Crystalline form of LNP023

Abstract

The present invention describes a crystalline hydrate form of LNP023 hydrochloride and a process for preparing the same. In addition, the present invention describes a pharmaceutical composition comprising a crystalline hydrate form of LNP023 hydrochloride and at least one pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be used to treat diseases and disorders mediated by complement activation.

Description

Technical Field

[0001] Crystalline forms of LNP023 hydrochloride and processes for preparing the same are described herein. Pharmaceutical compositions comprising the crystalline forms of LNP023 hydrochloride and at least one pharmaceutically acceptable excipient are also described herein. The pharmaceutical compositions described herein can be used to treat diseases or disorders mediated by complement activation. Background Art

[0002] LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the expansion of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 is currently under 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 a chemical structure according to the following formula (A)

[0003]

[0004] 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 is obtained as a crystalline solid by recrystallizing the obtained amorphous material and is characterized by X-ray powder diffraction. This crystalline form is referred to herein as Form A.

[0005] Different solid forms of active pharmaceutical ingredients generally have different properties. The differences in the physicochemical properties of the solid forms can play a key role in the improvement of pharmaceutical compositions, for example, due to the improvement of the solid forms of active pharmaceutical ingredients, pharmaceutical formulations with improved dissolution profiles or improved stability or shelf life can become readily available. Moreover, the processing or handling of active pharmaceutical ingredients during preparation and manufacturing can be improved. Therefore, new solid forms of active pharmaceutical ingredients can have desired processing characteristics. Compared with previously known solid forms, they are easier to handle, more suitable for storage, or allow better purification.

[0006] 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, there is a need for a more stable form of LNP023 HCl.

[0007] Therefore, there is a need to provide a solid-state form of LNP023 hydrochloride having physicochemical properties that allow for the reliable production of safe and efficacious drug products comprising LNP023 hydrochloride. Summary of the invention

[0008] The present disclosure provides a crystalline hydrate form of LNP023 hydrochloride, which is also referred to hereinafter as “Form HB.” “Form HB” of LNP023 hydrochloride has favorable physicochemical properties for a drug substance intended for oral solid dosage forms.

[0009] The favorable properties of Form HB of LNP023 include chemical stability, physical stability, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, compactability and wettability. Therefore, these properties make Form HB suitable for large-scale manufacturing processes.

[0010] In one embodiment, Form HB is a phase-pure, highly crystalline form of LNP023 hydrochloride that is physically and chemically stable during drug processing and storage. Form HB is a more thermodynamically stable form and can minimize the possibility of conversion to other forms. Form A can be converted to Form HB under certain conditions. The use of a thermodynamically stable form of a compound is highly appreciated because when the most stable form is used, conversion or polymorphic conversion from, for example, Form A to Form HB that may occur during the manufacturing process and storage of the drug substance can be excluded. This ensures reliable bioavailability and, therefore, consistent efficacy of the drug product.

[0011] abbreviation

[0012] PXRD Powder X-ray Diffraction

[0013] SXRD Single Crystal X-ray Diffraction

[0014] FTIR Fourier Transform Infrared

[0015] ATR Attenuated Total Reflection

[0016] DSC Differential Scanning Calorimetry

[0017] DVS Dynamic Vapor Sorption

[0018] TGA Thermogravimetric Analysis

[0019] MS mass spectrometry

[0020] NMR Nuclear Magnetic Resonance

[0021] GC Gas chromatography

[0022] KF Karl Fischer

[0023] RH Relative humidity

[0024] RT Room temperature

[0025] w-% weight percentage

[0026] vol-% Volume percentage

[0027] definition

[0028] In the context of this disclosure, the following definitions have the indicated meanings unless expressly stated otherwise:

[0029] As used herein, the term "room temperature" refers to a temperature in the range of 20°C to 30°C.

[0030] As used herein, the term "measured at a temperature in the range of 20°C to 30°C" refers to 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 may mean a temperature of about 22°C.

[0031] As used herein, when describing a solid form of LNP023 hydrochloride, the term "Form HB" refers to a specific crystalline hydrate form of LNP023 hydrochloride, for example, a monohydrate form. This form is further defined herein and in the claims.

[0032] As used herein, when describing a 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 being crystalline when subjected to a temperature in the range of 20°C to 30°C with a Cu-Kα wavelength of 0.15419 nm. 1,2 When measured by radiation, 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)°.

[0033] Form A was prepared according to WO 2015 / 009616 as follows (see Example 26d):

[0034] 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 5M aqueous HCl (500 μL, 2.500 mmol). The reaction mixture was then lyophilized to provide 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 approximately 5 h to provide 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 H NMR (HCl salt, 400MHz, CD3OD) δ10.73(br.s.,1H),8.23(d,J=8.44Hz,2H),7.74(d,J=8.44Hz ,2H),7.31-7.36(m,1H),6.77(s,1H),6.37(dd,J=1.77,3.12Hz,1H),4.33(d,J=12.72Hz ,1H),4.25(d,J=12.72Hz,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=6.97Hz,3H).

[0035] The X-ray powder diffraction pattern is described in Table 1 below.

[0036] Table 1

[0037]

[0038]

[0039] As used herein, the term "reflection" with respect to powder X-ray diffraction means a peak in an X-ray diffraction pattern which, at certain diffraction angles (Bragg angles), is caused by constructive interference of X-rays scattered by parallel planes of atoms in a solid material which is distributed in a sequential and repeating pattern in a long-range positional order. Such solid materials are classified as crystalline materials, while amorphous materials are defined as solid materials which lack long-range order and only show short-range order, thus resulting in broad scattering. According to the literature, long-range order, for example, extends over about 100 to 1000 atoms, while short-range order only exceeds 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, p. 3).

[0040] The term "substantially the same" with respect to powder X-ray diffraction means taking into account the variability of the peak positions and the relative intensities of the peaks. For example, the typical accuracy of 2-θ values ​​is within the range of ± 0.2 ° 2-θ, for example, within the range of ± 0.1 ° 2-θ. Therefore, on most X-ray diffractometers under standard conditions, the peak that usually appears at 9.2 ° 2-θ may appear, for example, 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, it will be understood by those skilled in the art that the relative peak intensity will show the variability between devices and the variability caused by other factors known to those skilled in the art, such as crystallinity, preferred orientation, particle size, sample preparation, and others, and should only be taken as a qualitative measurement.

[0041] The term "substantially the same" with respect to infrared spectroscopy means that the variability in the peak positions and the relative intensities of the peaks are taken into account. For example, the typical accuracy of the wavenumber values ​​is ±4 cm -1 within the range, for example, within ±2cm -1 Therefore, on most infrared spectrometers under standard conditions, 1692cm -1 The peaks at, for example, can appear at (1692-4) cm and (1692+4) cm -1 Between, for example, (1692-2) and (1692+2) cm -1 The peak intensity can be derived from the accompanying drawings, but those skilled in the art will understand that differences in peak intensity due to crystallinity, sample preparation, measurement method and other factors may also appear in infrared spectroscopy. Therefore, the peak intensity should only be used as a qualitative measurement.

[0042] Form HB of LNP023 hydrochloride described herein may be referred to herein as being characterized by graphical data "as shown in the accompanying drawings". Such data include, for example, powder X-ray diffraction and FTIR. It is understood by those skilled in the art that when presented in graphical form, factors such as changes in instrument type, responses and changes in sample orientation, sample concentration, and sample purity may cause slight changes in such data, such as changes related to precise peak positions and intensities. However, the comparison of the graphical data in the accompanying drawings herein with the graphical data generated for another or unknown solid form and the confirmation that the two sets of graphical data relate to the same crystalline form are completely within the knowledge of those skilled in the art.

[0043]

[0046] The terms "solid form" or "solid state form" as 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 not crystalline. An amorphous compound has no long-range order and does not display a definitive X-ray diffraction pattern with peaks.

[0045] As used herein, the term "polymorph" refers to crystalline forms having the same chemical composition but differing in the spatial arrangement of the molecules, atoms, or ions forming the crystals.

[0046] As used herein, the term "eutectic material" refers to a crystalline material comprising two or more different molecules or ionic compounds in the same crystal lattice, the two or more different molecules or ionic compounds being bound by non-ionic and non-covalent bonds, wherein at least two of the individual molecules or ionic compounds are solid at room temperature.

[0047] As used herein, the term "hydrate" refers to a crystalline solid in which water is incorporated into or contained in the crystal structure (e.g., as part of the crystal structure) or trapped in the crystal (water inclusions). Therefore, water can be present in a stoichiometric amount or a non-stoichiometric amount. When water is present in a stoichiometric amount, a hydrate can be referred to by adding a Greek numeral prefix. For example, depending on the stoichiometry of the water / compound, a hydrate may be referred to as a hemihydrate or as 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 contained in a crystal structure (e.g., as part of a crystal structure) or trapped in a crystal (solvent inclusion). Therefore, one or more organic solvents can be present in a stoichiometric amount or a non-stoichiometric amount. When one or more organic solvents are present in one or more stoichiometric amounts, solvates can be referred to by adding Greek numeral prefixes. For example, depending on the stoichiometry of one or more solvents / compounds, solvates can be referred to as hemisolvates or monosolvates. Solvent content can be measured, for example, by GC, NMR, SXRD or TGA / MS.

[0050] As used herein, the term "isostructural solvate" refers to a solvate having the same space group (with only a small unit cell size distortion) and a molecular network of the same type of host molecules. Isostructural solvates as defined herein differ in the type of organic solvent(s) present as one or more guest molecules.

[0051] The term "desolvating" or "desolvation" as used herein describes the at least partial removal of an organic solvent from the crystal structure of a host molecule.

[0052] The term "anhydrous form" or "anhydrate" as used herein refers to a crystalline solid in which no water is incorporated into or contained in the crystal structure. The anhydrous form may 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-%, e.g., no more than 1.0 w-% water, based on the weight of the crystalline form.

[0053] When referring to crystalline solids, the term "non-solvated" as used herein refers to a crystalline solid in which no organic solvent is incorporated into or accommodated by the crystal structure. The non-solvated form may still contain residual organic solvent that is not part of the crystal structure but may be adsorbed on the surface of the crystal or absorbed into the disordered regions of the crystal. In one embodiment, the non-solvated form contains no more than 3.0 w-%, e.g., no more than 1.0 w-%. In one embodiment, the non-solvated 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 the 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, a "predetermined amount" with respect to LNP023 HCl refers to the initial amount of LNP023 HCl used to prepare a pharmaceutical composition having a desired dosage strength of LNP023 HCl.

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

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

[0059] As used herein, the term "bisected" with respect to crystal shape refers to crystals of equal dimensions, such as cubes or spheres.

[0060] As used herein, the term "plate" or "plate-like" with respect to crystal shape refers to flat, plate-like crystals of similar width and breadth, which are thicker than flakes.

[0061] As used herein, the term "flake" or "flake-like" with respect to crystal shape refers to thin and flat crystals of similar width and breadth, which are thinner than a plate.

[0062] As used herein, the term "needle-like" or "needle-shaped" with respect to crystal shape refers to needle-like, thin, and highly elongated crystals having similar breadth and width.

[0063]

[0046] The terms "columnar" or "columnar" as used interchangeably herein with respect to crystal shape refer to elongated, prismatic crystals having greater breadth and thickness than needle-like crystals.

[0064] Such a definition of crystal habit is consistent with the definition commonly used in the art, see, for example, "Polymorphism in the Pharmaceutical Industry," edited by Rolf Hilfiker (WileyVCH, 2006); Chapter 7, Light Microscopy (Gary Nichols).

[0065] As used herein, the term "about" means approximately, within the range of, 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 numerical values ​​shown above. Generally speaking, the term "about" is used herein to modify a numerical value above and below the stated value by a 10% variation.

[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 includes at most 20 w-% (weight percent), 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 percent between 80 and 100 w-% of any other solid form of LNP023 hydrochloride, based on the weight of the composition.

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

[0068] As used herein, the term "subject" is intended to refer to a human. Exemplary human subjects include a human patient (referred to as a patient) having a disorder, such as a disorder described herein, or a normal subject.

[0069] As used herein, the term "physical stability" 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 specific free base or salt form will not change to 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 to 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 the specific compound changes to one or more different physical forms of the specific compound. In some embodiments, no detectable amount of the specific form of the compound changes to one or more different physical forms of the 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 the specific compound will not change to another compound (e.g., decompose). In some embodiments, when subjected to specific conditions, less than 25% of the form of the specific compound changes to 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 to one or more other compounds. In some embodiments, there is no detectable amount of the form of the specific compound changed to 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 show significant pharmacological activity at a given dose and is added to a pharmaceutical composition in addition to an active pharmaceutical ingredient. An excipient may act as a vehicle, diluent, release agent, disintegrant, dissolution modifier, absorption promoter, stabilizer, or manufacturing aid, etc. Excipients may include fillers (diluents), binders, disintegrants, lubricants, and glidants.

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

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

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

[0075] As used herein, the term "lubricant" refers to a substance added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. They aid in ejection of tablets from the die and can improve powder flowability.

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

[0077] Figure 1 : illustrates a representative PXRD of Form HB of the LNP023 hydrochloride salt 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 of detected photons / second).

[0078] Figure 2 : A comparison of a representative PXRD (bottom) of Form HB of the LNP023 hydrochloride described herein with a representative PXRD (top) of Form A of the LNP023 hydrochloride of WO 2015 / 009616 is illustrated. 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. Therefore, the y-axis is arbitrary and unlabeled.

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

[0080] Figure 4 : illustrates a representative DSC curve of Form HB of the hydrochloride salt of LNP023 described herein. The x-axis shows temperature in degrees Celsius (° C.) and the y-axis shows the heat flow rate in Watts / gram (W / g) as the endothermic peak rises.

[0081] Figure 5 : illustrates a representative TGA curve of Form HB of the LNP023 hydrochloride salt 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 : Representative DVS isotherms of Form HB of LNP023 hydrochloride described herein over a relative humidity range of 0 to 95%. The x-axis shows the relative humidity (in percentage (%)) measured at a temperature of (25.0 ± 1.0) °C, and the y-axis shows the equilibrium mass change (in weight percentage (w-%)) at 0% RH with respect to the sample weight. Adsorption cycles are marked with triangles, while desorption cycles are marked with squares.

[0083] Figure 7a and 7b : illustrates a scanning electron microscopy image of Form HB of the hydrochloride salt of LNP023 described herein when prepared according to Example 3 (scale bar overall size: 50 microns). DETAILED DESCRIPTION

[0084] Crystalline form

[0085] Examples of embodiments:

[0086] In one embodiment, the present invention is directed 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 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 of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, a Cu-Kα ion having a wavelength of 0.15419 nm is used. 1,2 When measured by radiometric method, PXRD peaks were identified at 2-θ angles of (4.6±0.2)°, (9.2±0.2)°, and (19.1±0.2)°.

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

[0093] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, a Cu-Kα ion having a wavelength of 0.15419 nm is used. 1,2 When measured by radiometric method, PXRD peaks were 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)°.

[0094] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measured by radiometric method, PXRD peaks were 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)°.

[0095] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 During the radiometric measurement, PXRD peaks were 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)°, (21.3±0.2)°, and (24.6±0.2)°.

[0096] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, a Cu-Kα ion having a wavelength of 0.15419 nm is used. 1,2 During the radiometric measurement, PXRD peaks were identified 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)°.

[0097] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 During the radiation measurement, PXRD peaks were 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)°.

[0098] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm,1,2 During the radiation measurement, PXRD peaks were 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 of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measured radiometrically, the crystalline form of LNP023 hydrochloride (Form HB) 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 of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 During the radiation measurement, PXRD peaks were 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 of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2During the radiation measurement, PXRD peaks were 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)°.

[0102] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 During the radiation measurement, PXRD peaks were 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)°.

[0103] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 During the radiation measurement, PXRD peaks were 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)°.

[0104] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2During the radiation measurement, PXRD peaks were 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)°.

[0105] In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measured by radiometric method, 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 multiple peak 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 is directed to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measured radiometrically, PXRD peaks were identified at the following 2-theta angles:

[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 of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2When measured by radiometric method, PXRD peaks identified at 2-θ angles of (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 Form HB described herein). Figure 2 ). For example, Form HB shows characteristic peaks at (4.6 ± 0.1) and (9.2 ± 0.1) ° 2-θ, while Form A shows no peaks in the same range. According to page 176 of WO 2015 / 009616, of the four most characteristic peaks of Form A, one is a peak at 11.6 ° 2-θ. In contrast, Form HB described herein does not show a peak in the same range.

[0123] In another embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measured by radiometric method, the PXRD pattern is as described in one of the above examples, but does not include a peak at a 2-theta angle of (11.6±0.2)°.

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

[0125] In another embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when subjected to a temperature in the range of 20°C to 30°C, using a Cu-Kα ion having a wavelength of 0.15419 nm, 1,2 When measuring radiation, the Figure 1 Essentially the same PXRD is shown in .

[0126] Due to the particle morphology of Form HB, the relative intensities of the peaks (e.g. Figure 1 The preferred orientation in the sample affects the intensity of the various peaks, so that some peaks are more intense and others are less intense than would be expected from a completely random sample.

[0127] Examples of FTIR embodiments:

[0128] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a peak at the following wavenumbers: (3452±4) cm -1 、(2875±4)cm -1 and (1692±4)cm -1 .

[0129] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) 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 comprising a peak at the following wavenumbers: (3452±4) cm -1 、(2875±4)cm -1 、(1692±4)cm -1 and (1439±4)cm -1 .

[0130] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -1 、(2875±4)cm -1 、(1692±4)cm -1 、(1439±4)cm -1 and (1243±4)cm -1 The peak of .

[0131] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -1 、(2875±4)cm -1、(1692±4)cm -1 、(1439±4)cm -1 、(1243±4)cm -1 and (767±4)cm -1 The peak at.

[0132] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) 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 comprising a peak at the following wavenumbers: (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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) 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 comprising a peak at the following wavenumbers: (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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) 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 comprising a peak at the following wavenumbers: (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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength 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 The peak at.

[0136] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak at.

[0137] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0138] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0139] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0140] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0141] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0142] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0143] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0144] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak of .

[0145] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wavelength of (3452±4) cm-1 at a temperature in the range of 20°C to 30°C as measured with a diamond ATR unit cell. -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 The peak at.

[0146] In one embodiment, the present invention is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wave number of (3452±4) cm-1 when measured with a diamond ATR cell at a temperature in the range of 20°C to 30°C. -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 and at least one peak 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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having a FTIR spectrum when measured with a diamond ATR cell at a temperature in the range of 20°C to 30°C comprising peaks at the following wavenumbers:

[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 and (767 ± 2) cm -1 ; or

[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 and (767 ± 2) cm -1 ; or

[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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized by having an FTIR spectrum comprising a wave number of (3452±2) cm-1 when measured with a diamond ATR cell at a temperature in the range of 20°C to 30°C. -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 peak 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 is directed to a crystalline form of LNP023 hydrochloride (Form HB) characterized in that it has the same molecular mass as described herein when measured with a diamond ATR unit cell at a temperature in the range of 20°C to 30°C. Figure 3 Essentially the same FTIR spectrum as shown in .

[0168] Examples of DSC embodiments:

[0169] In one embodiment, LNP023 hydrochloride (Form HB) can be obtained by having Figure 4In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized by having a DSC curve showing a broad endothermic event when measured at a heating rate of 10 K / min, which ends at about 170°C and is followed by an exothermic decomposition at about 200°C. In one embodiment, the broad endothermic event ending 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 prepared by Figure 5 In one embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that when heated from 30°C to 300°C at a rate of 20K / min, it has a TGA curve that shows a loss of no more than 4.5w-% due to water and residual solvents, and a mass loss of no more than 4.3w-%, such as no more than 4.0w-%, such as no more than 3.8w-%, such as no more than 3.4w-% at a temperature of about 220°C, such as at 200°C to 220°C, based on the weight of the crystalline form.

[0172] Examples of DVS implementations:

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

[0174] Examples of further embodiments:

[0175] In another embodiment, the present invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that it is 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 patterns

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

[0178] In one embodiment, the present invention relates to a crystalline form (Form HB) of LNP023 hydrochloride having a substantially equipartitioned or columnar crystal habit, e.g., substantially equipartitioned in shape. This results in preferred volume and flow characteristics, as opposed to small pinpoint (needle) or lath (blade) shaped crystals. Such preferred crystal shapes can be obtained by performing a process as described herein, e.g., when performing crystal engineering techniques, including temperature cycling, followed by grinding resulting in reduced particle size.

[0179] The resulting particles are characterized by a suitable aspect ratio. A (0<ψ A ≤1) The ratio of the minimum and maximum Feret diameters ψA = x 费雷特最小值 / x 费雷特最大值 Definition. It indicates the elongation of the particles, i.e., the smaller the value, the more the particles are elongated. Therefore, in other embodiments, the equally divided shaped particles of the crystalline form of LNP023 hydrochloride (Form HB) have an aspect ratio (a50) higher than about 0.4 (e.g., higher than about 0.45). In other embodiments, the equally divided 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 another embodiment, the particle size distribution of the aliquot-shaped particles of the crystalline form of LNP023 hydrochloride (Form HB) is X 90 Less than about 300 μm, such as less than about 200 μm, such as less than about 150 μm. In another embodiment, the particle size distribution X 90 From about 30 to about 150 μm, such as from about 35 to about 130 μm, such as from about 40 to about 105 μm.

[0181] In another embodiment, the particle size distribution X of the aliquot-shaped particles of Form HB is 50 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.

[0182] In yet another embodiment, the particle size distribution X of the equally spaced shaped particles of Form HB is 10 It is about 0.1 to about 50 μm, such as about 1 to about 30 μm, such as about 2 to about 20 μm.

[0183] In another embodiment, the aliquot-shaped particles of Form HB have a compacted (15 kPa) bulk density of less than about 0.8 g / ml (e.g., less than about 0.7 g / ml). In other embodiments, the aliquot-shaped particles of Form HB have a compacted (15 kPa) bulk density of about 0.4 to about 0.7 g / ml (e.g., about 0.50 to about 0.65 g / ml, e.g., 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 defined herein as any one of the above embodiments, the composition being substantially free of any other solid form of LNP023 hydrochloride. For example, a composition containing Form HB of LNP023 hydrochloride as described herein comprises up to 20 w-%, such as up to 10 w-%, such as up to 5, 4, 3, 2 or 1 w-% of any other solid form of LNP023 hydrochloride based on the weight of the composition. In one embodiment, any other solid form of LNP023 hydrochloride is Form A of WO 2015 / 009616 or is amorphous. When subjected to a temperature in the range of 20°C to 30°C and subjected to a Cu-Kα ion having a wavelength of 0.15419 nm, the composition is substantially free of any other solid form of LNP023 hydrochloride. 1,2 When measured by radiometric measurement, Form A of LNP023 hydrochloride exhibits a PXRD comprising, inter alia, a characteristic peak at a 2-θ angle of (11.6 ± 0.1) °. Therefore, 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 one of the above embodiments, when subjected to a temperature in the range of 20°C to 30°C with a Cu-Kα having a wavelength of 0.15419 nm. 1,2 The composition has a PXRD profile that does not include a peak at a 2-theta angle of (11.6±0.1)° when measured by radiometric analysis.

[0188] In one embodiment, the present invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, based on the total weight of the composition, and also comprising 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] Technology

[0190] Examples of embodiments:

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

[0199] 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 may include an additional organic solvent. In one embodiment, acetone and water may be the only solvents present in the suspension. The LNP023 hydrochloride concentration of 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 (g / g) of acetone to water 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, about 45 ° C to 55 ° C. Heating can be accompanied by any type of movement of the solid material suspended in the solvent, including but not limited to, for example, stirring, agitating, mixing, shaking, vibrating, sonication, wet grinding, etc. Once the solid material is dissolved, the solution can be cooled to a temperature in the range of about 20°C to 50°C, for example, 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 include another organic solvent 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 continuously. In one embodiment, when added continuously, acetone is added first and ethyl acetate is added subsequently. 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, such as 1:2. In one embodiment, the suspension may be further cooled to a temperature in the range of about 0°C to 25°C, such as about 5°C to 15°C (e.g., 10°C), to complete crystallization. Once Form HB is obtained in substantially pure form, at least a portion of the crystals may be separated from the mother liquor. In one embodiment, the crystals may be separated from their mother liquor by any conventional method, such as filtration, centrifugation, solvent evaporation, or decantation, such as by filtration or centrifugation. In one embodiment, the crystals may 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. Drying can be carried out at a temperature of about 70°C or lower (e.g., about 60°C or lower, for example, about 50°C). Drying can also be carried out at about room temperature. Drying can be carried out in a time period within the range of about 2 to 24 hours (e.g., about 4 to 16 hours, for example, about 6 to 10 hours). In one embodiment, drying can be carried out in a time period of about 6 to 8 hours. Drying can be carried out under ambient pressure or reduced pressure. In one embodiment, drying is carried out at about 200mbar or less, for example, at a pressure of about 150mbar or less. In one embodiment, drying is carried out at a pressure of about 80mbar or less. In one embodiment, drying is carried out, for example, under a vacuum of about 50mbar 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 adding a second solvent within an extended period of time (e.g., within 12 to 36 hours), for example, temperature cycling. The temperature cycling can be performed 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, for example, about 5°C to 15°C (e.g., 10°C), and then can be heated to a temperature as high as about 30°C to 45°C, for example, about 30°C to 40°C (e.g., 35°C). This temperature cycle can be performed at least 3 times, for example, at least 6 times, for example, at least 8 times, for example, 6 to 12 times. After the temperature cycle, the second solvent can be added. In one embodiment, the second solvent can be ethyl acetate.

[0204] After engineering, i.e., after applying certain crystallization techniques as described above, Form HB consists of crystals with well-defined morphology, which results in excellent powder properties and processability, allowing the formulation of drug products containing Form HB via standard manufacturing processes and equipment. In one embodiment, Form HB is less brittle than Form A, which cannot be engineered in this manner, 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 (particularly after engineering) combines high physicochemical stability with excellent powder properties. Therefore, it is superior to Form A and is an ideal solid form of LNP023 hydrochloride for standard manufacturing of improved pharmaceutical compositions.

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

[0206] a) cooling the solution obtained in step (ii) and subsequently reheating the solution again;

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

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

[0209] Grinding Example

[0210] Before the particles of Form HB of LNP023 hydrochloride described herein are filled into capsules or otherwise further processed, they are, for example, ground. The grinding may be performed so that the particles are easily filled directly into capsules, in particular without the need for additional excipients.

[0211] In one embodiment, the particle size of the 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 an impact element, a rotating pin disc with a static pin disc, or a rotating pin disc with a rotating pin disc. The form HB of LNP023 hydrochloride to be ground is delivered to the rotor impact mill by a suitable powder delivery system (e.g., a vibrating feeder or a double screw feeder) to fully control the relevant powder feed rate. The powder is further delivered to the impact tool element by an airflow, which is produced by the rotating element of the rotor impact mill or by a blower connected to the rotor impact mill. The particle size reduction of the form HB of LNP023 hydrochloride particles occurs by the impact of the rotating element, by the impact of the static element, or by the impact between the form HB particles of the collision. For the customized form HB of the physical properties of LNP023 hydrochloride, suitable 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 by, for example, filters, cyclones, the ground product with tailored physical properties is collected in a product container. The ground product may be finally blended by appropriate techniques (e.g., diffusion blender) to obtain appropriate physical homogeneity for the manufactured batch.

[0212] Rotor impact milling can be performed, for example, by rotor impact milling using a rotating pin disk with a static pin disk tool (generally described in the art as a pin mill). The scale-independent parameters of rotor speed and feed rate can be described by the rotor end speed and the specific feed rate. The rotor speed of a specific equipment scale is in principle associated with the pin disk diameter of the relevant equipment scale by the parameter rotor end speed (for scale-independent parameters). The feed rate of a specific equipment scale is in principle associated with the pin surface area of ​​the relevant equipment scale by the parameter specific feed rate (for scale-independent parameters). Form HB of LNP023 hydrochloride product with customized physical properties can be obtained using rotor impact milling, which has the following scale-independent milling parameters: the rotor end speed is 10 to 60 m / s, and the diameter of the external rotating pin is considered for standardization, or a specific feed rate of up to about 4,000 kg / (h·m 2 ), while the cylindrical pin surface area of ​​the rotating pin is considered for standardization.

[0213] In a scale-related example, Form HB of LNP023 hydrochloride can be ground using a rotor impact mill (e.g., Model 100UPZ by Hosokawa Alpine AG, Augsburg / Germany) and a rotating pin disk with a static pin disk tool (commonly described in the public domain as a pin mill). The rotor can be operated at a speed of to For example, 4'000 to 8'500 rpm, for example, the rotor speed is The process is used to obtain a product with customized physical properties. The feed rate is, for example, 1 to 22 kg / h, such as 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 use of the Form HB of LNP023 hydrochloride described herein or a composition comprising the Form HB of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof for preparing a pharmaceutical composition.

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

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

[0219] In one embodiment thereof, the pharmaceutical composition comprises LNP023 hydrochloride in an amount of about 10 mg to about 200 mg calculated as anhydrous LNP023 free base.

[0220] In one embodiment thereof, the pharmaceutical composition comprises LNP023 hydrochloride in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg or about 200 mg, each calculated as anhydrous LNP023 free base.

[0221] In one embodiment thereof, the pharmaceutical composition comprises LNP023 hydrochloride in an amount of 10 mg, 25 mg, 50 mg, 100 mg or 200 mg, each calculated as anhydrous LNP023 free base.

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

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

[0224] In a preferred embodiment, the pharmaceutical composition comprising the form HB of LNP023 hydrochloride or a composition containing the form HB of LNP023 hydrochloride as defined in any one of the above aspects and their corresponding embodiments 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 the form HB of LNP023 hydrochloride or a composition comprising the form HB of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof with at least one excipient (e.g., a filler, a diluent, a binder, a disintegrant, a lubricant, a glidant or a combination thereof). Optionally, a granulation step, such as a dry or wet granulation step, is performed before compression.

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

[0227] In one embodiment, the invention relates to a pharmaceutical composition comprising Form HB of LNP023 hydrochloride particles in a capsule (e.g., a size 0 capsule). In one embodiment, the aspect ratio of the Form HB particles 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 Form HB particles in the capsule is 50 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) volume density of the Form HB particles 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 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 use in 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 kidney disease C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy) and other renal 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] On the other hand, the present invention relates to a method for treating a disease and disorder in a subject in need thereof, which diseases and disorders are disclosed in WO 2015 / 009616 and WO 2019 / 043609, each of which is incorporated herein 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 renal 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 includes administering to the subject a therapeutically effective amount of a form of LNP023 hydrochloride as described herein, HB.

[0231] In another aspect, the 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, the dose is up to about 200 mg calculated as anhydrous LNP023 free base, administered twice daily (bid) (e.g., once about every 12 hours).

[0233] In one embodiment, a method for treating PNH 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, the dose is about 10 mg to about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., about once every 12 hours).

[0234] In one embodiment, the method of treating PNH in a subject comprises administering to the subject a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of Form HB of LNP023, calculated as anhydrous LNP023 free base. In one embodiment, the dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg twice daily (bid) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

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

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

[0237] In an embodiment of a method for treating PNH, 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, the dose is about 50 mg twice daily (bid) (e.g., about once every 12 hours).

[0238] In an embodiment of a method for treating PNH, 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, the dose is about 100 mg twice daily (bid) (e.g., about once every 12 hours).

[0239] In an embodiment of a method for treating PNH, 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, the dose is about 200 mg twice daily (bid) (e.g., about once every 12 hours).

[0240] In an embodiment of a method of treating PNH, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, about every 12 hours).

[0241] In an embodiment of a method of treating PNH, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, approximately once every 12 hours) at a dose of 200 mg calculated as anhydrous LNP023 free base.

[0242] In another aspect, the invention relates to a method of treating complement driven kidney disease C3G (C3 glomerulopathy) 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.

[0243] In one embodiment, the method of treating C3G 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, the dose is up to about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., once about every 12 hours).

[0244] In one embodiment, the method of treating C3G in a subject comprises administering to the subject a daily dose of about 20 mg to about 400 mg of LNP023 form HB, calculated as anhydrous LNP023 free base. In one embodiment, the dose of about 10 mg to about 200 mg is administered twice daily (bid) (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 a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of Form HB of LNP023, calculated as anhydrous LNP023 free base. In one embodiment, the dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg twice daily (bid) (e.g., about once every 12 hours), calculated as anhydrous LNP023 free base.

[0246] In an embodiment of a method for treating C3G, Form HB of LNP023 is administered to a subject at a total daily dose of about 20 mg, calculated as anhydrous LNP023 free base. In one embodiment, the dose is about 10 mg twice daily (bid) (e.g., about once every 12 hours).

[0247] In an embodiment of a method for treating C3G, Form HB of LNP023 is administered to a subject at a total daily dose of about 50 mg, calculated as anhydrous LNP023 free base. In one embodiment, the dose is about 25 mg twice daily (bid) (e.g., about once every 12 hours).

[0248] In an embodiment of a method for treating C3G, 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, the dose is about 50 mg twice daily (bid) (e.g., about once every 12 hours).

[0249] In an embodiment of a method for treating C3G, 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, the dose is about 100 mg twice daily (bid) (e.g., about once every 12 hours).

[0250] In an embodiment of a method for treating C3G, 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 twice daily (bid) (e.g., about every 12 hours) at a dose of about 200 mg.

[0251] In an embodiment of a method of treating C3G, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, about every 12 hours).

[0252] In an embodiment of a method of treating C3G, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, approximately once every 12 hours) at a dose of 200 mg calculated as anhydrous LNP023 free base.

[0253] In another aspect, the 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 Form HB of LNP023, thereby treating the subject.

[0254] In one embodiment, a method of treating IgAN 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, the dose is up to about 200 mg, calculated as anhydrous LNP023 free base, administered twice daily (bid) (e.g., once about every 12 hours).

[0255] In one embodiment, a method of treating IgAN 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, the dose is about 10 mg to about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., about once every 12 hours).

[0256] In one embodiment, the method of treating IgAN in a subject comprises administering to the subject 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, the dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., once every 12 hours).

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

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

[0259] In an embodiment of a method for treating IgAN, 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, the dose is about 50 mg twice daily (bid) (e.g., about once every 12 hours).

[0260] In an embodiment of a method for 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, the dose is about 100 mg twice daily (bid) (e.g., about once every 12 hours).

[0261] In an embodiment of a method for 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, the dose is about 200 mg twice daily (bid) (e.g., about once every 12 hours).

[0262] In an embodiment of a method of treating IgAN, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, about every 12 hours).

[0263] In an embodiment of a method of treating IgAN, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, approximately once every 12 hours) at a dose of 200 mg calculated as anhydrous LNP023 free base.

[0264] In another aspect, the 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, thereby treating the subject.

[0265] In one embodiment, a 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, the dose is up to about 200 mg calculated as anhydrous LNP023 free base, administered twice daily (bid) (e.g., once about every 12 hours).

[0266] In one embodiment, a 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, the dose is about 10 mg to about 200 mg calculated as anhydrous LNP023 free base, administered twice daily (bid) (e.g., once about every 12 hours).

[0267] In one embodiment, a 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, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, the dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., once every 12 hours).

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

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

[0270] In an embodiment of a method for treating MN, 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, the dose is about 50 mg twice daily (bid) (e.g., about once every 12 hours).

[0271] In an embodiment of a method for treating MN, 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, the dose is about 100 mg twice daily (bid) (e.g., about once every 12 hours).

[0272] In an embodiment of a method for treating MN, 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, the dose is about 200 mg twice daily (bid) (e.g., about once every 12 hours).

[0273] In an embodiment of a method of treating MN, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, about every 12 hours).

[0274] In an embodiment of a method of treating MN, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, approximately once every 12 hours) at a dose of 200 mg calculated as anhydrous LNP023 free base.

[0275] In another aspect, the 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 Form HB of LNP023, thereby treating the subject.

[0276] In one embodiment, a method of treating aHUS 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, the dose is up to about 200 mg calculated as anhydrous LNP023 free base, administered twice daily (bid) (e.g., once about every 12 hours).

[0277] In one embodiment, a method of treating aHUS 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, the dose is about 10 mg to about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., about once every 12 hours).

[0278] In one embodiment, the method of treating aHUS in a subject comprises administering to the subject 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, the dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, calculated as anhydrous LNP023 free base, twice daily (bid) (e.g., once every 12 hours).

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

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

[0281] In an embodiment of a method for 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, the dose is about 50 mg twice daily (bid) (e.g., about every 12 hours).

[0282] In an embodiment of a method for 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, the dose is about 100 mg twice daily (bid) (e.g., about once every 12 hours).

[0283] In an embodiment of a method for 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, the dose is about 200 mg twice daily (bid) (e.g., about every 12 hours).

[0284] In an embodiment of a method of treating aHUS, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, about every 12 hours).

[0285] In an embodiment of a method of treating aHUS, Form HB of LNP023 is orally administered to a subject twice daily (bid) (eg, approximately every 12 hours) at a dose of 200 mg calculated as anhydrous LNP023 free base.

[0286] All of the foregoing embodiments relating to methods of treating certain diseases at specific dosages also apply to:

[0287] Form HB of LNP023 for use in treating certain diseases at specific doses 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 specific dosages according to the present invention; and

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

[0291] Test methods for morphological properties

[0292] Aspect ratio: The aspect ratio refers to the ratio of the maximum length of a crystal to its minimum width. When the aspect ratio is 1, the crystals have an isometric crystal habit. As the aspect ratio decreases below 1, the crystal habit becomes increasingly plate-like. Conversely, as the aspect ratio increases above 1, the crystals approach a needle-like crystal habit. According to the present disclosure, the equidistant shaped particles of Form HB have, for example, an aspect ratio a 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: Particle size distribution was measured with the laser diffraction (LLD) method using a Helos instrument from Synpatek, Clausthal-Zellerfeld, Germany.

[0295] Compacted bulk density: 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 is obtained. 9.3 g of Form A of LNP023 hydrochloride is 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 is cooled to 40 ° C, and a mixture of 136 g of acetone and ethyl acetate is added within 24 hours (acetone: ethyl acetate = 1: 2 m: m). The suspension is cooled to 10 ° C to complete crystallization. The product is 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 Salt Using Seed Crystals

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

[0302] Example 3: Preparation of Engineered Form HB of LNP023 Hydrochloride Salt Using Temperature Cycling

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

[0304] Example 4: Characterization of Form HB of LNP023 Hydrochloride

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

[0306] Analysis examples and interpretation of results:

[0307] Powder X-ray diffraction

[0308] Using a Cu-Kα Bragg-Brentano geometry with a focusing lens 1,2PXRD was performed on a Bruker D8 Advance diffractometer with X-ray diffraction (wavelength 0.15419 nm) and a solid-state PIXcel detector. The diffraction pattern was recorded at a tube voltage of 30 to 40 kV, a tube current of 40 mA, and 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 under ambient conditions. The typical accuracy of the 2-θ values ​​is in the range of ± 0.2 ° 2-θ, for example, ± 0.1 ° 2-θ. Therefore, on most X-ray diffractometers under standard conditions, for example, the diffraction peak of the form HB of the LNP023 hydrochloride salt appearing 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 A representative diffraction pattern of Form HB of LNP023 hydrochloride is shown in FIG.

[0310] Table 2 provides the corresponding peak list.

[0311]

[0312]

[0313] Table 1: PXRD peak positions and corresponding relative intensities of Form HB of LNP023 hydrochloride salt in the range of 2 to 40° 2-θ; typical precision of 2-θ values ​​in the range of ±0.2° 2-θ, eg, ±0.1° 2-θ.

[0314] Due to the particle morphology of Form HB, the relative intensities (as shown in Table 2) may be subject to some degree of variation.

[0315] Fourier transform infrared spectroscopy

[0316] Using the attenuated total reflection (ATR) technique, a 4 cm -1 FTIR spectra were recorded on a Nicolet 6700 spectrometer with a resolution of 1.3 Å. The number of scans was 64, ranging from 650 to 4000 wavenumbers (cm -1 ).

[0317] To record the spectrum, the tip of a spatula of the sample is applied to the diamond surface in powder form. The sample is then pressed onto the diamond with a sapphire anvil and the spectrum is recorded. The spectrum of a clean diamond is used as a background spectrum. The typical accuracy of the wavenumber is about ±2 cm -1 Therefore, on most infrared spectrometers under standard conditions, the 3452 cm -1The infrared peaks of LNP023 hydrochloride form HB can be seen at (3452-2) and (3452+2) cm -1 between.

[0318] Figure 3 A representative FTIR spectrum of the crystalline Form HB described herein is shown in FIG. 1 and the corresponding peak list is provided below, with a typical accuracy of ±2 cm in wavenumbers. -1 within the range.

[0319] 3452, 3274, 2933, 2875, 2732, 1709, 1692, 1658, 1615, 1601, 1515, 1497, 1461, 1439, 1425, 1384, 1243, 1184, 1069, 767, 739cm -1 .

[0320] Differential Scanning Calorimetry

[0321] DSC was performed on a TA Discovery DSC 2500 instrument. The sample (2.7 mg) was heated in a Tzero aluminum pan with a perforated aluminum lid from 30 to 300° C. at a rate of 10° K / min. Nitrogen (purge rate 50 mL / min) was used as purge gas.

[0322] The following Figure 4 A representative DSC curve is shown in , and shows a broad endothermic event ending at about 170° C., followed by an exothermic decomposition at about 200° C., when measured at a heating rate of 10 K / min. More precisely, the endothermic event is in the range of 35° C. to 170° C.

[0323] Thermogravimetric analysis

[0324] 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 microliter aluminum pan (closed with an aluminum lid). At the start of the measurement, the lid was automatically pierced. Nitrogen (purge rate of 50 mL / min) was used as purge gas.

[0325] The following Figure 5Representative TGA curves are shown in Figure 1 and show a step from about 30°C to 220°C, which is due to dehydration (dehydration) and residual solvent. The mass during the step is determined to be about 4.1%. The water content of the sample is 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 is carried out on a Metrohm 831KF coulometer connected to a 774 oven sample processor, which is heated to 160°C for measurement.

[0326] Dynamic Vapor Sorption

[0327] Dynamic vapor adsorption isotherms were recorded with DVS Advantage instrument. The measurement cycle started at 40% ambient relative humidity (RH). Then RH was reduced to 0% in 10% stepping. Afterwards, in the adsorption cycle, RH was increased from 0% to 90% in 10% stepping, and increased from 90% to 95% in 5% stepping, and subsequently in the desorption cycle, each was reduced to 0% in 10%, 5% stepping, respectively. Finally, RH was increased to 40% ambient relative humidity in 10% stepping. Time / stepping was set to minimum 3 hours, maximum 6 hours. If equilibrium conditions (constant mass change is 0.002% / min, continues minimum 5min) are reached before the maximum time of all inspection samples, sequential humidity stepping is applied before 6 hours of the maximum time. If equilibrium is not reached, continuous humidity stepping is applied after 6 hours of the maximum time. Temperature is 25 ℃ ± 1.0 ℃.

[0328] Figure 6 The equilibrium mass change (δm weight %-reference weight at 0% RH on the y-axis) of Form HB of the hydrochloride salt of LNP023 during an adsorption cycle (marked with triangles) from 0% to 95% RH, and during a desorption cycle (marked with squares) from 95% to 0% RH (on the x-axis) is shown. The mass difference between 40% and 95% RH is less than 0.2 weight %, and no obvious hysteresis is observed between the adsorption and desorption curves. Therefore, Form HB of the hydrochloride salt of LNP023 described herein can be designated as non-hygroscopic. The PXRD of Form HB of the hydrochloride salt of LNP023 remains unchanged after the experiment.

[0329] Electron microscopy

[0330] Electron microscopy images were taken with a Gemini SE 300 (Zeiss) microscope using an SE detector. Figure 7a and 7bAs can be seen in , Form HB of LNP023 hydrochloride obtained using the engineered crystallization technique (eg, as shown in Example 3) comprises columnar and equally spaced particles, which explains the excellent flow properties of the powder.

[0331] Example 5: Preparation of pharmaceutical composition

[0332] The Form HB particles obtained as in Example 3 were transferred to a 100UPZ pin mill from Hosokawa Alpine, Augsburg / Germany. The particles were ground at a rotor speed of 2000 rpm and a feed rate of 15 kg / h.

[0333] The obtained aliquoted granules were filled in an amount of 50, 100 or 200 mg, each of which was filled into a size 0 hard gelatin capsule.

Claims

1. A crystalline monohydrate form of a compound of formula (A), Features When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern comprising peaks at 2-θ angles of (4.6±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (20.7±0.2)° and (24.0±0.2)°.

2. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, the powder X-ray diffraction pattern includes one or two peaks at a 2-θ angle of (6.8±0.2)° or (24.6±0.2)°.

3. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes at least five peaks at 2-θ angles selected from (6.8±0.2)°, (12.2±0,2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.6±0.2)° and (28.0±0.2)°.

4. The crystalline monohydrate form according to claim 3, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)° and (24.6±0.2)°.

5. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes one or two peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)° and (24.6±0.2)° and at least one additional peak selected from (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (22.2±0.2)° and (28.0±0.2)°.

6. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, and (24.6±0.2)°.

7. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (21.3±0.2)° and (24.6±0.2)°.

8. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (21.3±0.2)° and (24.6±0.2)°.

9. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (21.3±0.2)°, (24.6±0.2)° and (28.0±0.2)°.

10. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (21.3±0.2)° and (24.6±0.2)°.

11. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (24.6±0.2)° and (28.0±0.2)°.

12. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)° and (24.6±0.2)°.

13. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 The invention has a powder X-ray diffraction pattern when measured by radiation, the powder X-ray diffraction pattern further comprising peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (24.6±0.2)° and (28.0±0.2)°; and when measured at a temperature in the range of 20°C to 30°C with a diamond ATR unit cell, it has a Fourier transform infrared spectrum comprising peaks at a wave number of (3452±2) cm -1 、(2875±2)cm -1 、(1692±2)cm -1 、(1439±2)cm -1 and (1243±2)cm -1 The peak of .

14. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (22.2±0.2)° and (24.6±0.2)°.

15. The crystalline monohydrate form according to claim 1, characterized in that When the temperature is within the range of 20°C to 30°C, the Cu-Kα 1,2 When measured by radiation, it has a powder X-ray diffraction pattern, which also includes peaks at 2-θ angles of (6.8±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (17.2±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.6±0.2)° and (28.0±0.2)°.

16. 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 using a diamond ATR cell, the Fourier transform infrared spectrum comprises a wavelength of (3452±2) cm -1 、(2875±2)cm -1 、(1692±2)cm -1 、(1439±2)cm -1 and (1243±2)cm -1 The peak of .

17. The crystalline monohydrate form of claim 16, characterized in that When measured at a temperature in the range of 20°C to 30°C using a diamond ATR cell, the Fourier transform infrared spectrum comprises a wavelength 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 The peak of .

18. The crystalline monohydrate form according to claim 1, characterized in that When measured at a heating rate of 10 K / min, there is a differential scanning calorimetry curve comprising an endothermic event in the range of 35°C to 170°C.

19. The crystalline monohydrate form according to claim 1, characterized in that When heated from 30°C to 300°C at a rate of 20 K / min, it has a thermogravimetric curve which shows 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.

20. The crystalline monohydrate form according to claim 1, 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 no more than 4.5 w-% based on the weight of the crystalline hydrate form at 0% RH.

21. The crystalline monohydrate form according to claim 1 having a crystal habit of being substantially equipartite in shape.

22. The crystalline monohydrate form according to claim 1 having a crystal habit that is columnar in nature.

23. A composition comprising the crystalline monohydrate form of any one of claims 1-22, wherein the composition comprises up to 20% by weight, based on the weight of the composition, of a compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 22.

24. A composition according to claim 23, wherein the composition comprises up to 10% by weight, based on the weight of the composition, of a compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 22.

25. A composition according to claim 23, wherein the composition comprises up to 5% by weight, based on the weight of the composition, of a compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 22.

26. A composition according to claim 23, wherein the composition comprises up to 2% by weight, based on the weight of the composition, of a compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 22.

27. The composition of claim 23, wherein the composition comprises up to 1 wt. %, based on the weight of the composition, of a compound of formula (A) in a physical form other than the crystalline monohydrate of any one of claims 1 to 22.

28. The composition according to any one of claims 23 to 27, wherein the other physical form of the compound of formula (A) is characterized by being irradiated with a Cu-Kα ion having a wavelength of 0.15419 nm at a temperature in the range of 20°C to 30°C. 1,2 When measured by radiation, 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)°.

29. Use of the crystalline monohydrate form according to any one of claims 1 to 22 or the composition according to any one of claims 23 to 28 for the preparation of a pharmaceutical composition.

30. A pharmaceutical composition comprising the crystalline monohydrate form according to any one of claims 1 to 22 or the composition according to any one of claims 23 to 28, and at least one pharmaceutically acceptable excipient.

31. The pharmaceutical composition according to claim 30, which is an oral solid dosage form.

32. The pharmaceutical composition according to claim 30, which is a capsule.

33. A pharmaceutical composition according to any one of claims 30 to 32 comprising the crystalline monohydrate form having an aspect ratio of between 0.4 and 0.

7.

34. A pharmaceutical composition according to any one of claims 30 to 32, comprising a particle size distribution X of 10 to 70 μm. 50 of the crystalline monohydrate form.

35. A pharmaceutical composition according to any one of claims 30 to 32 comprising the crystalline monohydrate form having a compacted bulk density at 15 kPa of 0.50 to 0.65 g / ml.

36. A process for preparing the crystalline monohydrate form according to any one of claims 1 to 22, 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 isolated crystals; (v) optionally washing the separated crystals obtained in step (iv); and (vi) drying the separated crystals obtained in step (iv) or (v).

37. A process according to claim 36, comprising as step (iii) (a) cooling the solution obtained in step (ii), and then 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.

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