anhydrous LNP023 free base.

[0219] In one of its embodiments, the pharmaceutical composition contains from about 10 mg to about 200 mg of LNP023 hydrochloride calculated as the anhydrous LNP023 free base.

[0220] In one of its embodiments, the pharmaceutical composition contains LNP023 hydrochloride in doses of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg, each calculated as the anhydrous LNP023 free base.

[0221] In one of its embodiments, the pharmaceutical composition contains LNP023 hydrochloride in doses of 10 mg, 25 mg, 50 mg, 100 mg or 200 mg, each calculated as the anhydrous LNP023 free base.

[0222] In one embodiment, the therapeutically effective amounts of LNP023 hydrochloride in Form HB are selected from the group consisting of: 1, 5, 10, 25, 50, 100 and 200 mg, calculated as the anhydrous LNP023 free base. In one embodiment, the therapeutically effective amount of LNP023 hydrochloride in Form HB is 100 or 200 mg. In one embodiment, the therapeutically effective amount of LNP023 hydrochloride in Form HB is 50 mg. In one embodiment, the therapeutically effective amount of LNP023 hydrochloride in Form HB is 10 mg.

[0223] At least one pharmaceutically acceptable excipient that can be included in the pharmaceutical compositions described herein is, for example, selected from the group consisting of vehicle, filler, diluent, binder, disintegrant, lubricant, glidant and combinations thereof. Suitable vehicles are, for example, dispersions or capsules. In a preferred embodiment, the pharmaceutical composition contains a pharmaceutically acceptable excipient, for example, a vehicle.

[0224] In a preferred embodiment, a pharmaceutical composition comprising LNP023 hydrochloride in Form HB as defined in any of the above aspects and their corresponding embodiments or a composition containing LNP023 hydrochloride in Form HB is in an oral solid dosage form. In one embodiment, the oral solid dosage form is selected from the group consisting of tablets and capsules. In one embodiment, the oral dosage form is in the form of a tablet. In one embodiment, the oral dosage form is a capsule. In one embodiment, the capsule is a size 0 capsule.

[0225] Tablets can be prepared by mixing LNP023 hydrochloride in Form HB as defined in any of the above aspects and their corresponding embodiments, or a composition comprising LNP023 hydrochloride in Form HB, with at least one excipient (such as a filler, diluent, binder, disintegrant, lubricant, glidant, or a combination thereof). Optionally, a granulation step, such as a dry or wet granulation step, is carried out prior to compression.

[0226] Capsules can be prepared by mixing LNP023 hydrochloride in Form HB as defined in any of the above aspects and their corresponding embodiments, or a composition comprising LNP023 hydrochloride in Form HB, with at least one excipient (such as a filler, diluent, binder, disintegrant, lubricant, glidant, or a combination thereof), and filling the blend into a capsule used as a vehicle. Alternatively, the neat filling of LNP023 hydrochloride in Form HB into a capsule used as a vehicle is carried out. The capsule shell can be a gelatin shell or a hypromellose (HPMC) shell.

[0227] In one embodiment, the present invention relates to a pharmaceutical composition comprising LNP023 hydrochloride particles in Form HB in a capsule (such as a size 0 capsule). In one embodiment, the aspect ratio of the particles in Form HB in the capsule is between 0.4 and about 0.7, such as 0.45 to 0.6. In one embodiment, the particle size distribution X of the particles in Form HB in the capsule 50 is from about 5 to about 100 μm, such as from about 10 to about 70 μm, such as from about 15 to about 55 μm. In one embodiment, the compacted (15 kPa) bulk density of the particles in Form HB in the capsule is from about 0.4 to about 0.7 g / ml, such as from about 0.50 to about 0.65 g / ml, such as from about 0.55 to about 0.60 g / ml.

[0228] In another aspect, the present invention relates to LNP023 hydrochloride in Form HB, or a composition comprising LNP023 hydrochloride in Form HB, or a pharmaceutical composition comprising LNP023 hydrochloride in Form HB and a composition as defined in any of the above aspects and their corresponding embodiments, for treating the diseases and disorders described herein.

[0229] In yet another aspect, the present invention relates to Form HB of LNP023 hydrochloride, or a composition comprising Form HB of LNP023 hydrochloride, or a pharmaceutical composition comprising Form HB of LNP023 hydrochloride and a composition as defined in any of the above aspects and their corresponding embodiments, for treating or preventing the indications disclosed in WO 2015 / 009616 and WO 2019 / 043609, in particular for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH), complement-driven renal disease C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy) and other kidney diseases with signs of glomerular C3 deposition, such as MN (membranous nephropathy) and HUS (Escherichia coli-induced hemolytic uremic syndrome) and atypical hemolytic uremic syndrome (aHUS).

[0230] In another aspect, the present invention relates to a method of treating diseases and disorders in a subject in need thereof, which diseases and disorders are disclosed in WO 2015 / 009616 and WO 2019 / 043609, each of which is hereby incorporated by reference in its entirety. In one embodiment, the disease or disorder is selected from paroxysmal nocturnal hemoglobinuria (PNH), complement-driven renal disease C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy) and other kidney diseases with signs of glomerular C3 deposition, such as MN (membranous nephropathy) and HUS (Escherichia coli-induced hemolytic uremic syndrome) and atypical hemolytic uremic syndrome (aHUS). In one embodiment, the method comprises administering to the subject a therapeutically effective amount of Form HB of LNP023 as described herein.

[0231] In another aspect, the present invention relates to a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Form HB of LNP023, thereby treating the subject.

[0232] In one embodiment, the method of treating PNH in a subject comprises administering to the subject Form HB of LNP023 at a daily dose of up to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of up to about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0233] In one embodiment, a method of treating a subject with PNH comprises administering to the subject the form HB of LNP023 at a daily dose of from about 20 mg to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of from about 10 mg to about 200 mg, calculated as anhydrous LNP023 free base.

[0234] In one embodiment, a method of treating a subject with PNH comprises administering to the subject the form HB of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg or about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of from about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg, calculated as anhydrous LNP023 free base.

[0235] In an embodiment of the method of treating PNH, the form HB of LNP023 is administered to the subject at a total daily dose of about 20 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg.

[0236] In an embodiment of the method of treating PNH, the form HB of LNP023 is administered to the subject at a total daily dose of about 50 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 25 mg.

[0237] In an embodiment of the method of treating PNH, the form HB of LNP023 is administered to the subject at a total daily dose of about 100 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 50 mg.

[0238] In an embodiment of the method of treating PNH, the form HB of LNP023 is administered to the subject at a total daily dose of about 200 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 100 mg.

[0239] In an embodiment of the method of treating PNH, the form HB of LNP023 is administered to a subject at a total daily dose of about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0240] In an embodiment of the method of treating PNH, the form HB of LNP023 is orally administered to a subject twice daily (b.i.d.) (e.g., about once every 12 hours).

[0241] In an embodiment of the method of treating PNH, the form HB of LNP023 is orally administered to a subject at a dose of 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0242] In another aspect, the present invention relates to a method of treating a complement-driven renal disease C3G (C3 glomerulopathy) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the form HB of LNP023 so as to treat the subject.

[0243] In one embodiment, the method of treating C3G in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of up to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of up to about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0244] In one embodiment, the method of treating C3G in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of about 20 mg to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg to about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0245] In one embodiment, the method of treating C3G in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg or about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0246] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is administered to a subject at a total daily dose of about 20 mg. In one embodiment, it is administered at a dose of about 10 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0247] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is administered to a subject at a total daily dose of about 50 mg. In one embodiment, it is administered at a dose of about 25 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0248] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is administered to a subject at a total daily dose of about 100 mg. In one embodiment, it is administered at a dose of about 50 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0249] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is administered to a subject at a total daily dose of about 200 mg. In one embodiment, it is administered at a dose of about 100 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0250] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is administered to a subject at a total daily dose of about 400 mg. In one embodiment, it is administered at a dose of about 200 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0251] In an embodiment of the method of treating C3G, the form HB of LNP023 is orally administered to a subject twice a day (b.i.d.) (e.g., about once every 12 hours).

[0252] In an embodiment of the method of treating C3G, in terms of anhydrous LNP023 free base, the form HB of LNP023 is orally administered to a subject at a dose of 200 mg twice a day (b.i.d.) (e.g., about once every 12 hours).

[0253] In another aspect, the present invention relates to a method of treating IgAN (immunoglobulin A nephropathy) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the form HB of LNP023 so as to treat the subject.

[0254] In one embodiment, a method of treating IgAN in a subject comprises administering to the subject, in terms of anhydrous LNP023 free base, Form HB of LNP023 at a daily dose of up to about 400 mg. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of up to about 200 mg, in terms of anhydrous LNP023 free base.

[0255] In one embodiment, a method of treating IgAN in a subject comprises administering to the subject, in terms of anhydrous LNP023 free base, Form HB of LNP023 at a daily dose of about 20 mg to about 400 mg. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg to about 200 mg, in terms of anhydrous LNP023 free base.

[0256] In one embodiment, a method of treating IgAN in a subject comprises administering to the subject, in terms of anhydrous LNP023 free base, Form HB of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg or about 400 mg. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg, in terms of anhydrous LNP023 free base.

[0257] In an embodiment of the method of treating IgAN, Form HB of LNP023 is administered to the subject at a total daily dose of about 20 mg, in terms of anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg.

[0258] In an embodiment of the method of treating IgAN, Form HB of LNP023 is administered to the subject at a total daily dose of about 50 mg, in terms of anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 25 mg.

[0259] In an embodiment of the method of treating IgAN, Form HB of LNP023 is administered to the subject at a total daily dose of about 100 mg, in terms of anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 50 mg.

[0260] In an embodiment of the method of treating IgAN, Form HB of LNP023 is administered to a subject at a total daily dose of about 200 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 100 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0261] In an embodiment of the method of treating IgAN, Form HB of LNP023 is administered to a subject at a total daily dose of about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0262] In an embodiment of the method of treating IgAN, Form HB of LNP023 is orally administered to a subject twice daily (b.i.d.) (e.g., about once every 12 hours).

[0263] In an embodiment of the method of treating IgAN, Form HB of LNP023 is orally administered to a subject at a dose of 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0264] In another aspect, the present invention relates to a method of treating MN (membranous nephropathy), such as idiopathic MN (iMN), in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Form HB of LNP023 so as to treat the subject.

[0265] In one embodiment, the method of treating MN, such as iMN, in a subject comprises administering to the subject Form HB of LNP023 at a daily dose of up to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of up to about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0266] In one embodiment, the method of treating MN, such as iMN, in a subject comprises administering to the subject Form HB of LNP023 at a daily dose of about 20 mg to about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg to about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0267] In one embodiment, a method of treating a subject's MNs, such as iMNs, comprises administering to the subject a form HB of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, calculated as anhydrous LNP023 free base.

[0268] In an embodiment of the method of treating MNs, a form HB of LNP023 is administered to the subject at a total daily dose of about 20 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 10 mg.

[0269] In an embodiment of the method of treating MNs, a form HB of LNP023 is administered to the subject at a total daily dose of about 50 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 25 mg.

[0270] In an embodiment of the method of treating MNs, a form HB of LNP023 is administered to the subject at a total daily dose of about 100 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 50 mg.

[0271] In an embodiment of the method of treating MNs, a form HB of LNP023 is administered to the subject at a total daily dose of about 200 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 100 mg.

[0272] In an embodiment of the method of treating MNs, a form HB of LNP023 is administered to the subject at a total daily dose of about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered twice daily (b.i.d.) (e.g., about once every 12 hours) at a dose of about 200 mg.

[0273] In an embodiment of the method of treating MNs, form HB of LNP023 is orally administered to the subject twice daily (b.i.d.) (e.g., about once every 12 hours).

[0274] In an embodiment of the method of treating MN, the form HB of LNP023 is orally administered to a subject at a dose of 200 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours), calculated as the anhydrous LNP023 free base.

[0275] In another aspect, the present invention relates to a method of treating atypical hemolytic uremic syndrome (aHUS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the form HB of LNP023 so as to treat the subject.

[0276] In one embodiment, the method of treating aHUS in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of up to about 400 mg, calculated as the anhydrous LNP023 free base. In one embodiment, it is administered at a dose of up to about 200 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours), calculated as the anhydrous LNP023 free base.

[0277] In one embodiment, the method of treating aHUS in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of about 20 mg to about 400 mg, calculated as the anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg to about 200 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours), calculated as the anhydrous LNP023 free base.

[0278] In one embodiment, the method of treating aHUS in a subject comprises administering to the subject the form HB of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg or about 400 mg, calculated as the anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours), calculated as the anhydrous LNP023 free base.

[0279] In an embodiment of the method of treating aHUS, the form HB of LNP023 is administered to a subject at a total daily dose of about 20 mg, calculated as the anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 10 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours).

[0280] In an embodiment of the method of treating aHUS, the form HB of LNP023 is administered to a subject at a total daily dose of about 50 mg, calculated as the anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 25 mg twice daily (b.i.d.) (e.g., approximately once every 12 hours).

[0281] In an embodiment of a method of treating aHUS, Form HB of LNP023 is administered to a subject at a total daily dose of about 100 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 50 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0282] In an embodiment of a method of treating aHUS, Form HB of LNP023 is administered to a subject at a total daily dose of about 200 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 100 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0283] In an embodiment of a method of treating aHUS, Form HB of LNP023 is administered to a subject at a total daily dose of about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, it is administered at a dose of about 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours).

[0284] In an embodiment of a method of treating aHUS, Form HB of LNP023 is administered orally to a subject twice daily (b.i.d.) (e.g., about once every 12 hours).

[0285] In an embodiment of a method of treating aHUS, Form HB of LNP023 is administered orally to a subject at a dose of 200 mg twice daily (b.i.d.) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0286] All of the foregoing embodiments related to methods of treating certain diseases at a specific dose are equally applicable to:

[0287] Form HB of LNP023 for treating certain diseases at a specific dose according to the present invention;

[0288] Use of Form HB of LNP023 in the manufacture of a medicament for treating certain diseases at a specific dose according to the present invention;

[0289] Use of Form HB of LNP023 for treating certain diseases at a specific dose according to the present invention; and

[0290] A pharmaceutical composition comprising Form HB of LNP023 for treating certain diseases at a specific dose according to the present invention and one or more pharmaceutically acceptable carriers.

[0291] Test methods for morphological properties

[0292] Aspect ratio: The aspect ratio is the ratio of the maximum length of a crystal to its minimum width. When the aspect ratio is 1, the crystal has an equidimensional crystal habit. As the aspect ratio decreases below 1, the crystal habit becomes increasingly plate-like. Conversely, as the aspect ratio increases continuously above 1, the crystal approaches a needle-like crystal habit. According to the present disclosure, the equidimensional shape particles of Form HB have an aspect ratio a, for example, between about 0.4 and about 0.7 50 .

[0293] The aspect ratio was determined by the dynamic image analysis (DIA) method using a QICPIC dynamic image analyzer from Sympatec GmbH, Clausthal-Zellerfeld, Germany

[0294] Particle size distribution: The particle size distribution was measured by the laser light diffraction (LLD) method using a Helos instrument from Sympatec GmbH, Clausthal-Zellerfeld, Germany

[0295] Compacted bulk density: The compacted (15 kPa) bulk density was measured using an FT4 (Freeman Technology) powder rheometer

[0296] Examples

[0297] The following non-limiting examples are used to illustrate the present disclosure but should not be construed as limiting the present disclosure in any way

[0298] Example 1: Preparation of Form HB of LNP023 hydrochloride

[0299] As described in Example 26d of WO 2015 / 009616, Form A LNP023-HCl salt was obtained. 9.3 g of Form A of LNP023 hydrochloride was suspended in a mixture of 48.1 g of acetone and water (acetone: water = 78:22 m:m) and dissolved at about 50 °C. The solution was cooled to 40 °C and 136 g of a mixture of acetone and ethyl acetate (acetone: ethyl acetate = 1:2 m:m) was added over 24 hours. The suspension was cooled to 10 °C to complete crystallization. The product was separated by filtration and dried under vacuum at 50 °C to give 7.7 g of crystalline LNP023-HCl salt monohydrate (Form HB)

[0300] Example 2: Preparation of Form HB of LNP023 hydrochloride using a seed crystal

[0301] As described in Example 26d of WO 2015 / 009616, the Form A LNP023-HCl salt was obtained. 42 g of the Form A LNP023 hydrochloride salt was suspended in a mixture of 212 g of acetone and water (acetone: water = 80:20 m:m) and dissolved at about 50 °C. The solution was cooled to 25 °C and 0.4 g of crystalline LNP023-HCl salt monohydrate (Form HB) obtained according to Example 1 was added as a seed to initiate crystal growth. Then 207 g of acetone was added over 3 hours, followed by 414 g of ethyl acetate over 6 hours. The product was separated by filtration and dried under vacuum at 50 °C to give 36 g of crystalline LNP023-HCl salt monohydrate (Form HB).

[0302] Example 3: Engineered Form HB of LNP023 hydrochloride salt prepared using temperature cycling

[0303] As described in Example 26d of WO 2015 / 009616, the Form A LNP023-HCl salt was obtained. 80 g of the Form A LNP023 hydrochloride salt was suspended in a mixture of 409 g of acetone and water (acetone: water = 78:22 m:m) and dissolved at about 50 °C. The solution was cooled to 40 °C and 0.32 g of crystalline LNP023-HCl salt monohydrate (Form HB) obtained according to Example 1 was added as a seed to initiate crystal growth. Then temperature cycling was carried out 9 times by cooling to 10 °C and heating to 35 °C. Then 1090 g of ethyl acetate was added over 12 hours, followed by cooling to 5 °C. The product was separated by filtration and dried under vacuum at 50 °C to give 66 g of crystalline LNP023-HCl salt monohydrate (Form HB) containing columnar particles.

[0304] Example 4: Characterization of Form HB of LNP023 hydrochloride salt

[0305] The title compound has the same 1 1H NMR spectrum as Example 26d of WO 2015 / 009616.

[0306] Analysis examples and result interpretations:

[0307] Powder X-ray diffraction

[0308] Using a Cu-Kα with Bragg-Brentano geometry and a focusing mirror 1,2Powder X-ray diffraction (PXRD) was performed on a Bruker D8 Advance diffractometer with radiation (wavelength 0.15419 nm) and a solid-state PIXcel detector. The diffractogram was recorded at ambient conditions with a tube voltage of 30 to 40 kV, a tube current of 40 mA, a step size of 0.015 - 0.020° 2-θ (approximate step time of at least 40 s) in the angular range of 2° to 40° 2-θ. The typical accuracy of the 2-θ values is in the range of ±0.2° 2-θ, for example, ±0.1° 2-θ. Thus, on most X-ray diffractometers under standard conditions, the diffraction peak of Form HB of LNP023 hydrochloride, which appears at 9.2° 2-θ, can appear in the range of (9.2 - 0.2)° to (9.2 + 0.2)° 2-θ, for example, (9.2 - 0.1)° to (9.2 + 0.1)° 2-θ.

[0309] This article Figure 1 shows a representative diffractogram of Form HB of LNP023 hydrochloride. The

[0310] corresponding peak list is provided in Table 2.

[0311]

[0312] Table 1: PXRD peak positions and corresponding relative intensities of Form HB of LNP023 hydrochloride in the range of 2 to 40° 2-θ; the typical accuracy of the 2-θ values is in the range of ±0.2° 2-θ, for example, ±0.1° 2-θ.

[0313] Due to the particle morphology of Form HB, the relative intensities (as shown in Table 2) can undergo a certain degree of variation.

[0314] Fourier transform infrared spectroscopy

[0315] FTIR spectra were recorded using attenuated total reflection (ATR) technology with a Nicolet 6700 spectrometer having a resolution of 4 cm -1 at RT. The number of scans was 64 and the range was 650 to 4000 wavenumbers (cm -1 -1).

[0316] To record the spectra, the spatula tip of the sample was applied in powder form to the diamond surface. Then the sample was pressed onto the diamond with a sapphire anvil and the spectra were recorded. The spectrum of a clean diamond was used as the background spectrum. The typical accuracy of the wavenumber values is in the range of approximately ±2 cm -1 -1. Thus, on most infrared spectrometers under standard conditions, the infrared peak of Form HB of LNP023 hydrochloride at 3452 cm -1 described in this article can appear in the range of (3452 - 2) and (3452 + 2) cm -1between.

[0317] Figure 3 The representative FTIR spectrum of crystalline form HB described herein is shown in and a corresponding list of peaks, with typical precision of the wave numbers in the range of ±2 cm -1 is provided below.

[0318] 3452, 3274, 2933, 2875, 2732, 1709, 1692, 1658, 1615, 1601, 1515, 1497, 1461, 1439, 1425, 1384, 1243, 1184, 1069, 767, 739 cm -1 .

[0319] Differential scanning calorimetry

[0320] DSC was performed on a TA Discovery DSC 2500 instrument. The sample (2.7 mg) was heated from 30 °C to 300 °C at a rate of 10 °K / min in a Tzero aluminum pan with a perforated aluminum lid. Nitrogen (purge rate of 50 mL / min) was used as the purge gas.

[0321] The following Figure 4 shows a representative DSC curve, and it shows a broad endothermic event that ends at about 170 °C when measured at a heating rate of 10 K / min, followed by exothermic decomposition at about 200 °C. More precisely, the endothermic event is in the range of 35 °C to 170 °C.

[0322] Thermogravimetric analysis

[0323] TGA was performed on a Mettler Toledo DSC / TGA 1 instrument. The sample (10 to 20 mg) was heated from 30 °C to 300 °C at a rate of 20 K / min in a 100-μL aluminum pan (sealed with an aluminum lid). The lid was automatically pierced at the start of the measurement. Nitrogen (purge rate of 50 mL / min) was used as the purge gas.

[0324] The following Figure 5 shows a representative TGA curve, and it shows a step from about 30 °C to 220 °C, which is due to water loss (dehydration) and residual solvents. The mass during the step was determined to be about 4.1%. The water content of the sample was determined to be 3.7% by Coulometric Karl-Fischer titration, which is equivalent to 0.98 moles of water / mole of LNP023 HCl. The moisture determination was performed on a Metrohm 831KF coulometer connected to a 774 oven sample processor, which was heated to 160 °C for the measurement.

[0325] Dynamic Vapor Sorption

[0326] The dynamic vapor sorption isotherm was recorded using a DVS Advantage instrument. The measurement cycle started at 40% ambient relative humidity (RH). Then the RH was decreased to 0% in 10% steps. After that, in the adsorption cycle, the RH was increased from 0% to 90% in 10% steps, and from 90% to 95% in 5% steps, and subsequently in the desorption cycle, it was decreased to 0% in 10% and 5% steps respectively. Finally, the RH was increased to 40% ambient relative humidity in 10% steps. The time / step was set to a minimum of 3 hours and a maximum of 6 hours. If the equilibrium condition (constant mass change of 0.002% / min for at least 5 min) was reached before the longest time for all samples examined, the sequential humidity steps were applied before 6 hours, the longest time. If the equilibrium was not reached, the continuous humidity steps were applied after 6 hours, the longest time. The temperature was 25 °C ± 1.0 °C.

[0327] Figure 6 The equilibrium mass change of Form HB of LNP023 hydrochloride (δm weight % - reference weight at 0% RH on the y-axis) is shown during the adsorption cycle (marked with triangles) from 0% to 95% RH and during the desorption cycle (marked with squares) from 95% to 0% RH (on the x-axis). The mass difference between 40% and 95% RH is less than 0.2 weight %, and no significant hysteresis was observed between the adsorption and desorption curves. Thus, Form HB of LNP023 hydrochloride described herein can be designated as non-hygroscopic. The PXRD of Form HB of LNP023 hydrochloride remained unchanged after the experiment.

[0328] Electron Microscopy

[0329] Electron micrographs were taken using an SE detector on a Gemini SE 300 (Zeiss) microscope. As Figure 7a and 7b can be seen, Form HB of LNP023 hydrochloride obtained using engineered crystallization techniques (e.g., as shown in Example 3) contains columnar and equiaxed particles, which explains the excellent flow properties of the powder.

[0330] Example 5: Preparation of a Pharmaceutical Composition

[0331] The Form HB particles obtained as in Example 3 were transferred to a Hosokawa Alpine 100UPZ needle mill from Augsburg / Germany. The particles were milled at a rpm rotor speed and a feed rate of 15 kg / h.

[0332] Aliquots of the granules obtained by filling in an amount of 50, 100 or 200 mg, each filled into size 0 hard gelatin capsules.

[0333] 1. A crystalline hydrate form of LNP023 hydrochloride having the following formula (A)

[0334]

[0335] Characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (9.2 ± 0.2)° and (19.1 ± 0.2)°. 1,2 When measured with Cu-Kα radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 °C to 30 °C, it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (9.2 ± 0.2)° and (19.1 ± 0.2)°.

[0336] 2. The crystalline hydrate form according to claim 1, characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern that includes one or two peaks at 2-θ angles of (6.8 ± 0.2)° or (24.6 ± 0.2)°. 1,2 When measured with Cu-Kα radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 °C to 30 °C, it has a powder X-ray diffraction pattern that includes one or two peaks at 2-θ angles of (6.8 ± 0.2)° or (24.6 ± 0.2)°.

[0337] 3. The crystalline hydrate form according to claim 1 or 2, characterized in that when measured at a temperature in the range of 20 °C to 30 °C with a diamond ATR cell, it has a Fourier transform infrared spectrum that includes peaks at wavenumbers of (3452 ± 2) cm -1 、(2875 ± 2) cm -1 、(1692 ± 2) cm -1 、(1439 ± 2) cm -1 and (1243 ± 2) cm -1 .

[0338] 4. The crystalline hydrate form according to any one of the preceding claims, characterized in that when measured at a heating rate of 10 K / min, it has a differential scanning calorimetry curve that includes an endothermic event in the range of 35 °C to 170 °C.

[0339] 5. The crystalline hydrate form according to any one of the preceding claims, characterized in that when heated from 30 °C to 300 °C at a rate of 20 K / min, it has a thermogravimetric analysis curve that shows a mass loss of not more than 4.5 w-% based on the weight of the crystalline form at a temperature of 200 °C to 220 °C.

[0340] 6. The crystalline hydrate form according to any one of the foregoing aspects, characterized in that when measured by dynamic vapor sorption at a relative humidity in the range of 0 to 95% and at a temperature of (25 ± 1.0) °C, it shows a mass change of not more than 4.5 w-% based on the weight of the crystalline form at 0% RH.

[0341] 7. The crystalline hydrate form according to any one of the foregoing aspects, wherein the hydrate form is a monohydrate.

[0342] 8. The crystalline hydrate form according to any one of the foregoing aspects, which has a substantially equidimensional or columnar crystal habit, for example, substantially equidimensional in shape.

[0343] 9. A composition comprising the crystalline hydrate form according to any one of the foregoing aspects, wherein the composition comprises any other physical form of LNP023 hydrochloride at most 20 wt%, 10 wt%, 5 wt%, 2 wt% or 1 wt% based on the weight of the composition.

[0344] 10. The composition according to aspect 9, wherein the other physical form of LNP023 hydrochloride is Form A, characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising peaks at 2-θ angles of (11.6 ± 0.1) °, (15.3 ± 0.1) °, (16.5 ± 0.1) °, (20.1 ± 0.1) ° and (23.3 ± 0.1) °.

[0345] 11. Use of the crystalline hydrate form according to any one of aspects 1 to 8 or the composition according to aspect 9 or 10 for the preparation of a pharmaceutical composition.

[0346] 12. A pharmaceutical composition comprising the crystalline hydrate form according to any one of aspects 1 to 8, or the composition according to aspect 9 or 10, and optionally at least one pharmaceutically acceptable excipient.

[0347] 13. The pharmaceutical composition according to aspect 12, which is an oral solid dosage form, for example, a capsule.

[0348] 14. The pharmaceutical composition according to aspect 12 or 13, which comprises a crystalline hydrate form having an aspect ratio between about 0.4 and about 0.7.

[0349] 15. The pharmaceutical composition according to any one of aspects 12 to 14, which comprises a crystalline hydrate form having a particle size distribution X 50 in the range of about 10 to about 70 μm.

[0350] 16. The pharmaceutical composition according to any one of aspects 12 to 15, which comprises a crystalline hydrate form having a bulk (15 kPa) volume density of from about 0.50 to about 0.65 g / ml.

[0351] 17. The pharmaceutical composition according to any one of aspects 12 to 16, wherein the composition comprises up to about 200 mg of LNP023 hydrochloride, calculated as the anhydrous LNP023 free base.

[0352] 18. The pharmaceutical composition according to aspect 17, wherein the composition comprises from about 10 mg to about 200 mg of LNP023 hydrochloride, calculated as the anhydrous LNP023 free base.

[0353] 19. The pharmaceutical composition according to aspect 17, wherein the composition comprises from about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg of LNP023 hydrochloride, each calculated as the anhydrous LNP023 free base.

[0354] 20. The pharmaceutical composition according to aspect 17, wherein the composition comprises 10 mg, 25 mg, 50 mg, 100 mg or 200 mg of LNP023 hydrochloride, each calculated as the anhydrous LNP023 free base.

[0355] 21. The crystalline hydrate form according to any one of aspects 1 to 8, the composition according to aspect 9 or 10, or the pharmaceutical composition according to any one of aspects 12 to 20, for use as a medicament.

[0356] 22. The crystalline hydrate form according to any one of Aspects 1 to 8, the composition according to Aspects 9 or 10, or the pharmaceutical composition according to any one of Aspects 12 to 20, for treating or preventing a disease or disorder selected from the following: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nerve disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin 2-induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust diseases, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, asthma, arthritis, autoimmune heart diseases, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, Barraquer-Simons Syndrome, hemodialysis, antineutrophil cytoplasmic antibody vasculitis (anca vasculitis), cryoglobulinemia, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, central nervous system diseases such as Alzheimer's disease and other neurodegenerative disorders, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, dense deposit disease, vesicular skin disease, ocular cicatricial pemphigoid, and MPGN II.,

[0357] 23. A process for preparing a crystalline hydrate form according to any one of Schemes 1 to 8 or a composition according to Scheme 9 or 10, the process comprising:

[0358] (i) providing LNP023 hydrochloride in solid form;

[0359] (ii) suspending the LNP023 hydrochloride provided in step (i) in a first solvent comprising acetone and water and heating to dissolve the solid, thereby providing a solution;

[0360] (iii) cooling the solution obtained in step (ii) and adding a second solvent comprising acetone, ethyl acetate or a combination thereof to provide crystals in the mother liquor;

[0361] (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor;

[0362] (v) optionally washing the separated crystals obtained in step (iv); and

[0363] (vi) drying the crystals obtained in step (iv) or (v).

[0364] 24. The process according to Scheme 23, the process comprising as in step (iii)

[0365] (a) cooling the solution obtained in step (ii), and then reheating the solution again;

[0366] (b) repeating step (a) at least 3 times; and

[0367] (c) adding a second solvent comprising acetone, ethyl acetate or a combination thereof.

[0368] 25. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a crystalline hydrate form according to any one of Schemes 1 to 8, a composition according to Scheme 9 or 10, or a pharmaceutical composition according to any one of Schemes 12 to 20.

[0369] 26. The method according to embodiment 25, wherein the disease or disorder is selected from: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin 2-induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, post-pump syndrome in balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust diseases, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, asthma, arthritis, autoimmune heart diseases, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, Barraquer-Simons syndrome, hemodialysis, antineutrophil cytoplasmic antibody vasculitis, cryoglobulinemia, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, central nervous system diseases such as Alzheimer's disease and other neurodegenerative disorders, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, dense deposit disease, vesicular skin diseases, ocular cicatricial pemphigoid and MPGN II.

[0370] 27. A process for preparing a pharmaceutical composition comprising the crystalline hydrate form according to any one of embodiments 1 to 8 or the composition according to embodiment 9 or 10.

[0371] 28. The method according to embodiment 26, wherein the disease or disorder is selected from: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy) such as idiopathic MN (iMN), and aHUS (atypical hemolytic uremic syndrome).

[0372] 29. The method according to embodiment 28, wherein the crystalline hydrate form of LNP023 is administered to the subject at a daily dose of up to about 400 mg, calculated as anhydrous LNP023 free base.

[0373] 30. The method according to embodiment 28, wherein the crystalline hydrate form of LNP023 is administered to the subject at a daily dose of from about 10 mg to about 400 mg, calculated as anhydrous LNP023 free base.

[0374] 31. The method according to embodiment 28, wherein the crystalline hydrate form of LNP023 is administered to the subject at a daily dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, each calculated as anhydrous LNP023 free base.

[0375] 32. The method according to embodiment 28, wherein the crystalline hydrate form of LNP023 is administered to the subject at a daily dose of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg, each calculated as anhydrous LNP023 free base.

[0376] 33. The method according to any one of embodiments 28 to 32, wherein the crystalline hydrate form of LNP023 is administered to the subject twice daily (b.i.d.), for example, orally.

Claims

1. The crystalline monohydrate form of the compound of formula (A), Characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (9.2 ± 0.2)°, and (19.1 ± 0.2)°.

2. The crystalline monohydrate form according to claim 1, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes one or two peaks at 2-θ angles of (6.8 ± 0.2)° or (24.6 ± 0.2)°.

3. The crystalline monohydrate form according to claim 1 or 2, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes at least five peaks at 2-θ angles selected from (4.6 ± 0.2°), (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)°, (24.6 ± 0.2)° and (28.0 ± 0.2)°.

4. The crystalline monohydrate form according to claim 3, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (19.1 ± 0.2)° and (24.6 ± 0.2)°.

5. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes one or two peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)° and (24.6 ± 0.2)° and at least one additional peak selected from (10.0 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)° and (28.0 ± 0.2)°.

6. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)° and (24.6 ± 0.2)°.

7. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

8. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

9. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

10. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

11. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

12. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)° and (24.6 ± 0.2)°.

13. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (24.0 ± 0.2)° and (24.6 ± 0.2)°.

14. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-theta angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)°, and (24.6 ± 0.2)°.

15. The crystalline monohydrate form according to any one of the preceding claims, characterized in that When measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα radiation having a wavelength of 0.15419 nm 1,2 it has a powder X-ray diffraction pattern that includes peaks at 2-θ angles of (4.6 ± 0.2)°, (6.8 ± 0.2)°, (9.2 ± 0.2)°, (10.0 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, (15.3 ± 0.2)°, (16.6 ± 0.2)°, (17.2 ± 0.2)°, (19.1 ± 0.2)°, (20.7 ± 0.2)°, (21.3 ± 0.2)°, (22.2 ± 0.2)°, (24.0 ± 0.2)°, (24.6 ± 0.2)° and (28.0 ± 0.2)°.

16. The crystalline monohydrate form according to any one of the preceding claims, wherein When measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has a Fourier transform infrared spectrum that includes peaks at wave numbers of (3452 ± 2) cm -1 , (2875 ± 2) cm -1 , (1692 ± 2) cm -1 , (1439 ± 2) cm -1 and (1243 ± 2) cm -1 .

17. The crystalline monohydrate form according to claim 16, characterized in that When measured with a diamond ATR cell at a temperature in the range of 20 °C to 30 °C, it has a Fourier transform infrared spectrum that includes peaks at wave numbers of (3452 ± 4) cm -1 , (3274 ± 4) cm -1 , (2933 ± 4) cm -1 , (2875 ± 4) cm -1 , (2732 ± 4) cm -1 , (1709 ± 4) cm -1 , (1692 ± 4) cm -1 , (1658 ± 4) cm -1 , (1615 ± 4) cm -1 , (1601 ± 4) cm -1 , (1515 ± 4) cm -1 , (1497 ± 4) cm -1 , (1461 ± 4) cm -1 , (1439 ± 4) cm -1 , (1425 ± 4) cm -1 , (1384 ± 4) cm -1 , (1243 ± 4) cm -1 , (1184 ± 4) cm -1 , (1069 ± 4) cm -1 , (767 ± 4) cm -1 and (739 ± 4) cm -1 .

18. The crystalline monohydrate form according to any one of the preceding claims, characterized in that which has a differential scanning calorimetry curve comprising an endothermic event in the range of 35 °C to 170 °C when measured at a heating rate of 10 K / min.

19. The crystalline monohydrate form according to any one of the preceding claims, characterized in that which has a thermogravimetric analysis curve showing a mass loss of no more than 4.5 w-% based on the weight of the crystalline hydrate form at a temperature of 200 °C to 220 °C when heated from 30 °C to 300 °C at a rate of 20 K / min. The crystalline monohydrate form according to any one of the preceding claims, characterized in that which shows a mass change of no more than 4.5 w-% based on the weight of the crystalline hydrate form at 0% RH when measured by dynamic vapor sorption at relative humidities in the range of 0 to 95% and at a temperature of (25 ± 1.0) °C.

21. The crystalline monohydrate form according to any one of the preceding claims, which has a crystal habit that is substantially equidimensional in shape.

22. The crystalline monohydrate form according to any one of the preceding claims, which has a crystal habit that is columnar in morphology.

23. The crystalline monohydrate form according to any one of the preceding claims, wherein the crystalline monohydrate form of the compound of formula (A) has a purity of a specific solid form of LNP023 hydrochloride greater than 90 w-% based on the weight of the compound, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 w-%, and also including equal to about 100 w-%.

24. The crystalline monohydrate form according to any one of the preceding claims, wherein the equidimensional-shaped particles of the crystalline monohydrate form have an aspect ratio (a50) higher than about 0.4, higher than about 0.45, from about 0.4 to about 0.7, or from about 0.45 to 0.

6.

25. The crystalline monohydrate form according to any one of the preceding claims, wherein the particle size distribution X of the equidimensional shaped particles of the crystalline monohydrate form 90 is less than about 300 μm, such as less than about 200 μm, less than about 150 μm, about 30 to about 150 μm, about 35 to about 130 μm, or about 40 to about 105 μm.

26. The crystalline monohydrate form according to any one of the preceding claims, wherein the particle size distribution X of the equidimensional shaped particles of the crystalline monohydrate form 50 is from about 5 to about 100 μm, from about 10 to about 70 μm, or from about 15 to about 55 μm.

27. The crystalline monohydrate form according to any one of the preceding claims, wherein the particle size distribution X of the equidimensional shaped particles of the crystalline monohydrate form 10 is from about 0.1 to about 50 μm, from about 1 to about 30 μm, or from about 2 to about 20 μm.

28. The crystalline monohydrate form according to any one of the preceding claims, wherein the equidimensional-shaped particles of the crystalline monohydrate form have a tapped (15 kPa) bulk density less than about 0.8 g / ml, less than about 0.7 g / ml, from about 0.4 to about 0.7 g / ml, from about 0.50 to about 0.65 g / ml, or from about 0.55 to about 0.60 g / ml.

29. A composition comprising the crystalline monohydrate form according to any one of the preceding claims, wherein the composition comprises up to 20 wt% of the compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 28 based on the weight of the composition.

30. The composition according to claim 29, wherein the composition comprises up to 10 wt% of the compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 28 based on the weight of the composition.

31. The composition according to claim 29, wherein the composition comprises up to 5 wt% of the compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 28 based on the weight of the composition.

32. The composition according to claim 29, wherein the composition comprises, based on the weight of the composition, at most 2% by weight of the compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 28.

33. The composition according to claim 29, wherein the composition comprises, based on the weight of the composition, at most 1% by weight of the compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 28.

34. The composition according to any one of claims 29 to 33, wherein the other physical form of the compound of formula (A) is characterized in that when measured at a temperature in the range of 20 °C to 30 °C with Cu-Kα 1,2 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising peaks at 2-θ angles of (11.6 ± 0.1)°, (15.3 ± 0.1)°, (16.5 ± 0.1)°, (20.1 ± 0.1)° and (23.3 ± 0.1)°.

35. Use of the crystalline monohydrate form according to any one of claims 1 to 28 or the composition according to any one of claims 30 to 34 for the preparation of a pharmaceutical composition.

36. A pharmaceutical composition comprising the crystalline monohydrate form according to any one of claims 1 to 28 or the composition according to any one of claims 30 to 34, and at least one pharmaceutically acceptable excipient.

37. The pharmaceutical composition according to claim 36, which is an oral solid dosage form.

38. The pharmaceutical composition according to claim 36, which is a capsule.

39. The pharmaceutical composition according to any one of claims 36 to 38, which comprises the crystalline monohydrate form having an aspect ratio between about 0.4 and about 0.

7.

40. The pharmaceutical composition according to any one of claims 36 to 39, which comprises the crystalline monohydrate form having a particle size distribution X of from about 10 to about 70 μm 50 thereof.

41. The pharmaceutical composition according to any one of claims 36 to 40, which comprises the crystalline monohydrate form having a compacted (15 kPa) bulk density of about 0.50 to about 0.65 g / ml.

42. The pharmaceutical composition according to any one of claims 36 to 41, wherein the composition comprises, calculated as the anhydrous free base of the compound of formula (A), a dose of the compound of formula (A) not exceeding about 200 mg.

43. The pharmaceutical composition according to claim 42, wherein the composition comprises, calculated as the anhydrous free base of the compound of formula (A), a dose of the compound of formula (A) from about 10 mg to about 200 mg.

44. The pharmaceutical composition according to claim 42, wherein the composition comprises, each calculated as the anhydrous free base of the compound of formula (A), a dose of the compound of formula (A) of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg.

45. The pharmaceutical composition according to claim 42, wherein the composition comprises, each calculated as the anhydrous free base of the compound of formula (A), a dose of the compound of formula (A) of 10 mg, 25 mg, 50 mg, 100 mg or 200 mg.

46. The pharmaceutical composition according to any one of claims 29 - 45, wherein the pharmaceutical composition comprises, based on the weight of the composition, at most 20 w-% (weight percentage), at most 15 w-%, at most 10 w-%, at most 9 w-%, at most 8 w-%, at most 7 w-%, at most 6 w-%, at most 5 w-%, at most 4 w-%, at most 3 w-%, at most 2 w-%, at most 1 w-%, at most 0.5 w-%, or at most 0.1 w-%, or any weight percentage between 80 and 100 w-% of any other solid form of formula (A).

47. Use of the crystalline monohydrate form according to any one of claims 1 to 28, the composition according to any one of claims 29 to 35, or the pharmaceutical composition according to any one of claims 36 to 46 in the manufacture of a medicament.

48. Use of the crystalline monohydrate form according to any one of claims 1 to 28, the composition according to any one of claims 29 to 35, or the pharmaceutical composition according to any one of claims 36 to 46 in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder selected from the group consisting of: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, Guillain-Barré syndrome, traumatic brain injury, hemodialysis complications, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, mesenteric artery reperfusion after aortic reconstruction, sepsis, immune complex disorders, systemic lupus erythematosus (SLE) nephritis, hemolytic anemia, myasthenia gravis, pauci-immune vasculitis, antiphospholipid syndrome, glomerulonephritis, antineutrophil cytoplasmic antibody vasculitis (ANCA vasculitis), cryoglobulinemia, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, dense deposit disease, and MPGN II.

49. A process for preparing the crystalline monohydrate form according to any one of claims 1 to 28 or the composition according to any one of claims 29 to 35, the process comprising: (i) providing a compound of formula (A) in solid form; (ii) suspending the compound of formula (A) provided in step (i) in a first solvent comprising acetone and water and heating to dissolve the solid form, thereby providing a solution; (iii) cooling the solution obtained in step (ii) and adding a second solvent comprising acetone, ethyl acetate, or a combination thereof to provide crystals in the mother liquor; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor to provide separated crystals; (v) optionally washing the separated crystals obtained in step (iv); and (vi) drying the separated crystals obtained in step (iv) or (v).

50. The process according to claim 49, the process comprising the following steps as step (iii) (a) cooling the solution obtained in step (ii), and subsequently reheating the solution again; (b) repeating step (a) at least 3 times; and (c) adding a second solvent comprising acetone, ethyl acetate, or a combination thereof.

51. Use of the crystalline monohydrate form according to any one of claims 1 to 28, the composition according to any one of claims 29 to 35, or the pharmaceutical composition according to any one of claims 36 to 46 in the manufacture of a medicament for treating or preventing a disease or disorder selected from the following in a subject: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, Guillain-Barré syndrome, traumatic brain injury, hemodialysis complications, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, mesenteric artery reperfusion after aortic reconstruction, sepsis, immune complex disorders, systemic lupus erythematosus (SLE) nephritis, hemolytic anemia, myasthenia gravis, pauci-immune vasculitis, antiphospholipid syndrome, glomerulonephritis, antineutrophil cytoplasmic antibody vasculitis (anca vasculitis), cryoglobulinemia, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, dense deposit disease, and MPGN II.

52. Use according to claim 51, wherein the medicament is for treating or preventing a disease or disorder selected from the following: paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, myasthenia gravis, antineutrophil cytoplasmic antibody vasculitis (anca vasculitis), MPGN II, and aHUS (atypical hemolytic uremic syndrome).

53. Use according to claim 51, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject at a daily dose of up to about 400 mg, calculated as the anhydrous free base of the compound of formula (A).

54. Use according to claim 51, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject at a daily dose of about 10 mg to about 400 mg, calculated as the anhydrous free base of the compound of formula (A).

55. Use according to claim 51, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject at a daily dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, each calculated as the anhydrous free base of the compound of formula (A).

56. Use according to claim 51, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject at a daily dose of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg, each calculated as the anhydrous free base of the compound of formula (A).

57. Use according to any one of claims 51 to 56, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject twice daily (b.i.d.).

58. Use according to any one of claims 51 to 57, wherein the crystalline monohydrate form of the compound of formula (A) is administered to the subject twice daily (b.i.d.) at a daily dose of 200 mg calculated as the anhydrous free base of the compound of formula (A).

59. A process for preparing a composition comprising the crystalline monohydrate form according to any one of claims 1 to 28, or the composition according to claims 29 to 35, said process comprising: (i) providing a compound of formula (A) in solid form; (ii) suspending the compound of formula (A) provided in step (i) in a first solvent comprising acetone and water and heating to dissolve the solid form, thereby providing a solution; (iii) cooling the solution obtained in step (ii) and adding a second solvent comprising acetone, ethyl acetate or a combination thereof to provide crystals in the mother liquor; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor to provide separated crystals; (v) optionally washing the separated crystals obtained in step (iv); and (vi) drying the separated crystals obtained in step (iv) or (v).

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