Crystalline form of LNP023

Abstract

To provide a crystalline form of LNP023 hydrochloride and a process for preparation thereof.SOLUTION: A crystalline hydrate of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride having Formula (A) in the figure has a powder X-ray diffractogram comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (19.1±0.2)° and (24.6±0.2)°, when measured at a temperature of 20-30°C with Cu-Kα1, 2 radiation having a wavelength of 0.15419 nm.SELECTED DRAWING: None

Description

[Technical field]

[0001] Described herein are crystalline forms of LNP023 hydrochloride and processes for its manufacture. A pharmaceutical composition comprising a crystalline form of the hydrochloride salt of 023 and at least one pharma- ceutical acceptable excipient. Pharmaceutical compositions are also described herein. The pharmaceutical compositions described herein are useful for treating complement activation. These can be used in the treatment of diseases or disorders mediated by [Background technology]

[0002] LNP023 belongs to the class of factor B inhibitors of the complement pathway and is involved in the early mechanism of activation. It acts by inhibiting or suppressing the amplification of the complement system caused by unrelated C3 activation. It is currently classified as paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), immunoglobulin G (IGG), and Developmental drugs for the treatment or prevention of immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) Chemically, LNP023 hydrochloride is 4-((2S,4S)-(4-ethoxy-1-(( 5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl It is designated as benzoic acid hydrochloride and can be represented by the following chemical structure according to formula (A): Cut. [ka]

[0003] LNP023 hydrochloride and methods for its preparation are incorporated herein by reference in their entirety. This is disclosed in International Publication No. 2015 / 009616. In Example 26d of 15 / 009616, LNP023 hydrochloride is obtained The solid was obtained by recrystallization of the amorphous material and characterized by X-ray powder diffraction. This crystalline form is referred to herein as Form A.

[0004] Various solid state forms of an active pharmaceutical ingredient often have different properties. Differences in physicochemical properties can play an important role in improving pharmaceutical compositions, e.g., improved Pharmaceutical formulations having a dissolution profile or with improved stability or shelf life include Improved solid state forms of active pharmaceutical ingredients may become available. The processing or handling of active pharmaceutical ingredients during processing and manufacturing may thus be improved. The novel solid state forms of the ingredients have desirable processing properties. They are easier to handle, more suitable for storage, or can be purified better than solid forms that are available in the form of It may be possible.

[0005] Crystal of LNP023 HCl in International Publication No. 2015 / 009616 "A The "morphology" has certain characteristics that make it less suitable for large-scale manufacturing processes. Therefore, a more stable form of LNP023 HCl is desirable.

[0006] This allows for the reliable manufacture of safe and effective medicines, including LNP023 hydrochloride. There is a need to provide a solid state form of LNP023 hydrochloride that has physicochemical properties that enable There is a gender. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides a crystalline hydrate form of LNP023 hydrochloride, hereinafter also referred to as the "HB form." The "HB Form" of LNP023 hydrochloride is a drug substance intended for use in an oral solid dosage form. The preferred physicochemical properties are:

[0008] Advantageous properties of the HB form of LNP023 include chemical stability, physical stability, hygroscopicity, Solubility, dissolution, morphology, crystallinity, fluidity, compactibility As a result, this property makes the HB form more suitable for large-scale manufacturing processes. This will be appropriate for Seth.

[0009] In one embodiment, the HB form is physically and chemically stable during pharmaceutical processing and storage. The HB form is a phase-pure, highly crystalline form of LNP023 hydrochloride, which is thermodynamically more stable. Form A is a specific form in which the possibility of conversion to other forms can be minimized. It can be converted to the HB form under certain conditions. If the most stable form is used, Eliminates conversion of, for example, Form A to Form HB or polymorphic conversion that may occur during processing and storage. The use of thermodynamically stable forms of compounds is highly valued, as this allows to ensure reliable bioavailability of medicines and therefore consistent efficacy of medicines. It becomes certain.

[0010] Abbreviation PXRD Powder X-ray diffraction SXRD Single crystal X-ray diffraction FTIR Fourier transform infrared spectroscopy ATR total reflectance measurement method DSC Differential Scanning Calorimetry DVS Dynamic Vapor Sorption TGA thermogravimetric analysis MS mass spectrometry NMR nuclear magnetic resonance GC Gas Chromatography KF Karl Fischer method RH Relative Humidity RT room temperature w-% Weight% vol-% Volume %

[0011] definition In the context of this disclosure, unless otherwise specified, the following definitions have the meanings indicated: As used herein, the term "room temperature" refers to a temperature in the range of 20-30° C. .

[0012] As used herein, the term "measured at a temperature in the range 20 to 30° C." Generally, standard conditions refer to temperatures in the range of 20-30°C, i.e. room temperature. Standard conditions may mean a temperature of about 22° C.

[0013] As used herein, the term "HB Form" refers to a solid form of LNP023 hydrochloride. When describing, a particular crystalline hydrate form of LNP023 hydrochloride is intended, e.g., the monohydrate form. This form is further defined herein and in the claims. .

[0014] As used herein, the term "Form A" describes a solid form of LNP023 hydrochloride. In this case, the LNP023 salt disclosed in WO 2015 / 009616 is Form A of LNP023 hydrochloride has a wavelength of 0.15419. Cu-Kα with nm 1,2 When measured at temperatures in the range 20-30°C using the ,(11.6±0.1)°,(15.3±0.1)°,(16.5±0.1)°,(20 Powder containing peaks at 2θ (theta) angles of (23.3±0.1)° and (23.3±0.1)° It may be characterized as having an X-ray diffraction diagram.

[0015] Form A is prepared as follows according to International Publication No. WO 2015 / 009616: It is prepared (see Example 26d): 4-((2S,4S)-(4-ethoxy-1H-pyridyl) -((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidine- A solution of 2-(2-yl)benzoic acid (620 mg, 1.467 mmol) was added to 5 M aqueous HCl. The reaction mixture was then freeze-dried. The amorphous compound was obtained, which was then suspended in iPrOH (300 mL). The mixture was heated to 0°C. The suspension turned into a solution after 1.5 hours. The solution was then stirred. After cooling to room temperature for about 5 hours, a solid was obtained. The resulting solid was collected by filtration and purified by high purity. Drying at 50° C. under reduced pressure gave the title compound as a crystalline solid. 1 H NMR (HCl salt,400MHz,CD3OD)δ 10.73(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=1.77,3.12H z,1H),4.33(d,J=12.72Hz,1H),4.25(d,J=12.7 2Hz,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).

[0016] The X-ray powder diffraction pattern is shown in Table 1 below.

[0017] [Table 1]

[0018] As used herein, the term "reflection" in reference to powder X-ray diffraction refers to long-range reflections. The mechanism is characterized by parallel planes of atoms in a solid material that are distributed in a regular and repeating pattern with positional order. Constructive interference from X-rays scattered from the The peak in the X-ray diffraction pattern that occurs at a specific diffraction angle (Bragg angle) due to the Such solid materials are classified as crystalline materials, whereas amorphous materials are characterized by long-range It is defined as a solid material that lacks order and exhibits only short-range order, thus resulting in extensive scattering. According to the literature, the long-range order extends, for example, over 100 to 1000 atoms. In contrast, short-range order extends to only a few atoms (Fundamentals of Powder Diffraction and Structural Chara cterization of Materials by Vitalij K.Pe charsky and Peter Y. Zavalij, Kluwer Acade (See MIC Publishers, 2003, page 3).

[0019] The term "essentially the same" in reference to powder X-ray diffraction refers to the peak positions and relative intensities of the peaks. This means that the variation in the degree of the chromatic aberration must be taken into account. For example, the usual precision of the 2θ value is Within the range of ±0.2°2θ, for example within the range of ±0.1°2θ. Therefore, for example, 9. The peaks that usually appear at 2°2θ are (9.2-0.2) on most ray diffractometers under standard conditions. °~(9.2+0.2)°2θ, e.g., (9.2-0.1)°~(9.2+0.1)° In addition, the relative peak intensities can be used to account for variations between instruments, as well as the degree of crystallinity, which is preferred. exhibit variability due to different orientations, particle sizes, sample preparation, and other factors known to those skilled in the art; Those skilled in the art will appreciate that this should only be interpreted as a qualitative measurement.

[0020] The term "essentially the same" with respect to infrared spectroscopy refers to the peak positions and the phases of the peaks. This means that the scatter in the intensity of the wavenumbers should be taken into account. ±4cm -1 Within the range of, for example, ±2cm -1 Therefore, for example, 1692cm -1 The peak at (1692-4) is observed in most X-ray diffractometers under standard conditions. ~(1692+4)cm -1 For example, (1692-2)~(1692+2)cm -1 in The peak intensities can be derived from the corresponding figures, but the skilled artisan will recognize the degree of crystallinity. However, differences in peak intensities due to sample preparation, measurement method, and other factors can occur in infrared spectroscopy. It will be appreciated that peak intensity should therefore be interpreted only as a qualitative measurement.

[0021] The HB form of LNP023 hydrochloride salt described herein is shown in the graphical data "shown in" FIG. Such data may be referred to herein as characteristics such as, for example, powder X-ray diffraction. and FTIR. Instrument type, differences in response, and sample orientation, sample concentration Factors such as differences in sample purity and sample composition can cause small variations in such data when presented in graphical form. Those skilled in the art will appreciate that various variations, such as differences relating to exact peak positions and intensities, may occur. However, graphs made for other or unknown solid forms may be used. Comparison of the clinical data with the graphical data in the figures herein, as well as the two sections Confirmation that the graphical data of the same crystal form is well within the knowledge of a person skilled in the art. is located.

[0022] As used herein, the term "solid form" or "solid state form" refers to a compound The term "crystalline phase" refers to either the crystalline phase or the amorphous phase of the above-mentioned compound.

[0023] As used herein, the term "amorphous" refers to a solid form of a compound that is not crystalline. Amorphous compounds do not have long-range order and do not have definitive X-ray diffraction patterns with peaks. Does not indicate a turn.

[0024] As used herein, the term "polymorph" refers to a compound having the same chemical composition but in the form of a crystal. It refers to the crystalline forms that form having different spatial arrangements of molecules, atoms, or ions.

[0025] As used herein, the term "cocrystal" refers to a compound that is formed by non-ionic and non-covalent bonding. A bond that contains two or more different molecular or ionic compounds in the same crystal lattice that are associated with each other through A crystalline material, in which at least two of the individual molecules or ionic compounds are solid at room temperature. It means a crystalline material.

[0026] As used herein, the term "hydrate" refers to a compound in which water is incorporated into the crystal structure or Contained by a crystal structure, e.g., part of a crystal structure or incorporated within a crystal As a result, water can be present in stoichiometric or non-stoichiometric amounts. When water is present in stoichiometric amounts, hydrates are designated by Greek numeral prefixes. For example, a hydrate may be referred to by adding the hydrate / hydroxide prefix. Depending on the compound stoichiometry, it may be called a hemihydrate or a monohydrate. The water content can be determined, for example, by Can be measured by Fischer coulometry.

[0027] As used herein, the term "dehydrate" or "dehydration" refers to the dehydration of the crystalline structure of a host molecule. This means that water is at least partially removed from the

[0028] As used herein, the term "solvate" refers to a compound in which one or more organic solvents are present. Incorporated into or accommodated by a crystal structure, e.g. part of a crystal structure It means a crystalline solid in which the solvent is present or incorporated within the crystal (solvent inclusion). The organic solvent or solvents may be present in stoichiometric or non-stoichiometric amounts. When organic solvents are present in stoichiometric amounts, solvates are designated by the addition of Greek numeral prefixes. For example, solvates may be referred to as hemisolvates or may be referred to as a monosolvate. The solvent content may be determined, for example, by GC, NMR, SXRD, or TG. It can be measured by A / MS.

[0029] As used herein, the term "isostructural solvate" means , with very little distortion of the unit cell dimensions, and the same type of molecular network of the host molecule. As defined herein, an isomorphous solvate refers to a solvate having the same space group as the guest molecule. The types of organic solvents present as molecules are different.

[0030] As used herein, the term "desolvation" or "desolvation" refers to the crystallization of a host molecule. It refers to at least partially removing the organic solvent from the structure.

[0031] As used herein, the term "anhydrous form" or "anhydrate" refers to a compound that does not incorporate water into the crystal structure. "Water" refers to a crystalline solid in which water is not embedded in or accommodated by the crystal structure. The anhydrous form may still contain residual water that is not part of the crystal structure, but is adsorbed to the surface of the crystal. The anhydrous form usually has a weight average molecular weight of 1.5g / kg or is absorbed into the disordered regions of the crystals. The water content does not exceed 3.0% by weight, for example, does not exceed 1.0% by weight. do not have.

[0032] As used herein, the term "non-solvated" when referring to a crystalline solid means The organic solvent is not incorporated into or accommodated by the crystal structure. The unsolvated forms still contain residual organic solvent that is not part of the crystal structure. However, it may be adsorbed onto the surface of the crystal or absorbed into the disordered regions of the crystal. In the present invention, the unsolvated form does not contain more than 3.0% by weight of organic solvent, for example 1.0% by weight. In one embodiment, the unsolvated form does not contain more than 100% by volume of an organic solvent. It does not contain more than 0.5% by weight of organic solvent.

[0033] As used herein, the term "mother liquor" refers to the solution remaining after crystallization of a solid from said solution. It means liquid.

[0034] As used herein, the term "poor solvent" refers to the solubility of LNP023 hydrochloride in a solvent. This means a liquid that reduces

[0035] As used herein, with respect to LNP023 hydrochloride, the term "predetermined amount" refers to A pharmaceutical composition having the desired dosage strength of P023 hydrochloride "LNP023 hydrochloride" refers to the initial amount of LNP023 hydrochloride used in the manufacture of the product.

[0036] As used herein, the term "therapeutically effective amount" with respect to LNP023 hydrochloride means This encompasses an amount of LNP023 hydrochloride that produces the desired therapeutic or prophylactic effect.

[0037] As used herein, the term "non-hygroscopic" refers to a compound that is stable at a relative humidity of 80% relative to its weight. %, means less than 0.2% mass gain (due to water uptake) at 25°C.

[0038] As used herein with respect to crystalline form, the term "equant" means means a crystal that is equi-dimensional, such as a cube or sphere. do.

[0039] As used herein, the terms "plate" or "plate-like" with respect to crystal shape refer to flakes. By "flat, plate-like crystals" is meant flat, tabular crystals having a similar extent and width but thicker than 100 mm.

[0040] The term "flake" or "flaky" as used herein with respect to crystalline shape means a thin, flat crystal having a similar extent and width, thinner than a plate.

[0041] As used herein, with respect to crystal shape, the term "needle" or "acicular" refers to a crystal having a similar width. By "crystals" is meant needle-like, thin and very elongated crystals having dimensions of 0.1 mm and 0.2 mm.

[0042] With respect to crystal shape, the terms "cylinder" and "cylindrical" are used interchangeably herein. The term refers to elongated, columnar crystals having a width and thickness greater than that of a needle.

[0043] The definition of such crystal habit is consistent with the definition commonly used in the art, e.g., “Poly morphism in the Pharmaceutical Industry” edited by Rolf Hilfiker(Wiley-VCH,2006) ;Chapter 7,Light Microscopy(Gary Nichols ) for more information.

[0044] As used herein, the term "about" means an approximation within the region of approximately or around. When the term "about" is used in conjunction with a numerical range, it means more than the stated numerical value and The term "about" generally modifies the range by broadening the boundaries below. This is used to modify values ​​that exceed the specified value and fall below the specified value with a 10% fluctuation. Used in the specification.

[0045] As used herein, with respect to compositions comprising a particular solid form of LNP023 hydrochloride, The term "substantially free of other solid forms" means that the composition is Any other solid form of the composition in a maximum amount of 20% by weight (weight percent ), up to 15% by weight, up to 10% by weight, up to 9% by weight, up to 8% by weight, up to 7% by weight %, up to 6%, up to 5%, up to 4%, up to 3%, up to 2 %, at most 1%, at most 0.5%, or at most 0.1%, or 80% by weight It means to include any percentage by weight up to 100% by weight.

[0046] As used herein, "substantially pure" when used in reference to a form of a compound More than 90% by weight of a particular solid form of LNP023 hydrochloride, e.g. More than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, Furthermore, it means a compound having an amount of purity equal to about 100% by weight. The remaining material is the compound or other forms of reaction or processing impurities resulting from their manufacture. For example, L The crystalline forms of NP023 hydrochloride are known and accepted in the art at this time. Substantially pure in that it has a purity of greater than 90% by weight as measured by any suitable method. The remaining less than 10% of the material is considered to be other forms of LNP023 hydrochloride, reaction impurities, or Contains processing impurities.

[0047] As used herein, the term "subject" is intended to mean a human. A typical human subject includes a human patient (referred to as a patient) having a disease, e.g., a disease described herein. It means a subject that is not aware of the presence of a substance, or a normal subject.

[0048] As used herein, the term "physically stable" means that a particular free base or salt form is , a specified period, 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 more under specified conditions, e.g. room temperature, ambient temperature When subjected to ambient humidity or 40°C / 75% relative humidity, one or more different physical forms ( (e.g., different solid forms as measured by XRPD, DSC, etc.) In some embodiments, less than 25% of the compound forms are subjected to the specified conditions. In some embodiments, the compound changes into one or more different physical forms when exposed to heat. Less than about 20%, less than about 15%, less than about 10%, less than about 5%, or about 3% of a particular compound form Less than about 1% or less than about 0.5% of a particular compound when subjected to specified conditions In some embodiments, the compound is transformed into one or more different physical forms. A detectable amount of a particular form does not change into one or more different physical forms of the compound. .

[0049] As used herein, the term "chemically stable" refers to a compound whose chemical structure is , a specified period, 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 more under specified conditions, e.g. room temperature, ambient temperature When exposed to ambient humidity or 40°C / 75% relative humidity, it does not change into other compounds (e.g. In some embodiments, 25% of a particular compound in a form that is Less than a certain amount of a compound will be transformed into one or more other compounds when subjected to specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, Less than approximately 5%, less than approximately 3%, less than approximately 1%, and less than approximately 0.5% when subject to specified conditions In some embodiments, the specific compound is converted to one or more other compounds. A detectable amount of a form is converted into one or more different physical forms of that particular compound. do not have.

[0050] As used herein, the term "pharmaceutical acceptable excipient" refers to a compound that, at a given dose, It means a substance that does not show significant pharmacological activity and is added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients are, among others, vehicles, diluents, release agents, disintegrants, dissolution modifiers, absorption enhancers, stabilizers, Excipients may serve as fillers (diluents), binders, disintegrants, , lubricants and glidants.

[0051] As used herein, the term "filler" or "diluent" refers to a material that is mixed with an active pharmaceutical ingredient prior to delivery. Diluents and fillers act as stabilizers. It can also be achieved.

[0052] As used herein, the term "binder" refers to a material that acts to maintain cohesiveness and separate parts. " refers to a substance that binds together an active pharmaceutical ingredient and a pharma- ceutical acceptable excipient for the purpose of do.

[0053] As used herein, "disintegrant" or "disintegrant" refers to a The term "integrating agent" refers to a compound that, when added to a solid pharmaceutical composition, After administration, it is necessary to promote its decomposition or disintegration, release the active pharmaceutical ingredient as efficiently as possible, and It means a material that allows rapid dissolution.

[0054] The term "lubricant" as used herein refers to a lubricant that acts on the surface of the tablet during the tableting or encapsulation process. A substance added to a powder blend to keep compacted powder lumps from sticking to equipment. Lubricants aid in ejection of the tablet from the die and may improve powder flow.

[0055] As used herein, the term "flow enhancer" refers to an agent that enhances flow during tablet compression. In order to prevent caking and to provide an anti-caking effect, "Tablet and capsule formulations" refers to substances used in tablet and capsule formulations for the purpose of [Brief description of the drawings]

[0056] [Figure 1]1 illustrates a representative PXRD of the HB form of LNP023 hydrochloride salt described herein, where the x-axis represents the scattering angle in degrees 2θ and the y-axis represents the intensity of the scattered X-ray beam in counts of detected photons per second. [Diagram 2] 1 illustrates a comparison of a representative PXRD of the HB form of LNP023 hydrochloride described herein (bottom) and a representative PXRD of Form A of LNP023 hydrochloride from WO 2015 / 009616 (top). The x-axis shows the scattering angle in 2θ degrees. The powder X-ray diffractogram of Form A was shifted along the y-axis, and the diffractogram was split for clarity. The y-axis is therefore arbitrary and has not been labeled. [Diagram 3] 1 illustrates a representative FTIR spectrum of the HB form of LNP023 hydrochloride salt described herein, where the x-axis shows wavenumber in cm-1 and the y-axis shows relative intensity in percent transmittance. [Figure 4] 1 illustrates a representative DSC curve for the HB form of LNP023 hydrochloride salt described herein, where the x-axis shows temperature in degrees Celsius (° C.) and the y-axis shows heat flow in watts / g (W / g) with an ascending endothermic peak. [Diagram 5] 1 illustrates a representative TGA curve for the HB form of LNP023 hydrochloride salt described herein, where the x-axis represents temperature in degrees Celsius (° C.) and the y-axis represents sample mass (loss) in weight percent (wt%). [Figure 6] 1 illustrates a representative DVS isotherm for the HB form of LNP023 hydrochloride salt described herein over the range of 0-95% relative humidity. The x-axis represents the relative humidity in percent (%) measured at a temperature of (25.0±1.0)° C., and the y-axis represents the equilibrium mass change in weight % (wt%) relative to the sample weight at 0% relative humidity. Adsorption (sorption) cycles are marked with triangles and desorption cycles are marked with squares. [Figure 7] FIG. 7: FIGS. 7a and 7b illustrate scanning electron microscope images of the HB form of LNP023 hydrochloride salt described herein when prepared according to Example 3 (total bar scale: 50 micrometers). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Crystal morphology Illustrative embodiments: In one embodiment, the present invention provides LNPs, also referred to herein as "HB forms." 023 relates to the crystalline hydrate of the hydrochloride salt.

[0058] LNP023 hydrochloride can be represented by the following chemical structure according to formula (A): [ka]

[0059] The HB form of LNP023 hydrochloride described herein is suitable for pharmaceutical production with respect to solid state characterization. The composition may be characterized by analytical methods well known in the art, including but not limited to: , PXRD, SXRD, FTIR, DSC, DVS, TGA and SEM. Characterized by one of the aforementioned analytical methods or by a combination of two or more of them In particular, the HB form of LNP023 hydrochloride described herein may be prepared in the following embodiments: The present invention is characterized by any one of the following embodiments or by a combination of two or more of the following embodiments: It can be said that

[0060] Illustrative PXRD embodiments: In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... PXRD peaks identified at 2θ angles of (19.1±0.2)° and (19.1±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), which can be characterized by:

[0061] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... Identified at 2θ angles of (8±0.2)°, (9.2±0.2)°, and (19.1±0.2)° The crystalline form of LNP023 hydrochloride (HB) can be characterized by the PXRD peaks shown in Table 1. (shape).

[0062] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 8±0.2)°, (9.2±0.2)°, (19.1±0.2)°, and (24.6±0 LNP02 can be characterized by a PXRD peak identified at a 2θ angle of .2)°. This relates to the crystalline form of the trihydrochloride salt (HB form).

[0063] In one embodiment, the present invention relates to a Cu-Kα 1,2 Line When measured at temperatures in the range of 20 to 30°C, the results were (4.6±0.2)°, (6.8 ±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)° PXRD peaks identified at 2θ angles of (24.6±0.2)° and (24.6±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), which may be

[0064] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2 )°, (21.3±0.2)°, and (24.6±0.2)° 2θ angles. The crystalline form of LNP023 hydrochloride (HB form) can be characterized by XRD peaks. Regarding.

[0065] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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 The compound is characterized by PXRD peaks identified at 2θ angles of 24.6±0.2°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form).

[0066] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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)°, ( PXRD peaks identified at 2θ angles of (21.3±0.2)° and (24.6±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) which can be characterized by a crystal structure comprising:

[0067] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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)°, ( PXRD peaks identified at 2θ angles of (21.3±0.2)° and (24.6±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) which can be characterized by a crystal structure comprising:

[0068] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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)°, ( 2θ angles of (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)° Crystalline forms of LNP023 hydrochloride that can be characterized by PXRD peaks identified at This concerns the HB form.

[0069] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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 LN is characterized by a PXRD peak identified at a 2θ angle of 0.6±0.2°. This concerns the crystalline form of P023 hydrochloride (HB form).

[0070] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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 PXRD peaks identified at 2θ angles of (24.6±0.2)° and (24.6±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), which is characterized by:

[0071] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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 The 2θ angles were identified as (24.0±0.2)°, (24.0±0.2)°, and (24.6±0.2). The crystalline form of LNP023 hydrochloride (HB form) is characterized by PXRD peaks ) regarding.

[0072] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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 LNP023 is characterized by a PXRD peak identified at a 2θ angle of .2)°. It concerns the crystalline form of the hydrochloride salt (HB form).

[0073] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 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)° 2θ angles. This relates to the crystalline form of LNP023 hydrochloride (HB form).

[0074] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2 )°, and (24.6±0.2)° 2θ angles, as well as (1 0.0±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) LNP02, characterized by at least one more peak selected from the group consisting of This relates to the crystalline form of the trihydrochloride salt (HB form).

[0075] In another embodiment, the present invention provides a Cu-Kα 1,2 When measured at temperatures in the range of 20 to 30°C using the line, the .2±0.1)°, and (19.1±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, and (19.1 ±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (19.1±0 .1)°, and (24.6±0.1)°; or (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 (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 (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 (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 teeth (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 teeth (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 (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 0.3±0.2)°, and (24.6±0.2)°; or (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 (0.7±0.2)°, (21.3±0.2)°, and (24.6±0.2)°; or (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 (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 (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 The 2θ angles are identified as (24.6±0.1)°, (24.6±0.1)° and (28.0±0.1)°. The crystalline form of LNP023 hydrochloride (HB form) is characterized by PXRD peaks: Regarding.

[0076] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the FT-IR ... 8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1 )°, and (24.6±0.1)° 2θ angles, as well as (1 0.0±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)° LNP0 is characterized by at least one more peak selected from the group consisting of This relates to the crystalline form of 23 hydrochloride (HB form).

[0077] The HB form of PXRD described herein is described in WO 2015 / 009616. The PXRD of Form A of the compound can be clearly distinguished from that of Form A of the compound (shown in FIG. 2 herein). (See also the PXRD overlays shown in the figure). The HB form has, for example, (4.6±0.1) and Form A exhibits characteristic peaks at and (9.2±0.1)°2θ, whereas form B exhibits peaks in the same range. According to page 176 of International Publication No. 2015 / 009616, Among the four most characteristic peaks of Form A, one is at 11.6° 2θ. In contrast, the HB form described herein does not show a peak in the same range.

[0078] In another embodiment, the present invention provides a Cu-Kα 1,2 When measured at temperatures in the range of 20-30° C. using a line, the method according to one of the above embodiments but does not contain a peak at a 2θ angle of (11.6±0.2)°. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) that may be characteristic of the present invention.

[0079] In one embodiment, the present invention relates to a Cu-Kα 1,2 line When measured at a temperature in the range of 20 to 30° C. using LNP0 may be characterized as having no peak at a 2θ angle of 11.6±0.1)° 2θ. This relates to the crystalline form of 23 hydrochloride (HB form).

[0080] In another embodiment, the present invention provides a Cu-Kα 1,2 The lines shown in FIG. 1 herein are used to represent the temperature distribution when measured at temperatures in the range 20-30° C. The result of LNP023 hydrochloride can be characterized as having a PXRD essentially the same as that of The crystal form (HB form)

[0081] For example, the relative intensities of the peaks shown in FIG. 1 and listed in Table 2 are indicative of the actual morphology of the HB form. Generally, the morphology of most crystal grains varies to some extent depending on the grain size. This tends to give the specimen some preferred orientation in the sample holder. This is particularly true for needle- or plate-like crystals, where the reduction in size results in fine needles or small platelets. It is clear that the preferred orientation of the sample affects the intensities of the various peaks. As a result, some samples will be stronger and others weaker than would be expected from a completely random sample. do.

[0082] Illustrative FTIR embodiments: In one embodiment, the present invention provides a method for determining the molecular weight of a compound having a molecular weight of (3452±4) cm -1 , (2875±4)cm - 1 , and (1692±4) cm -1 has an FTIR spectrum containing a peak at a wave number of The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized in that:

[0083] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (1 692±4)cm -1 , and (1439±4) cm -1FTIR, including peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by having a spectrum do.

[0084] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (1 692±4)cm -1 , (1439±4)cm -1 , and (1243±4) cm -1 Waves The LNP023 hydrochloride salt has an FTIR spectrum including a peak at Concerning the crystalline form (HB form).

[0085] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (1 692±4)cm -1 , (1439±4)cm -1 , (1243±4)cm -1 and (7 67±4)cm -1 The present invention is characterized by having an FTIR spectrum including a peak at a wave number of This relates to the crystalline form of LNP023 hydrochloride (HB form).

[0086] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1692±4)cm -1 , (1439±4)cm -1 , (12 43±4)cm -1 , and (767±4) cm -1 The FTIR spectrum includes peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by having a tetramer structure.

[0087] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1439±4)cm -1 , (1243±4)cm -1 , and (7 67±4)cm -1 The present invention is characterized by having an FTIR spectrum including a peak at a wave number of This relates to the crystalline form of LNP023 hydrochloride (HB form).

[0088] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1439±4)cm -1 , (124 3±4)cm -1 and (767±4) cm -1 FTIR spectrum containing peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by having a crystalline structure.

[0089] In one embodiment, the present invention provides a method for determining the molecular weight of a compound having a molecular weight 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 Waves The LNP023 hydrochloride salt has an FTIR spectrum including a peak at Concerning the crystalline form (HB form).

[0090] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±4)cm -1 , (1439±4)cm -1 , (1243±4)cm -1 and (767 ±4)cm -1 L characterized by having an FTIR spectrum including a peak at a wave number of Concerning the crystalline form of NP023 hydrochloride (HB form).

[0091] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±4)cm -1 , (1497±4)cm -1 , (1439±4)cm -1 , (1243 ±4)cm -1 and (767±4) cm -1 FTIR spectrum containing peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized in that it has:

[0092] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±4)cm -1 , (1497±4)cm -1 , (1461±4)cm -1 , (1439 ±4)cm -1 , (1243±4)cm -1 and (767±4) cm -1 Peak at wavenumber A crystalline form of LNP023 hydrochloride characterized by having an FTIR spectrum comprising: HB form).

[0093] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±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 LN characterized by having an FTIR spectrum including a peak at a wave number of This concerns the crystalline form of P023 hydrochloride (HB form).

[0094] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±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 FTIR spectrum contains a peak at a wave number of The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized in that it has

[0095] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±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 Peak at wavenumber A crystalline form of LNP023 hydrochloride (H B type).

[0096] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±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 LNP characterized by having an FTIR spectrum including a peak at a wave number of This relates to the crystalline form of the 023 hydrochloride salt (HB form).

[0097] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm -1 , (2 732±4)cm -1 , (1709±4)cm -1 , (1692±4)cm -1 , (16 58±4)cm -1 , (1615±4)cm -1 , (1601±4)cm -1 , (151 5±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 FTIR spectrum contains peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), which is characterized by the following:

[0098] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (3274±4)cm -1 , (2 875±4)cm -1 , (2732±4)cm -1 , (1709±4)cm -1 , (16 92±4)cm -1 , (1658±4)cm -1 , (1615±4)cm -1 , (160 1±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 Contains a peak at wavenumber The crystalline form of LNP023 hydrochloride (HB form) is characterized by having an FTIR spectrum (state of mind).

[0099] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (3274±4)cm -1 , (2 933±4)cm -1 , (2875±4)cm -1 , (2732±4)cm -1 , (17 09±4)cm -1 , (1692±4)cm -1 , (1658±4)cm -1 , (161 5±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)c m -1 LNP02, characterized in that it has an FTIR spectrum including a peak at a wave number of This relates to the crystalline form of the trihydrochloride salt (HB form).

[0100] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±4) cm -1 , (2875±4)cm-1 , (2 732±4)cm -1 , (1692±4)cm -1 , (1439±4)cm -1 , (12 43±4)cm -1 and (767±4) cm -1 and a peak at wavenumber (3274±4) cm -1 , (2933±4)cm -1 , (1709±4)cm -1 , (1658±4)c m -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 and at least one more peak selected from the group consisting of A crystalline form of LNP023 hydrochloride ( HB form).

[0101] In another embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at a temperature of: (3452±2)cm -1 , (2875±2)cm -1 , and (1692±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , and (1439±2)cm-1 or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , ( 1439±2)cm -1 and (1243±2) cm -1 or (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 (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 (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 439±2)cm -1 , (1243±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm-1 , (1439±2)cm -1 , (1243±2)cm -1 and (7 67±2)cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1439±2)cm -1 , (12 43±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 39±2)cm -1 , (1243±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm-1 , (14 97±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 and (76 7±2)cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (124 3±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1243±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1, (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 and (767 ±2)cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184 ±2)cm -1 and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1, ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±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 (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±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 or (3452±2)cm-1 、(3274 ± 2) cm -1 、(2875 ± 2) cm -1 、( 2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1692 ± 2) cm -1 、(1 658 ± 2) cm -1 、(1615 ± 2) cm -1 、(1601 ± 2) cm -1 、(15 15 ± 2) cm -1 、(1497 ± 2) cm -1 、(1461 ± 2) cm -1 、(143 9 ± 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 ; or (3452 ± 2) cm -1 、(3274 ± 2) cm -1 、(2933 ± 2) cm -1 、( 2875 ± 2) cm -1 、(2732 ± 2) cm -1 、(1709 ± 2) cm -1 、(1 692 ± 2) cm -1 、(1658 ± 2) cm -1 、(1615 ± 2) cm -1 、(16 01 ± 2) cm -1 、(1515 ± 2) cm -1 、(1497 ± 2) cm -1 、(146 1 ± 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 Contains a peak at wavenumber The crystalline form of LNP023 hydrochloride (HB) characterized by having an FTIR spectrum (shape).

[0102] In one embodiment, the present invention uses a diamond ATR cell in the range of 20 to 30°C. When measured at temperature, it is (3452±2) cm -1 , (2875±2)cm -1 , (2 732±2)cm -1 , (1692±2)cm -1 , (1439±2)cm -1 , (12 43±2)cm -1 , and (767±2) cm -1 and a peak at wavenumber (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)c m -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 At least one more peak selected from the group consisting of and a crystalline form of LNP023 hydrochloride characterized by having an FTIR spectrum comprising: (HB form).

[0103] In yet another embodiment, the present invention provides a method for measuring the temperature in the range of 20 to 400° C. using a diamond ATR cell. When measured at a temperature of 30° C., the FT is essentially the same as that shown in FIG. 3 herein. Crystalline form of LNP023 hydrochloride (HB form) characterized by having an IR spectrum Regarding.

[0104] Illustrative DSC embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is essentially the same as shown in FIG. In one embodiment, the present invention provides a method for producing a fluororesin having ... When measured at a heating rate of 10 K / min, it shows a broad endothermic event that ends at about 170 °C, followed by LNP023 hydrochloric acid is characterized by having a DSC curve showing exothermic decomposition at about 200°C. In one embodiment, the crystalline form of the salt (HB form) has a broad absorption spectrum that terminates at about 170° C. The thermal phenomenon is endothermic in the range of 35℃ to 170℃ when measured at a heating rate of 10K / min. be.

[0105] Illustrative TGA embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is essentially the same as shown in FIG. The same can be characterized by thermogravimetric analysis (TGA). In one embodiment, the present invention provides When heated from 30 to 300 °C at a rate of 20 K / min, due to loss of water and residual solvents , 4.5% by weight or less, for example 4.3% by weight or less, for example 4.0% by weight or less, based on the weight of the crystalline form. % by weight or less, for example 3.8% by weight or less, for example 3.4% by weight or less, at about 220° C., for example LNPs characterized by having a TGA curve showing mass loss at temperatures between 200 and 220°C. This relates to the crystalline form of the 023 hydrochloride salt (HB form).

[0106] Illustrative DVS embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is essentially the same as shown in FIG. In one embodiment, the present invention can be characterized by the same DVS. By weight of the crystalline form, as measured by DVS at 5% and temperature (25±1.0)°C and 4.5% by weight or less, for example 4.0% by weight or less, for example 3.0% by weight or less, for example 2. 0% by weight or less, for example 1.8% by weight or less, 1.6% by weight or less, 1.5% by weight or less, or 1.4% by weight or less The crystalline form of LNP023 hydrochloride (HB form) is characterized by a mass change of less than 1% by weight. (state of mind).

[0107] Further illustrative embodiments: In another embodiment, the present invention relates to LNP023, which is characterized in that it is in a non-solvated form. In one embodiment, the crystal form of LNP023 hydrochloride is The crystalline form may be in the form of a hydrate, for example a monohydrate.

[0108] Morphology Illustration In one embodiment, the present invention provides a cylindrical or cubic morphology. The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized in that it exhibits the following formula:

[0109] In one embodiment, the present invention is cubic or cylindrical in nature, e.g., the shape is Regarding the crystalline form of LNP023 hydrochloride (HB form) with a qualitatively cubic crystal habit This results in a preferred crystal structure, as opposed to small needle-like or thin blade-like crystals. Such a preferred crystalline form can be achieved by, for example, temperature cycling. When subjected to crystallization engineering techniques followed by grinding to reduce particle size, the crystals described herein can be The method is obtained by carrying out the process described above.

[0110] The resulting particles are characterized by a suitable aspect ratio. ratio ψ A (0<ψ A ≦1) is defined as the ratio of the minimum and maximum values, and is the Feret diameter (Fer and diameter)ψ A =x Feret min / x Feret max It is. It gives an index of particle elongation; the smaller its value, the greater the particle length. Thus, in a further embodiment, the cubic crystalline form of LNP023 hydrochloride (HB form) The crystalline particles have an aspect ratio (a50) of greater than about 0.4, for example greater than about 0.45. In another embodiment, the cubic particles of the HB morphology have a molecular weight of about 0.4 to about 0.7, e.g. For example, it has an aspect ratio of about 0.45 to 0.6.

[0111] In a further embodiment, the cubic crystalline form of LNP023 hydrochloride (HB form) Particle size distribution of X 90 is less than about 300 μm, for example less than about 200 μm, for example less than about 150 μm In a further embodiment, the particle size distribution X 90 is about 30 to about 150 μm, e.g. For example, it is about 35 to about 130 μm, for example, about 40 to about 105 μm.

[0112] In a further embodiment, the particle size distribution of the cubic particles of the HB morphology is X 50 is about 5 to about 1 00 μm, for example, about 10 to about 70 μm, for example, about 15 to about 55 μm.

[0113] In a further embodiment, the particle size distribution of the cubic particles of the HB morphology is X 10 is about 0.1~ It is about 50 μm, for example, about 1 to about 30 μm, for example, about 2 to about 20 μm.

[0114] In a further embodiment, the cubic particles of the HB Form have a density of less than about 0.8 g / ml, e.g. In another embodiment, the composition has a compressed (15 kPa) bulk density of less than about 0.7 g / ml. The cubic particles of the HB form have a concentration of about 0.4 to about 0.7 g / ml, for example about 0.50 to about 0 A compressed (15 kPa) bulk density of 0.65 g / ml, e.g., about 0.55 to about 0.60 g / ml has.

[0115] composition Illustrative embodiments: In another aspect, the present invention relates to a method for the treatment of a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of ... pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis, A composition comprising the HB form of LNP023 hydrochloride according to claim 1, further comprising LNP023 hydrochloride. For example, the present invention relates to a composition that is essentially free of any solid form of any of the compounds described herein. A composition comprising the HB form of LNP023 hydrochloride may contain, by weight of the composition, Up to 20% by weight, for example up to 10% by weight, for example up to In one embodiment, the other component of LNP023 hydrochloride is 5, 4, 3, 2 or 1% by weight. Either solid form may be Form A as described in WO 2015 / 009616. Form A of LNP023 hydrochloride is the most commonly used form, with a wavelength of 0.15419 nm. Cu-Kα with 1,2 When measured at temperatures in the range of 20 to 30°C using the line, ( The PXRD shows a characteristic peak at a 2θ angle of 11.6±0.1°. The absence of this peak at a 2θ angle of (11.6±0.1)° in XRD indicates that The absence of Form A of LNP023 hydrochloride in the composition is confirmed.

[0116] In one embodiment, the present invention provides a method for the treatment of a pulmonary circulation disease, comprising the steps of: A composition comprising the HB form of LNP023 hydrochloride as described in the document, wherein the HB form has a wavelength of 0.15419n Cu-Kα with m 1,2 When measured at temperatures in the range 20-30°C using the line, Regarding the composition having a PXRD that does not contain a peak at a 2θ angle of (11.6±0.1)° .

[0117] In one embodiment, the present invention provides a composition comprising, by weight of the total composition, any of the above embodiments. The HB crystalline form of LNP023 hydrochloride as defined above is at least 90% by weight, e.g. At least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99% by weight, in an amount equal to about 100% by weight, with the remaining material being LNP023 hydrochloride. or reaction or processing impurities resulting from the manufacture of the composition. .

[0118] process Illustrative embodiments: In another aspect, the present invention provides the HB form of LNP023 hydrochloride as described herein, or of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof. 1. A process for producing a composition comprising an HB form, comprising: (i) providing LNP023 hydrochloride in a solid form; (ii) dissolving the LNP023 hydrochloride provided in step (i) in a first solvent comprising acetone and water; and heating to dissolve the solids and provide a solution; (iii) cooling the solution obtained in step (ii) and adding acetone, ethyl acetate, or a combination thereof; adding a second solvent comprising a mixture to provide crystals in the mother liquor; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor; (v) optionally washing the isolated crystals obtained in step (iv); and (vi) drying the crystals obtained in step (iv) or (v); The present invention relates to a process comprising:

[0119] Process content example: The solid LNP023 hydrochloride starting material was prepared according to the method described in WO 2015 / 009616. It can be prepared according to the procedure disclosed in Example 26d of the present invention.

[0120] The solid starting material provided in step (i) may be suspended in a first solvent of acetone and water. The solvent may include other organic solvents. In one embodiment, acetone and water are used to form a suspension. The concentration of LNP023 hydrochloride in the suspension may be, for example, about 0.07 to 0.30 g / g, for example, about 0.10 to 0.25 g / g, for example, about 0.15 to 0 In one embodiment, the concentration is in the range of about 0.20 g / g. In the above, the ratio of acetone to water (g / g) is, for example, 60:40 to 90:10, for example, 65: In one embodiment, the ratio is 45 to 85:15, for example, 75:25 to 80:20. The heating in ii) is carried out at an elevated temperature, for example, in the range of about 30 to 56° C., for example, about 45 to 55° C. Heating may be performed at any temperature within the range of 100° C. Heating may be performed by, but is not limited to, stirring, agitating, mixing, shaking, vibrating, etc. by any type of movement of a solid material suspended in a solvent, such as by centrifugation, sonication, wet grinding, etc. Once the solid materials are dissolved, the solution can be heated to about 20-50° C., e.g., about The mixture may be cooled to a temperature in the range of 35 to 45° C. and may be diluted with acetone, ethyl acetate, or a combination thereof. A second solvent may be added, the second solvent may comprise a further organic solvent or water. In the present embodiment, acetone and ethyl acetate are the only solvents added in step (iii). When both acetone and ethyl acetate are used as second solvents, they The mixture may be added as a solvent mixture of ethyl acetate and ethyl acetate or may be added sequentially. In the case of sequential addition, acetone is added first, followed by ethyl acetate. The concentration of LNP023 hydrochloride is, for example, about 0.04 to 0.15 g / g, for example, about 0.05 to 0.10 g / g, and for example in the range of about 0.05 to 0.07 g / g, e.g. For example, the concentration is about 0.06 g / g. The ratio of acetone to ethyl acetate (g / g) is In one embodiment, the suspension further comprises a diluent having a ratio of about 0.5:3 to 1:1, for example 1:2. The crystallization is completed by cooling to a temperature in the range of about 25°C, for example about 5 to 15°C, for example 10°C. When the HB form is obtained in essentially pure form, at least a portion of the crystals may be separated from the mother liquor. In one embodiment, the mixture may be separated by filtration, centrifugation, solvent evaporation, or decantation. The crystals are separated from their mother liquor by conventional methods such as filtration or centrifugation. In one embodiment, the crystals may be separated from their mother liquor by filtration.

[0121] Optionally, in a further step, the isolated crystals are dissolved in a suitable solvent, e.g. an organic solvent. Suitable organic solvents include, but are not limited to, acetone and ethyl acetate. include.

[0122] The resulting crystals can then be dried. Drying can be carried out at a temperature of about 70° C. or less, for example about 60° C. The drying may be carried out at a temperature below 50° C., for example at about 50° C. Drying may also be carried out at about room temperature. Drying may be performed for a period ranging from about 2 to 24 hours, such as from about 4 to 16 hours, such as from about 6 to 10 hours. In one embodiment, drying may be performed for a period of about 6 to 8 hours. The drying may be carried out at pressure or under reduced pressure. In one embodiment, the drying is carried out at a pressure of about 200 mbar. In one embodiment, the drying is carried out at a pressure of about 150 mbar or less. In one embodiment, the drying is carried out at a pressure of about 80 mbar or less. This is carried out under a vacuum below ar.

[0123] In one embodiment, specific crystallization techniques are applied to the process to provide improved product processability. The HB form crystals can be obtained by using techniques such as, but not limited to, temperature cycling, or adding a second solvent for an extended period of time, e.g., 12 to 36 hours, e.g., temperature cycling The temperature cycle may be carried out as follows: in step (iii), Before adding the solvent, the mixture is dissolved at a temperature in the range of about 0 to 25°C, for example about 5 to 15°C, for example at 10°C. The liquid may be cooled and then cooled to a temperature in the range of about 30-45°C, e.g. about 30-40°C, e.g. The temperature cycle may be repeated at least three times, for example at least six times, for example at 35° C. For example, the temperature cycle may be performed at least 8 times, for example 6 to 12 times. After the temperature cycle, a second solvent is added. In one embodiment, the second solvent may be ethyl acetate.

[0124] After engineering, i.e., after applying the specific crystallization techniques mentioned above, the HB morphology is clearly The morphology of the crystals provides excellent powder properties and Processability occurs and formulation of pharmaceuticals containing HB forms is performed using standard manufacturing processes and equipment. In one embodiment, this technique allows for engineering. In contrast to the A form, which cannot be crushed, the HB form is not brittle and therefore prone to fracture and wide cracking. Problems with particle size distribution can be minimized. Furthermore, the flowability of the HB form is Therefore, the HB morphology is preferred, especially when engineered. It combines good powder properties with high physicochemical stability. Therefore, it is more stable than Form A. Ideal combination of LNP023 hydrochloride for standard manufacturing of superior and improved pharmaceutical compositions It is in solid state form.

[0125] In one embodiment, the present invention provides, as step (iii) of the above procedure, a) cooling the solution obtained in step (ii) followed by reheating the solution again; b) repeating step (a) at least three times; and c) adding a second solvent comprising acetone, ethyl acetate, or a combination thereof; HB form of LNP023 hydrochloride as described herein, or any of the above embodiments and equivalents thereof. A composition comprising the HB form of LNP023 hydrochloride as defined in any one of the embodiments. Regarding the manufacturing process.

[0126] Crushing illustration The particles of the HB form of LNP023 hydrochloride described herein may be loaded into capsules. or otherwise further processed. To facilitate filling of the particles directly into the capsule without the need for grinding, This can be done.

[0127] In one embodiment, the particle size of the HB form of LNP023 hydrochloride is determined by rotor impact microscopy. Rotor impact mills use different stationary and rotating tool elements, e.g. For example, a rotating wing beater with a stationary screen, a stationary screen and an impact element. a rotating wing beater having a stationary pin disc, or a rotating This can be done using a rotating pin disk with a pin disk. The HB form of 023 hydrochloride provides adequate powder transport for proper control of the feed rate of the associated powder. The rotor impact mill is operated by a system such as a vibratory feeder or a twin-shaft feeder. The material is transported into the rotor impact mill by the rotating elements or by the rotor impact The powder is further infused with gas flow generated by a blower connected to the injector. The particles are transported to the Pacttool element. Particle size reduction of the HB form of LNP023 hydrochloride particles is generated by impact with a rotating element, by impact with a stationary element, or by collision between HB particles. The physical properties of the HB form of LNP023 hydrochloride were adjusted Appropriate process parameters such as rotor speed and feed rate are important for the rotor impact mill. related to specific equipment parameters of the filter, e.g. gas transport by filters, cyclones and collecting the ground product having controlled physical properties in a product container after separation from the ground product. The milled product is finally blended by suitable techniques, e.g., a diffusion blender, to produce the product. Adequate physical uniformity of the produced batches is achieved.

[0128] Rotor impact mills, for example, are used to mill pins. The pin disc rotation with a stationary pin disc tool is often described in the art as The scale-independent parameters of rotor speed and feed rate are It can be described by the rotor tip speed and the specific feed rate. The rotor speed for a given instrument scale is essentially: The parameter rotor tip speed is related to the pin disc diameter of the associated instrument scale. The feed rate for a particular equipment scale is essentially determined in terms of scale-independent parameters. , which is related to the pin surface area of ​​the relevant equipment scale by the parameter specific feed rate. The scale-independent grinding parameters were adjusted using a rotor impact mill. The HB form of LNP023 hydrochloride with the following physical properties is obtained: diameter of the external rotating pin However, normalization is taken into account, whereas the rotor tip speed is 10 to 60 m / s, or the rotational Taking into account normalization, the cylindrical pin surface area of ​​the m 2 ) for a specific feed rate.

[0129] In a scale-dependent example, the HB form of LNP023 hydrochloride was used in Model 100UPZ ,Hosokawa Alpine AG,Augsburg / Germany It uses rotor impact mills such as those from Germany and is in the public domain. A rotating pin disc with a stationary pin disc tool, often described as a pin mill, is used. The rotor speed is 1,800 to 10,500 rpm, for example 4 ,000 to 8,500 rpm, e.g., a process using a rotor speed of 6,000 rpm By manipulating the feed rate, products with tailored physical properties can be obtained. , for example 1-22 kg / h, for example 6-18 kg / h, for example at a feed rate of 15 kg / h be.

[0130] Pharmaceutical Compositions and Uses Illustrative embodiments: In a further aspect, the present invention relates to a method for producing a pharmaceutical composition comprising administering to a subject a compound according to the present invention ... compound according to the present invention. P023 hydrochloride in its HB form or in any one of the above aspects and corresponding embodiments thereof The present invention relates to the use of a composition comprising the HB form of LNP023 hydrochloride as defined above.

[0131] In yet another embodiment, the present invention provides a method for the treatment of LNP0, e.g., in a predetermined or therapeutically effective amount. 23 HCl HB form or any of the above aspects and corresponding embodiments thereof. The HB form of LNP023 hydrochloride defined as either one of the following and at least one drug and a suitably acceptable excipient.

[0132] In one embodiment, the method may be implemented as defined in any one of the above aspects and corresponding embodiments thereof. A pharmaceutical composition comprising the HB form of LNP023 hydrochloride, as an anhydrous LNP023 free base, Calculated doses of up to about 200 mg contain LNP023 hydrochloride.

[0133] In that embodiment, the pharmaceutical composition comprises: Contains LNP023 hydrochloride in a dosage of about 10 mg to about 200 mg.

[0134] In that embodiment, the pharmaceutical compositions are each calculated as anhydrous LNP023 free base. and about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg. Contains LNP023 hydrochloride.

[0135] In that embodiment, the pharmaceutical compositions are each calculated as anhydrous LNP023 free base. The LNP0 was administered at doses of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Contains 23 hydrochloride.

[0136] In one embodiment, a therapeutically effective amount of the HB form of LNP023 hydrochloride is 3 Consisting of 1, 5, 10, 25, 50, 100 and 200 mg calculated as free base In one embodiment, a therapeutically effective amount of the HB form of LNP023 hydrochloride is selected from the group consisting of: In one embodiment, the treatment of the HB form of LNP023 hydrochloride is The therapeutically effective amount is 50 mg. In one embodiment, the treatment of the HB form of LNP023 hydrochloride The effective dose is 10 mg.

[0137] At least one pharma- ceutical acceptable salt may be included in the pharmaceutical compositions described herein. The additives include, for example, excipients, fillers, diluents, binders, disintegrants, lubricants, flow agents, and the like. Suitable excipients are, for example, dispersible liquids or capsules. In a preferred embodiment, the pharmaceutical composition comprises one pharma- ceutical acceptable additive. Additives include, for example, excipients.

[0138] In a preferred embodiment, a pharmaceutical composition comprising the HB form of LNP023 hydrochloride, or H of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof. The composition comprising Form B is an oral solid dosage form. In one embodiment, the oral solid dosage form is In one embodiment, the oral dosage form is selected from the group consisting of tablets, tablets, and capsules. In one embodiment, the oral dosage form is a capsule. In this case, the capsule is a size 0 capsule.

[0139] The tablet may be prepared in the HB form of LNP023 hydrochloride or in accordance with any of the above-mentioned embodiments and corresponding embodiments thereof. The present invention relates to a composition comprising the HB form of LNP023 hydrochloride, At most one excipient, such as a filler, diluent, binder, disintegrant, lubricant, flow agent or the like. Optionally, the composition may be prepared by mixing with a combination of dry or wet granulation. A granulation process such as a pelletizing step is carried out before compression.

[0140] The capsules contain the HB form of LNP023 hydrochloride, or the above-mentioned embodiments and corresponding embodiments thereof. The present invention relates to a composition comprising the HB form of LNP023 hydrochloride as defined in any one of the above aspects. At least one excipient, such as a filler, diluent, binder, disintegrant, lubricant, flow agent or the like By mixing with the combination and filling the blend into capsules used as excipients Alternatively, the HB form of LNP023 hydrochloride may be prepared using Fill neat into capsules used. Capsule shells are made of gelatin selenite. The shell may be a shell or a hydroxypropyl methylcellulose (HPMC) shell.

[0141] In one embodiment, the present invention provides a capsule containing LNP02, such as a size 0 capsule. In one embodiment, the present invention relates to a pharmaceutical composition comprising particles of the HB form of the trihydrochloride salt. The HB particles have an aspect ratio of 0.4 to about 0.7, for example, 0.45 to 0.6. In embodiments, the HB form particles within the capsules have a diameter of about 5 to about 100 μm, e.g., about 10 to about 20 μm. Particle size distribution X of about 70 μm, for example about 15 to about 55 μm 50 In one embodiment, The HB form particles in the capsule are about 0.4 to about 0.7 mg / ml, for example about 0.50 to about Compressed (15 kPa) bulk density of 0.65 g / ml, e.g., about 0.55 to about 0.60 g / ml Has a degree.

[0142] In a further aspect, the present invention relates to a compound for use in the treatment of diseases and disorders as described herein: the HB form of LNP023 hydrochloride, or a composition comprising the HB form of LNP023 hydrochloride, or of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof. It relates to pharmaceutical compositions comprising the HB form.

[0143] In yet another aspect, the present invention relates to a method for producing a composition according to the invention. and for the treatment or indications disclosed in WO 2019 / 043609. For prevention, specifically, paroxysmal nocturnal hemoglobinuria ( Glomerular C3 precipitation in patients with PNH, IgAN (immunoglobulin A nephropathy), and MN (membranous nephropathy) Other nephropathies with evidence of infection, and HUS (E. coli-induced hemolytic uremic syndrome) group), and for the treatment or prevention of atypical hemolytic uremic syndrome (aHUS), the HB form of LNP023 hydrochloride, or a composition comprising the HB form of LNP023 hydrochloride, or of LNP023 hydrochloride as defined in any one of the above aspects and corresponding embodiments thereof. It relates to pharmaceutical compositions comprising the HB form.

[0144] In another aspect, the present invention relates to a method for the treatment of a variety of conditions, each of which is incorporated herein by reference in its entirety. , International Publication No. 2015 / 009616 and International Publication No. 2019 / 0436 Methods of treating the diseases and disorders disclosed in Brochure No. 09 in a subject in need thereof In one embodiment, the disease or disorder is complement-induced renal disease C3G (C3 glomerulonephropathy). Paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN) and MN Other nephropathies with evidence of glomerular C3 deposition, such as membranous nephropathy, HUS (E. coli li) Induced hemolytic uremic syndrome (IHS) and atypical hemolytic uremic syndrome (aHUS) In one embodiment, the method comprises administering to the subject a HB- The method includes administering to a subject a therapeutically effective amount of the composition.

[0145] In another aspect, the present invention provides a method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a patient in need thereof. A method of treating an elephant comprising administering to the elephant a therapeutically effective amount of the HB form of LNP023 hydrochloride. and treating the subject.

[0146] In one embodiment, the method of treating PNH in a subject includes administering anhydrous LNP023 free base Subjects will be administered the HB form of LNP023 at a daily dose of up to approximately 400 mg, calculated based on the baseline. In one embodiment, the administration is twice daily (bid), e.g. Approximately every 12 hours at a dose of up to approximately 200 mg calculated as anhydrous LNP023 free base is administered.

[0147] In one embodiment, the method of treating PNH in a subject includes administering anhydrous LNP023 free base The HB form of LNP023 was administered to subjects at a daily dose of approximately 20 mg to approximately 400 mg, calculated based on the baseline. In one embodiment, the administration is twice daily (bid). For example, about 10 mg to about 2 mg of anhydrous LNP023 free base every 12 hours. 00mg dose.

[0148] In one embodiment, the method of treating PNH in a subject includes administering anhydrous LNP023 free base About 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 4 In one embodiment, the method comprises administering to the subject the HB form of LNP023 at a daily dose of 100,000 mg. In the present case, the administration is twice daily (bid), for example about every 12 hours, with anhydrous LNP0 23 Approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, or is administered at a dose of approximately 200 mg.

[0149] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 is administered to the subject at a total daily dose of about 20 mg, calculated as the free base. In the present invention, the administration is twice daily (bid), for example about every 12 hours, at a dose of about 10 Administered in mg.

[0150] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 is administered to the subject at a total daily dose of about 50 mg, calculated as the free base. In the present invention, the administration is twice daily (bid), for example about every 12 hours, at a dose of about 25 Administered in mg.

[0151] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 is administered to the subject at a total daily dose of about 100 mg, calculated as the free base. In some embodiments, the administration is twice daily (bid), for example about every 12 hours, at a dose of about 5 The dose was 0 mg.

[0152] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 is administered to the subject at a total daily dose of about 200 mg calculated as the free base. In some embodiments, the administration is twice daily (bid), for example about every 12 hours, at a dose of about 1 The dose is 00mg.

[0153] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 is administered to the subject at a total daily dose of about 400 mg, calculated as the free base. In some embodiments, the administration is twice daily (bid), for example about every 12 hours, at a dose of about 2 The dose is 00mg.

[0154] In one embodiment of the method of treating PNH, the HB form of LNP023 is administered twice daily ( bid), for example, orally administered to a subject about every 12 hours.

[0155] In one embodiment of the method of treating PNH, the HB form of LNP023 is 023 200 mg, calculated as the free base, twice daily (bid), e.g. The compound is orally administered to the subject approximately every 12 hours.

[0156] In another aspect, the present invention relates to a complement-induced kidney disease, C3G (C3 glomerulopathy), A method of treating a subject in need thereof, comprising administering to a subject a therapeutically effective amount of the HB form of LNP023. administering to a subject, thereby treating the subject.

[0157] In one embodiment, the method of treating C3G in a subject includes administering to a subject the HB form of LNP023. Subjects will be administered a maximum daily dose of 400 mg, calculated as anhydrous LNP023 free base. In one embodiment, the dose is calculated as anhydrous LNP023 free base. up to 200 mg twice daily (bid), e.g., about every 12 hours It is.

[0158] In one embodiment, the method of treating C3G in a subject includes administering to a subject the HB form of LNP023. The daily dose is approximately 20 mg to approximately 400 mg calculated as anhydrous LNP023 free base. In one embodiment, the administration comprises administering LNP023 as an anhydrous free base. At a dose of about 10 to about 200 mg calculated based on the above, twice a day (bid), for example about 1 It is given every two hours.

[0159] In one embodiment, the method of treating C3G in a subject includes administering to a subject the HB form of LNP023. is calculated as about 20 mg, about 50 mg, about 100 mg, about In one embodiment, the method comprises administering to a subject a daily dose of about 200 mg, or about 400 mg. The dosage is about 10 mg, about 25 mg, calculated as anhydrous LNP023 free base. , at a dose of about 50 mg, about 100 mg, or about 200 mg, twice a day (bid) , for example about every 12 hours.

[0160] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 is administered to the subject at a daily dose of about 20 mg calculated as the free base. In this case, the administration is at a dose of about 10 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0161] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 is administered to the subject at a total daily dose of about 50 mg, calculated as the free base. In the present invention, the administration is at a dose of about 25 mg, twice a day (bid), for example about 1 It is given every two hours.

[0162] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 is administered to the subject at a total daily dose of about 100 mg, calculated as the free base. In some embodiments, the administration is at a dose of about 50 mg, twice a day (bid), for example about It is given every 12 hours.

[0163] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 is administered to the subject at a total daily dose of about 200 mg calculated as the free base. In some embodiments, the administration is twice daily (bid) at a dose of about 100 mg, for example It is given approximately every 12 hours.

[0164] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 is administered to the subject at a total daily dose of about 400 mg, calculated as the free base. In some embodiments, the administration is twice daily (bid) at a dose of about 200 mg, e.g. It is given approximately every 12 hours.

[0165] In one embodiment of the method of treating C3G, the HB form of LNP023 is administered twice daily ( bid), for example, orally administered to a subject about every 12 hours.

[0166] In one embodiment of the method of treating C3G, the HB form of LNP023 is anhydrous LNP 023 Approximately 200 mg calculated as the free base, twice daily (bid), e.g. The compound is orally administered to the subject approximately every 12 hours.

[0167] In another aspect, the present invention provides a method for treating IgAN (Immunoglobulin A Nephropathy) in a patient in need thereof. A method of treatment in a subject, comprising administering to the subject a therapeutically effective amount of the HB form of LNP023. and thereby treating a subject.

[0168] In one embodiment, the method of treating IgAN in a subject comprises administering anhydrous LNP023 free Subjects will be administered the HB form of LNP023 at a daily dose of up to approximately 400 mg calculated as the base. In one embodiment, the administration comprises administering Doses of up to about 200 mg administered twice a day (bid), e.g., about every 12 hours is administered.

[0169] In one embodiment, the method of treating IgAN in a subject comprises administering anhydrous LNP023 free The HB form of LNP023 was detected at daily doses of about 20 to about 400 mg calculated as the base. In one embodiment, the administration comprises administering to an elephant anhydrous LNP023 free base. About 10 to about 200 mg, calculated as It is given every 12 hours.

[0170] In one embodiment, the method of treating IgAN in a subject comprises administering anhydrous LNP023 free About 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 4 mg calculated as base In one embodiment, the method comprises administering to the subject the HB form of LNP023 at a daily dose of 100,000 mg. In this case, the dosage is about 10 mg, about 25 mg, calculated as anhydrous LNP023 free base. g, about 50 mg, about 100 mg, or about 200 mg, twice daily (bid) , for example about every 12 hours.

[0171] In one embodiment of the method of treating IgAN, the HB form of LNP023 is P023 is administered to the subject at a total daily dose of about 20 mg, calculated as the free base. In some embodiments, the administration is at a dose of about 10 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0172] In one embodiment of the method of treating IgAN, the HB form of LNP023 is P023 is administered to the subject at a total daily dose of about 50 mg, calculated as the free base. In some embodiments, the administration is at a dose of about 25 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0173] In one embodiment of the method of treating IgAN, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 100 mg calculated as the free base. In one embodiment, the administration is at a dose of about 50 mg, twice a day (bid), for example about 1 It is given every two hours.

[0174] In one embodiment of the method of treating IgAN, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 200 mg calculated as the free base. In one embodiment, the administration is at a dose of about 100 mg, twice a day (bid), for example about It is given every 12 hours.

[0175] In one embodiment of the method of treating IgAN, the HB form of LNP023 is Subjects will be administered a total daily dose of approximately 400 mg calculated as P023 free base. In one embodiment, the administration is at a dose of about 200 mg, twice a day (bid), for example at about It is given every 12 hours.

[0176] In one embodiment of the method of treating IgAN, the HB form of LNP023 is administered twice daily. (bid), for example, orally administered to a subject about every 12 hours.

[0177] In one embodiment of the method of treating IgAN, the HB form of LNP023 is P023: Approximately 200 mg, calculated as the free base, twice daily (bid) For example, the compound is orally administered to a subject about every 12 hours.

[0178] In another embodiment, the present invention provides a method for treating MN (membranous nephropathy), such as idiopathic MN (iMN), The method of treating a subject in need thereof, comprising administering a therapeutically effective amount of the HB form of LNP023. to a subject, thereby treating the subject.

[0179] In one embodiment, the method of treating MN, e.g., iMN, in a subject comprises administering anhydrous LNPs. Subjects were administered the HBsAg of LNP023 at daily doses of up to approximately 400 mg calculated as the 023 free base. In one embodiment, the administration comprises administering an anhydrous LNP023 free base form. up to about 200 mg daily, calculated on a daily basis, twice a day (bid), e.g., about It is given every 12 hours.

[0180] In one embodiment, the method of treating MN, e.g., iMN, in a subject comprises administering anhydrous LNPs. Subjects were administered LNP023 at a daily dose of about 20 to about 400 mg, calculated as the 023 free base. In one embodiment, the administration comprises administering an anhydrous LNP023 free form. Approximately 10 to 200 mg, calculated as the free base, twice daily (bid), e.g. For example, approximately every 12 hours.

[0181] In one embodiment, the method of treating MN, e.g., iMN, in a subject comprises administering anhydrous LNPs. 023 Approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg calculated as the free base or administering to the subject the HB form of LNP023 at a daily dose of about 400 mg. In an embodiment, the dose is about 10 mg calculated as anhydrous LNP023 free base. , about 25 mg, about 50 mg, about 100 mg, or about 200 mg, twice daily (b. id), for example about every 12 hours.

[0182] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 A total daily dose of about 20 mg, calculated as the 23 free base, is administered to the subject. The administration is at a dose of about 10 mg, twice a day (bid), for example about 12 hours. It is administered once a day.

[0183] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 A total daily dose of about 50 mg, calculated as the 23 free base, is administered to the subject. The administration is at a dose of about 25 mg, twice a day (bid), for example about 12 hours. It is administered once a day.

[0184] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 The subject is administered a total daily dose of about 100 mg, calculated as the 23 free base. In this case, the administration is at a dose of about 50 mg, twice a day (bid), for example at about 12:00 p.m. It is administered at intervals.

[0185] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 The subject is administered a total daily dose of about 200 mg, calculated as the 23 free base. In this case, the administration is at a dose of about 100 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0186] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 A total daily dose of about 400 mg, calculated as the 23 free base, is administered to the subject. In this case, the administration is at a dose of about 200 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0187] In one embodiment of the method of treating MN, the HB form of LNP023 is administered twice daily (b .id), which is orally administered to the subject, for example, about every 12 hours.

[0188] In one embodiment of the method of treating MN, the HB form of LNP023 is 23 200 mg calculated as the free base, twice daily (bid), e.g., approximately To be administered orally to subjects every 12 hours.

[0189] In another aspect, the present invention provides a method for treating atypical hemolytic uremic syndrome (aHUS) in a patient in need thereof. A method of treatment in a subject, comprising administering to the subject a therapeutically effective amount of the HB form of LNP023. and administering to the subject, thereby treating the subject.

[0190] In one embodiment, the method of treating aHUS in a subject includes administering anhydrous LNP023 free Subjects will be administered the HB form of LNP023 at a daily dose of up to approximately 400 mg calculated as the base. In one embodiment, the administration comprises administering Doses of up to about 200 mg administered twice a day (bid), e.g., about every 12 hours is administered.

[0191] In one embodiment, the method of treating aHUS in a subject includes administering anhydrous LNP023 free The subjects were administered the HB form of LNP023 at a daily dose of about 20 to about 400 mg calculated as the base. In one embodiment, the administration comprises administering anhydrous LNP023 free base and A dose of about 10 to about 200 mg calculated based on the above formula is administered twice a day (bid), for example about 1 It is given every two hours.

[0192] In one embodiment, the method of treating aHUS in a subject includes administering anhydrous LNP023 free About 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 4 mg calculated as base 00mg daily dose of the HB form of LNP023 to the subject. In the present study, the dosage is about 10 mg, about 25 mg, calculated as anhydrous LNP023 free base. mg, about 50 mg, about 100 mg, or about 200 mg, twice daily (bid ), for example, about every 12 hours.

[0193] In one embodiment of the method of treating aHUS, the HB form of LNP023 is P023 is administered to the subject at a total daily dose of about 20 mg, calculated as the free base. In some embodiments, the administration is at a dose of about 10 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0194] In one embodiment of the method of treating aHUS, the HB form of LNP023 is P023 is administered to the subject at a total daily dose of about 50 mg, calculated as the free base. In some embodiments, the administration is at a dose of about 25 mg, twice a day (bid), for example about 12 It is dosed hourly.

[0195] In one embodiment of the method of treating aHUS, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 100 mg calculated as the free base. In one embodiment, the administration is at a dose of about 50 mg, twice a day (bid), for example about 1 It is given every two hours.

[0196] In one embodiment of the method of treating aHUS, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 200 mg calculated as the free base. In one embodiment, the administration is at a dose of about 100 mg, twice a day (bid), for example about It is given every 12 hours.

[0197] In one embodiment of the method of treating aHUS, the HB form of LNP023 is Subjects will be administered a total daily dose of approximately 400 mg calculated as P023 free base. In one embodiment, the administration is at a dose of about 200 mg, twice a day (bid), for example at about It is given every 12 hours.

[0198] In one embodiment of the method of treating aHUS, the HB form of LNP023 is administered twice daily. (bid), for example, orally administered to a subject about every 12 hours.

[0199] In one embodiment of the method of treating aHUS, the HB form of LNP023 is P023 200 mg calculated as the free base, twice daily (bid), e.g. For example, the compound is orally administered to a subject about every 12 hours.

[0200] All of the above embodiments relating to methods of treating a particular disease at a particular dose include: the HB form of LNP023 used in the treatment of a particular disease at a particular dose according to the present invention; L in the manufacture of a drug for treating a particular disease in a particular dose according to the present invention Use of the HB form of NP023; HB form of LNP023 for treating certain diseases in specific doses according to the present invention Use of form; and HB forms of LNP023 used in the treatment of specific diseases at specific doses according to the present invention and one or more pharma- ceutical acceptable carriers; are equally applicable to

[0201] Test methods for morphological properties Aspect ratio: Aspect ratio refers to the ratio of the maximum length of a crystal to its minimum width. At an aspect ratio of 1, the crystal has an equiaxed habit. As the aspect ratio decreases below 1, On the other hand, as the aspect ratio increases beyond 1, the crystal habit becomes more tabular. In accordance with the present disclosure, the cubic shaped particles of the HB morphology have a crystallographic habit approaching that of about 0.4 ~Aspect ratio a of about 0.7 50 has.

[0202] Sympatec GmbH,Clausthal-Zellerfeld,Germ Dynamic image analysis using the QICPIC dynamic image analyzer available from any The aspect ratio was determined by the DIA (Discrete Image Analysis) method. do.

[0203] Particle size distribution: Particle size distribution is determined by Sympatec GmbH, Clausthal-Zell Laser light diffraction was performed using a commercially available Helos instrument from Erfeld, Germany. It is measured by the LLD method.

[0204] Compressed bulk density: Compressed (15 kPa) bulk density is FT4 (Freeman Techno logy) powder rheometer. EXAMPLES

[0205] The following non-limiting examples are illustrative of the present disclosure and are not intended to be limiting in any way. It should not be interpreted.

[0206] Example 1: Preparation of the HB form of LNP023 hydrochloride As described in Example 26d of WO 2015 / 009616, Form LNP023-HCl salt was obtained. 9.3 g of Form A of LNP023 hydrochloride salt was dissolved in acetone. The mixture was suspended in 48.1 g of acetone and water (acetone:water = 78:22 m:m) and dissolved at approximately 50°C. The solution was cooled to 40° C. and 136 g of a mixture of acetone and ethyl acetate (acetone A 1:2 m:m solution of ethyl acetate was added within 24 hours. The suspension was cooled to 10°C. Crystallization was completed by filtration and drying under vacuum at 50° C. 7.7 g of crystalline LNP023-HCl salt monohydrate (HB form) was obtained.

[0207] Example 2: Preparation of the HB form of LNP023 hydrochloride using seed crystals As described in Example 26d of WO 2015 / 009616, Form LNP023-HCl salt was obtained. 42 g of Form A of LNP023 hydrochloride was dissolved in acetone. The mixture was suspended in 212 g of acetone and water (acetone:water = 80:20 m:m) and dissolved at approximately 50°C. The solution was cooled to 25° C. and the crystalline LNP023-HCl salt obtained according to Example 1 was added. 0.4 g of hydrate (HB form) seeds were added to initiate crystal growth. 207 g of ethanol was added within 3 hours, followed by 414 g of ethyl acetate within 6 hours. The product was isolated by filtration and dried under vacuum at 50° C. to give crystalline LNP023-HC 36 g of l-salt monohydrate (HB form) was obtained.

[0208] Example 3: Engineered LNP0 with temperature cycling Preparation of the HB form of 23 hydrochloride As described in Example 26d of WO 2015 / 009616, Form LNP023-HCl salt was obtained. 80 g of Form A of LNP023 hydrochloride was dissolved in acetone. The mixture was suspended in 409 g of acetone and water (78:22 m:m) and dissolved at approximately 50°C. The solution was cooled to 40° C. and the crystalline LNP023-HCl salt obtained according to Example 1 was added. 0.32 g of hydrate (HB form) seeds were added to initiate crystal growth. Temperature cycles were performed 9 times by cooling to 35°C and heating to 35°C. Within 2 hours, 1090 g of ethyl acetate was added, followed by cooling to 5° C. The product was separated by filtration. The crystalline LNP023- 66 g of HCl salt monohydrate (HB form) was obtained.

[0209] Example 4: Characterization of the HB form of LNP023 hydrochloride The title compound is the same as Example 26d in WO 2015 / 009616. character 1 H NMR spectrum.

[0210] Illustration of the analysis and interpretation of the results: Powder X-ray diffraction Together with the focusing mirror and solid-state PIXcel detector, the Bragg-Brentano geometry Bruker D8 Advance diffractometer with Cu-Kα 1,2 line (wavelength 0 PXRD was performed using a 35 nm spectrophotometer (15419 nm) at ambient conditions over the 2° to 40° 2θ angle range. in the 0.015 to 0.020° 2θ range, with an approximate process time of at least 40 seconds Applying the step size, the tube voltage was 30 to 40 kV and the tube current was 40 mA. The typical accuracy of the 2θ values ​​is ±0.2° 2θ, e.g., ±0.1° 2θ. Thus, for example, the HB of LNP023 hydrochloride, which appears at 9.2° 2θ, The diffraction peaks of this form range from (9.2-0.2)° to (9 .2+0.2)°2θ, for example in the range of (9.2-0.1)°~(9.2+0.1)°2θ It can appear in.

[0211] A representative diffractogram of the HB form of LNP023 hydrochloride is shown in FIG. 1. The corresponding peaks are listed in Table 2 below.

[0212] [Table 2]

[0213] The relative intensities shown in Table 2 may be subject to a certain degree of variation due to particle morphology in the HB form. do.

[0214] Fourier transform infrared spectroscopy At room temperature, 4 cm -1 Using a Nicolet 6700 spectrometer with a resolution of 1000 Hz, FTIR spectra were recorded using attenuated total reflectance (ATR) technique. The number of scans was 64. The range is 650 to 4000 wavenumbers (cm -1 ) The spectrum was recorded. To do this, a spatula tip sample was applied in powder form to the diamond surface. The sample was pressed onto the diamond in a fire anvil and the spectrum was recorded. A spectrum of clean diamond was used as the background spectrum. The typical accuracy of wave numbers is about ±2cm. -1 Therefore, the range of The HB form of LNP023 hydrochloride is shown at 3452 cm -1 The infrared peak at is Most infrared spectrometers use the (3452-2)~(3452+2) cm -1 It can appear between. A representative FTIR spectrum of the crystalline form HB described herein is shown in FIG. A list of parameters is provided below, with a typical accuracy of ±2 cm for wavenumbers. -1 is within the range. 3452, 3274, 2933, 2875, 2732, 1709, 1692, 1658, 1615, 1601, 1515, 1497, 1461, 1439, 1425, 1384, 1243, 1184, 1069, 767, 739cm -1 .

[0215] Differential scanning calorimetry DSC was performed on a TA Discovery DSC2500 instrument. Samples (2.7 mg) were heated at a rate of 10°K / °C in Tzero aluminum pans with aluminum lids. The mixture was heated from 30 to 300°C in 1 min. Nitrogen (purge rate 50 mL / min) was used as the purge gas. and used it.

[0216] A typical DSC curve is shown in Figure 4 below, which shows that when measured at a heating rate of 10 K / min, It shows a broad endothermic event ending at 170°C followed by an exothermic decomposition at about 200°C. More precisely, The endothermic phenomenon is in the range of 35℃ to 170℃.

[0217] thermogravimetric analysis TGA was performed on a Mettler Toledo DSC / TGA1 instrument. Samples (10-20 mg) were transferred to 100 μL aluminum dishes closed with lids at a rate of 20 K / min. The flask was heated from 30°C to 300°C at 40°C. At the start of the measurement, a hole was automatically opened in the lid. Nitrogen (purge rate 50 mL / min) was used as the purge gas.

[0218] A representative TGA curve is shown in Figure 5 below and shows that due to loss of water (dehydration) and residual solvent, approximately The process is shown in Fig. 3. The mass during the process was determined to be about 4.1%. Water content of 3.7% was determined by Karl Fischer coulometric titration in LNP023H It corresponds to 0.98 moles of water per mole of Cl. It is heated to 160°C for measurement. Metrohm 83 connected to 74 Oven Sample Processor Water determination was performed with a 1KF coulometer.

[0219] Dynamic Vapor Sorption Dynamic vapor sorption isotherms were recorded on a DVS Advantage instrument. Ambient relative humidity (RH) started at 40%. RH was then reduced to 0% in 10% steps. Then, in the sorption cycle, the RH was increased from 0% to 90% in steps of 10%, and The process was increased from 90% to 95% in the desorption cycle, followed by 10%, 5% steps in the desorption cycle. Finally, the RH was increased to 40% ambient relative humidity in 10% steps. The time per run was set at a minimum of 3 hours and a maximum of 6 hours. and equilibrate for a minimum of 5 minutes with a constant mass change of 0.002% / min before the maximum time. If equilibrium was not reached, a successive humidity step was applied prior to the 6 hour maximum. Successive humidity steps were applied after a maximum time of 6 hours. The temperature was 25 ± 1.0 °C. Ta.

[0220] Figure 6 shows the results during the sorption cycle from RH 0% to 95% (marked with triangles) as well as during the sorption cycle from RH 95% to 95% (marked with triangles). H of LNP023 hydrochloride during the desorption cycle (marked with a square) at ~0% (on the x-axis). Figure 2 shows the equilibrium mass change (delta m (wt%) - reference weight at 0% relative humidity on the y-axis) of the B-form The mass difference between 40 and 95% relative humidity is less than 0.2 wt%, and the difference between the sorption and desorption curves is No significant hysteresis was observed. Therefore, the LNP023 hydrochloride salt described herein The HB form of LNP023 hydrochloride can be characterized as non-hygroscopic. The PXRD of remains unchanged after the experiment.

[0221] Electron microscopy Electron microscopy using a Gemini SE300 (Zeiss) microscope with an SE detector As can be seen from Figures 7a and 7b, the engineered The HB form of LNP023 hydrochloride obtained by the sieving crystallization technique is composed of cylindrical and cubic particles. which explains the excellent flowability of the powder.

[0222] Example 5: Preparation of pharmaceutical compositions The HB particles obtained in Example 3 were obtained from Hosokawa Alpine AG, Auk Commercially available 100UPZ pin from Augsburg / Germany The particles are then transferred to a mill at a rotor speed of 6,000 rpm and a feed rate of 15 kg / h. do.

[0223] The resulting cubic particles were placed in size 0 hard gelatin capsules at 50, 100, or 200 μm. or filled in 200 mg quantities.

Claims

[Claim 1] The invention described in the present specification.

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