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. 023 A pharmaceutical composition comprising a crystalline form of the hydrochloride salt and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are also described herein. The pharmaceutical compositions described herein are directed to complement activation. These compounds 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, which are 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 used for the treatment of 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 its method of manufacture 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 was obtained The resulting crystalline 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 dissolution profiles or improved stability or shelf life include: Improved solid state forms of active pharmaceutical ingredients may become available. and the processing or handling of active pharmaceutical ingredients during manufacturing. The novel solid state forms of the ingredients have desirable processing properties. They may be easier to handle, more suitable for storage, or may have superior purification properties compared to solid forms. It may be possible.

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

[0006] This will ensure the reliable production 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 "HB Form." The "HB Form" of LNP023 hydrochloride is a drug substance intended for use in oral solid dosage forms. It has favorable physicochemical properties.

[0008] The advantageous properties of the HB form of LNP023 include chemical stability, physical stability, hygroscopicity, Solubility, dissolution, morphology, crystallinity, flowability, compactibility As a result, this property makes the HB form suitable for large-scale manufacturing processes. It 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. 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, it will be Eliminates conversion of, for example, Form A to Form HB, or polymorphic conversion, which may occur during processing and storage. The use of thermodynamically stable forms of compounds is highly valued, as they can be easily synthesized. 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 20-30°C" refers to a standard 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 described, a specific crystalline hydrate form of LNP023 hydrochloride, e.g., the monohydrate form, is intended. 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 (0.1±0.1)° and (23.3±0.1)° It may be characterized by having an X-ray diffraction pattern.

[0015] Form A is prepared as follows in accordance with International Publication No. 2015 / 009616: It is prepared (see Example 26d): 4-((2S,4S)-(4-ethoxy-1H-pyridyl)-1H-pyridyl)-1H-pyridyl in HO / CHCN (10 / 3 mL) -((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidine- To a solution of 2-(2-yl)benzoic acid (620 mg, 1.467 mmol), 5 M aqueous HCl was added. 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. 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 a long-range reflection. by parallel planes of atoms in a solid material that are distributed in a regular and repeating pattern with positional order Constructive interference from scattered X-rays The peak in the X-ray diffraction pattern that occurs at a specific diffraction angle (Bragg angle) due to 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 over, for example, approximately 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 degree of variation should be taken into account. For example, the typical accuracy of 2θ values ​​is Within the range of ±0.2°2θ, for example, within the range of ±0.1°2θ. Therefore, for example, 9. The peak that normally appears at 2° 2θ is (9.2-0.2) on most RD diffractometers under standard conditions. °~(9.2+0.2)°2θ, e.g., (9.2-0.1)°~(9.2+0.1)° Furthermore, relative peak intensities can be affected by instrumental variations as well as crystallinity, exhibiting variability due to misalignment, particle size, sample preparation, and other factors known to those skilled in the art; Those skilled in the art will understand that this should only be interpreted as a qualitative measurement.

[0020] The term "essentially the same" in reference to infrared spectroscopy refers to the peak positions and the phases of the peaks. This means that the variations in the pair intensities should be taken into account. For example, the usual precision of the wavenumber values ±4cm -1 Within the range of, for example, ±2 cm -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 those skilled in the art will appreciate that the crystallinity It is known that differences in peak intensities due to sample preparation, measurement method, and other factors can also occur in infrared spectroscopy. It will be appreciated that peak intensities should therefore be interpreted only as qualitative measurements.

[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 size can cause small variations in such data when presented in graphical form. Those skilled in the art will appreciate that variations, such as differences related 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 in each batch relate to the same crystalline form is well within the knowledge of one 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 a crystalline phase or an amorphous phase.

[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 different crystals. It refers to crystalline forms that have different spatial arrangements of the molecules, atoms, or ions that form.

[0025] As used herein, the term "cocrystal" refers to a compound formed by non-ionic and non-covalent bonding. A bond containing two or more different molecular or ionic compounds within the same crystal lattice that are associated with each other. crystalline materials, wherein 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 crystalline structure, e.g., part of a crystalline 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 the Greek numeral prefixes ( For example, hydrates can be referred to by adding the 'water / hydroxide' prefix. Depending on the compound stoichiometry, it may be called a hemihydrate or a monohydrate. 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 housed by a crystalline structure, e.g., part of a crystalline structure It means a crystalline solid that is in a state where the solvent is present or incorporated within the crystal (solvent inclusion). The organic solvent(s) may be present in stoichiometric or non-stoichiometric amounts. When organic solvents are present in stoichiometric amounts, solvates are identified by adding Greek numeral prefixes. For example, solvates may be referred to as hemisolvates or The solvent content can be determined by, for example, 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 structure of the host molecule. Isomorphous solvates, as defined herein, refer to solvates having the same space group as the guest molecule. The types of organic solvents present as components are different.

[0030] As used herein, the term "desolvation" or "desolvation" refers to the crystallization of a host molecule. This 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 in which water is incorporated into the crystalline structure. "crystalline solids" means crystalline solids in which water is not embedded or accommodated by the crystalline 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 percent of the crystalline form. It does not contain more than 3.0% by weight of water, for example, more than 1.0% by weight of water. do not have.

[0032] As used herein, the term "non-solvated" when referring to a crystalline solid is The organic solvent is not incorporated into or accommodated by the crystalline structure. The unsolvated forms still contain residual organic solvent that is not part of the crystalline structure. However, it may be adsorbed onto the surface of the crystal or absorbed into the disordered regions of the crystal. In the unsolvated form, the unsolvated form does not contain more than 3.0% by weight of organic solvent, e.g., 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 "anti-solvent" refers to the solubility of LNP023 hydrochloride in a solvent. This means a liquid that reduces

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

[0036] As used herein, the term "therapeutically effective amount" with respect to LNP023 hydrochloride means It encompasses the 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 resistant to 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 "cubic" refers to means a crystal that is equi-dimensional, such as a cube or sphere. do.

[0039] As used herein, the term "plate" or "plate-like" with respect to crystalline shape refers to a flake. "Plate-like" refers to flat, plate-like crystals having a similar breadth and width to those of a crystal that is thicker than a plate-like crystal.

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

[0041] As used herein, the term "needle" or "acicular" with respect to crystalline shape refers to a crystal having a similar width. "Needle-like" refers to thin, highly elongated crystals having a diameter of 1 / 2 and a width of 1 / 2.

[0042] With respect to crystalline shape, the terms "cylinder" or "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 approximation within the region of approximately or roughly. 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 qualify values ​​that are above and below the specified value with a 10% variation. Used in the specification.

[0045] As used herein, "solid form" refers to a composition comprising a particular solid form of LNP023 hydrochloride. The term "substantially free of other solid forms" means that the composition is free of LNP023 hydrochloride any other solid form of the compound in an amount of up to 20% by weight (weight percent) based on the weight of the composition. ), 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 % by weight, up to 6% by weight, up to 5% by weight, up to 4% by weight, up to 3% by weight, up to 2% by weight %, at most 1%, at most 0.5%, or at most 0.1%, or 80% by weight It means to include any weight percentage up to 100% by weight.

[0046] As used herein, "substantially pure" when used in reference to a form of a compound of a particular solid form of LNP023 hydrochloride, e.g., more than 90% by weight, based on the weight of the More than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, Furthermore, it refers to a compound having an amount of purity equal to about 100% by weight. The remaining material is the compound or other forms of L, or reaction or processing impurities resulting from its manufacture. 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) with a disease, such as a disease described herein. It means a normal subject.

[0048] As used herein, the term "physically stable" means that a particular free base or salt form is ,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 when 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 the specific compound when subjected to the 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 convert to 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 ,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, it does not change into other compounds (e.g. In some embodiments, 25% of the form of a particular compound is Less than 10% of a compound will be converted 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 subjected 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 "pharmaceutically acceptable excipient" refers to a substance that, at a given dose, It refers to a substance that does not exhibit significant pharmacological activity and is added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients are, among others, vehicles, diluents, exfoliants, disintegrants, dissolution modifiers, absorption enhancers, stabilizers, Excipients may also serve as fillers (diluents), binders, disintegrants, , lubricants and glidants.

[0051] As used herein, the term "filler" or "diluent" refers to a substance 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 maintains cohesiveness and separate parts. means a substance that binds together an active pharmaceutical ingredient and a pharmaceutically 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, the drug is degraded or disintegrated to release the active pharmaceutical ingredient as efficiently as possible. It means a substance that allows rapid dissolution.

[0054] The term "lubricant" as used herein refers to a lubricant that is added during the tableting or encapsulation process. A substance added to a powder blend to prevent compacted powder clumps 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 a compound that enhances flow during tablet compression. To prevent caking and to provide an anti-caking effect It refers to substances used in tablet and capsule formulations for the purpose of [Brief explanation 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. [Figure 2] 1 illustrates a comparison of a representative PXRD of the HB Form of LNP023 hydrochloride salt described herein (bottom) and a representative PXRD of Form A of LNP023 hydrochloride salt from WO 2015 / 009616 (top). The x-axis represents the scattering angle in degrees 2θ. The powder X-ray diffractogram of Form A was shifted along the y-axis, and the diffractogram was split for clarity. Therefore, the y-axis is arbitrary and not labeled. [Figure 3] 1 illustrates a representative FTIR spectrum of the HB form of LNP023 hydrochloride salt described herein, where the x-axis represents wavenumber in cm and the y-axis represents 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. [Figure 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] Figure 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 relative humidity in percent (%) measured at a temperature of (25.0±1.0) °C, and the y-axis represents equilibrium mass change in weight percent (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 INVENTION

[0057] Crystalline 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 industry, including but not limited to: , PXRD, SXRD, FTIR, DSC, DVS, TGA and SEM. Characterized by one of the aforementioned analytical methods or 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: characterized by any one of the following embodiments or by a combination of two or more of the following embodiments: It can be done.

[0060] Illustrative PXRD embodiments: In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (9. 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 provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 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. (form).

[0062] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 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 0.2°. This relates to the crystalline form of the trihydrochloride salt (HB form).

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

[0064] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2 )°, (21.3±0.2)°, and (24.6±0.2)° 2θ angles. The crystalline form of LNP023 hydrochloride (HB form) can be characterized by XRD peaks. Regarding.

[0065] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (12.6±0.2 )°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and It is characterized by PXRD peaks identified at 2θ angles of (24.6±0.2)°. This relates to a crystalline form of LNP023 hydrochloride (HB form).

[0066] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2 )°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0.2)°, ( 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 peak.

[0067] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2 )°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0.2)°, ( 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 peak.

[0068] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (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)°, ( 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 Regarding the HB form.

[0069] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2 )°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, ( 17.2±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24 LN is characterized by a PXRD peak identified at a 2θ angle of 0.6±0.2°. This relates to the crystalline form of P023 hydrochloride (HB form).

[0070] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (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 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), characterized by:

[0071] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (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 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 provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2 )°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, ( 17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3 ±0.2)°, (22.2±0.2)°, (24.0±0.2)°, and (24.6±0 LNP023 is characterized by a PXRD peak identified at a 2θ angle of 0.2°. It concerns the crystalline form of the hydrochloride salt (HB form).

[0073] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (4.6±0.2)°, (6. 8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2 )°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, ( 17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3 ±0.2)°, (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2 )° and (28.0±0.2)° 2θ angles. This relates to the crystalline form of LNP023 hydrochloride (HB form).

[0074] In one embodiment, the present invention provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, 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 (1 )° and (24.6±0.2)°, and 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 between 20 and 30°C using the line, the 0.2±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 0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0 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 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 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 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 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 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 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 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)°, (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 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 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 Identified at 2θ angles of (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 provides a Cu-Kα 1,2 line When measured at temperatures in the range of 20 to 30°C using the method, the results were (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)° 2θ angles, and (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 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 is clearly distinguishable from that of Form A of the compound (as shown in Figure 2 herein). (See also the PXRD superposition shown). The HB form is e.g. (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 the pamphlet 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 exhibit a peak in the same range.

[0078] In another embodiment, the present invention provides a Cu-Kα 1,2 1. The method of claim 1, wherein the temperature is measured at a temperature in the range of 20 to 30°C using a fluorine-containing compound. It is noted that the PXRD of the compound has a peak of 11.6±0.2° but does not contain a peak at a 2θ angle of (11.6±0.2)°. This relates to a crystalline form of LNP023 hydrochloride (HB form) that may be characteristic of LNP023.

[0079] In one embodiment, the present invention provides a Cu-Kα 1,2 line The PXRD of the compound is as described above when measured at a temperature in the range of 20 to 30°C using LNP0 may be characterized as not containing a 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 curves shown in FIG. 1 herein are used to represent the temperature range of 20-30° C. The result of LNP023 hydrochloride can be characterized as having a PXRD essentially identical to that of The crystal form (HB form)

[0081] For example, the relative intensities of the peaks shown in Figure 1 and listed in Table 2 are the actual morphology of the HB form. Generally, the morphology of many 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 platelets. It is clear that the preferred orientation in the sample affects the intensity of the various peaks and 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 detecting a β-glucan-containing compound having a β-glucan content of (3452±4) cm -1 , (2875±4)cm - 1 , and (1692±4) cm -1 has an FTIR spectrum containing a peak at a wavenumber of The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by:

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

[0084] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (3452±4) cm -1 , (2875±4)cm -1 , (1 692±4)cm -1 , (1439±4)cm -1 , and (1243±4) cm -1 Waves of LNP023 hydrochloride is characterized by an FTIR spectrum containing a number of peaks. It concerns the crystalline form (HB form).

[0085] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 FTIR spectrum includes 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 to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 FTIR spectrum, including peaks at wavenumbers The present invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by having a crystalline structure.

[0087] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 FTIR spectrum includes 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 to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 detecting a β-glucan-containing compound having a β-glucan content 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 of LNP023 hydrochloride is characterized by an FTIR spectrum containing a number of peaks. It concerns the crystalline form (HB form).

[0090] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 This relates to the crystalline form of NP023 hydrochloride (HB form).

[0091] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 the following structure:

[0092] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 an FTIR spectrum comprising: HB form).

[0093] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 relates to the crystalline form of P023 hydrochloride (HB form).

[0094] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 wavenumber of The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized by having:

[0095] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 The peak at the wave number A crystalline form of LNP023 hydrochloride (H) characterized by an FTIR spectrum containing B type).

[0096] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 wavenumber of 023 hydrochloride salt crystalline form (HB form).

[0097] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 a peak at a wave number of The present invention relates to a crystalline form of LNP023 hydrochloride (HB form), characterized by:

[0098] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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) characterized by the FTIR spectrum Regarding (state).

[0099] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 by having 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 to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 to measure temperature in the range of 20-30°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​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-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 (HB) of LNP023 hydrochloride characterized by its FTIR spectrum is (form).

[0102] In one embodiment, the present invention uses a diamond ATR cell to measure temperatures in the range of 20-30°C. When measured at a temperature of (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 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 1000 s by 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 an IR spectrum Regarding.

[0104] Illustrative DSC embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is prepared essentially as shown in FIG. In one embodiment, the present invention provides a method for producing a cellulose acetate ester having the same DSC profile. 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 an endothermic phenomenon in the range of 35°C to 170°C when measured at a heating rate of 10 K / min. be.

[0105] Illustrative TGA embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is prepared essentially as shown in FIG. In one embodiment, the present invention provides a method for producing a cellulose acetate ester copolymer, which can be characterized by the same thermogravimetric analysis (TGA). When heated at a rate of 20 K / min from 30 to 300 °C, due to the 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. 023 hydrochloride salt crystalline form (HB form).

[0106] Illustrative DVS embodiments: In one embodiment, LNP023 hydrochloride (HB Form) is prepared essentially as shown in FIG. In one embodiment, the present invention provides a method for producing a refrigerant having a relative humidity of 0 to 9 5% and temperature (25±1.0) °C, measured by DVS, based on the weight of the crystalline form. 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 A crystalline form of LNP023 hydrochloride (HB form) characterized by a mass change of less than 1% by weight. Regarding (state).

[0107] Further illustrative embodiments: In another embodiment, the present invention provides LNP023, which is characterized in that it is in an unsolvated form. In one embodiment, the crystalline 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:

[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 This can be achieved 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 by the ratio of the minimum value to the maximum value, and the Feret diameter (Fer et diameter)ψ A =x Feret min / x Feret max 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 other embodiments, the cubic particles of 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 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 X of the cubic particles of HB morphology 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 X of the cubic particles of HB morphology 10 is approximately 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 morphology have a density of less than about 0.8 g / ml, e.g., In other embodiments, 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 It has.

[0115] composition Illustrative embodiments: In another aspect, the present invention relates to a method for treating a pulmonary arthritis, as defined in any one of the above embodiments. A composition comprising the HB form of LNP023 hydrochloride according to claim 1, wherein in addition to LNP023 hydrochloride, For example, compositions that are 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, other than LNP023 hydrochloride may contain up to 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 particularly known as the crystalline form, which has a wavelength of 0.15419 nm. Cu-Kα with 1,2 When measured at temperatures in the range of 20-30°C using the 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 manufacturing a cellular phone according to the present invention, comprising the steps of: 1. A composition comprising the HB form of LNP023 hydrochloride as described in the document, wherein the wavelength is 0.15419n Cu-Kα with m 1,2 When measured using a line at temperatures in the range 20-30°C, 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% by weight of the HB crystalline form of LNP023 hydrochloride as defined above. 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 containing 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 including:

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

[0120] The solid starting material provided in step (i) can 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 the 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 this case, 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 a high temperature, for example, in the range of about 30 to 56°C, for example, about 45 to 55°C. Heating may be performed at ambient temperatures, including but not limited to, stirring, agitating, mixing, shaking, vibrating, etc. by any kind of movement of a solid material suspended in a solvent, such as by sonication, wet milling, etc. Once the solid materials are dissolved, the solution can be heated to a temperature of 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 contain acetone, ethyl acetate, or a combination thereof. A second solvent may be added, which may comprise a further organic solvent or water. In this 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 solvent mixture of ethyl acetate and ethanol may be added as a solvent mixture or may be added sequentially. In this case, when the additions are sequential, 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 ratio is from 0.5:3 to 1:1, for example 1:2. The crystallization is completed by cooling to a temperature of about 25°C, for example, in the range of about 5 to 15°C, for example, 10°C. If the HB form is obtained in essentially pure form, at least a portion of the crystals will be removed from the mother liquor. In one embodiment, the product can 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 of about 50° C. or less, for example about 50° C. Drying may also be carried out at about room temperature. Drying may be carried out for a period ranging from about 2 to 24 hours, for example, from about 4 to 16 hours, for example, from about 6 to 10 hours. In one embodiment, drying may be carried out 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, drying is performed at a pressure of about 80 mbar or less. It is carried out under 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 techniques including, 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 cycling may be carried out as follows: in step (iii), Before adding the solvent, the solution is heated to a temperature in the range of about 0 to 25°C, for example, about 5 to 15°C, for example, 10°C. The liquid may be cooled and then cooled to a temperature in the range of about 30-45°C, for example about 30-40°C, e.g. The temperature may be cycled at least three times, for example at least six times, to 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., 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 approach allows for engineering. In contrast to the A form, which cannot be broken down, the HB form is not brittle and therefore can be broken down and spread. 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 has excellent physicochemical stability as well as good powder properties. Ideal for the standard manufacture of superior and improved pharmaceutical compositions using LNP023 hydrochloride 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) and subsequently 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 preceding embodiments. Regarding the manufacturing process.

[0126] Crushing illustration The particles of the HB form of LNP023 hydrochloride salt described herein may be filled into capsules. or otherwise further processed, e.g., milled. To enable easy filling of particles directly into capsules without grinding, This can be done.

[0127] In one embodiment, the particle size of the HB form of LNP023 hydrochloride is determined by rotor impact milling. 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 comprising a stationary pin disc, or a rotating This can be done using a rotating pin disc with a pin disc. The HB form of 023 hydrochloride provides adequate powder transport for proper control of the associated powder feed rate. The rotor impact mill is operated by a system such as a vibratory feeder or a twin-shaft feeder. The rotor impact mill is then transported into the rotor impactor. The powder is further infused with a gas flow generated by a blower coupled to the toner mill. Transported to the Pact Tool 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 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, e.g. filters, cyclones transporting gas 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 Adequate physical uniformity of the produced batch is achieved.

[0128] Rotor impact mills, for example, can be used as pin mills by rotor impact mills. 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 relevant equipment 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 salt 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 10-60 m / s, or the rotational speed is The cylindrical pin surface area of ​​the 1000mm is approximately 4,000 kg / (h· m 2 ) specific feed rate up to

[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 operating, a product having adjusted physical properties is obtained. The supply rate is , for example, 1 to 22 kg / h, for example, 6 to 18 kg / h, for example, at a supply rate of 15 kg / h exists.

[0130] Pharmaceutical composition and use Illustration of embodiments: In a further aspect, the present invention relates to the use of the LN described herein for manufacturing a pharmaceutical composition in the HB form of P023 hydrochloride, or in any one of the above aspects and their corresponding embodiments relates to the use of a composition containing the HB form of LNP023 hydrochloride defined.

[0131] In yet another aspect, the present invention relates to a pharmaceutical composition containing the HB form of LNP0 23 hydrochloride, for example, in a predetermined amount or a therapeutically effective amount, or in any one of the above aspects and their corresponding embodiments relates to a composition containing the HB form of LNP023 hydrochloride defined in any one of them and at least one pharmaceutically acceptable excipient as a drug.

[0132] In one embodiment, the pharmaceutical composition containing the HB form of LNP023 hydrochloride defined in any one of the above aspects and their corresponding embodiments contains LNP023 hydrochloride at a dose of up to about 200 mg, calculated as anhydrous LNP023 free base.

[0133] In that embodiment, the pharmaceutical composition contains LNP023 hydrochloride at a dose of about 10 mg to about 200 mg, calculated as anhydrous LNP023 free base.

[0134] In that embodiment, the pharmaceutical composition contains LNP023 hydrochloride at doses of about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, each calculated as anhydrous LNP023 free base respectively.​

[0135] In that embodiment, the pharmaceutical compositions are each calculated as anhydrous LNP023 free base. LNP0 at doses of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg was administered. 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 In one embodiment, the therapeutic dose of the HB form of LNP023 hydrochloride is 100 or 200 mg. 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 pharmaceutically acceptable salt thereof 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 pharmaceutically acceptable additive. Additives, such as excipients, are included.

[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 preceding 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 and capsules. In one embodiment, the oral dosage form is a capsule. The capsules are size 0 capsules.

[0139] The tablet may be prepared in the HB form of LNP023 hydrochloride or in accordance with any of the above-mentioned embodiments and their corresponding embodiments. and a composition comprising at least one of the HB forms of LNP023 hydrochloride, wherein the HB form is defined as any one of the forms. At least one excipient, such as a filler, diluent, binder, disintegrant, lubricant, flow agent or the like Optionally, dry or wet granulation may be used. Granulation steps such as the step 1000 are carried out before compression.

[0140] The capsules contain the HB form of LNP023 hydrochloride, or the above-mentioned embodiments and their corresponding embodiments. and 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, glidant or the like by mixing the combination with the steroids and filling the blend into capsules used as excipients. Alternatively, the HB form of LNP023 hydrochloride may be used as an excipient. Fill neat into capsules to be used. The capsule shell is made of gelatin. The shell may be a shell or a hydroxypropyl methylcellulose (HPMC) shell.

[0141] In one embodiment, the present invention provides LNP02 in a capsule, such as a size 0 capsule. In one embodiment, the present invention relates to a pharmaceutical composition comprising HB form particles 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, for example about 10 to about 100 μm. Particle size distribution X of about 70 μm, for example about 15 to about 55 μm 50 In one embodiment, The HB particles in the capsules 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 of formula (I) for use in the treatment of the diseases and disorders 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 provides a method for producing a pharmaceutical composition according to the method of WO 2015 / 009616. and for the treatment or indications disclosed in WO 2019 / 043609. For prevention, specifically, paroxysmal nocturnal hemoglobinuria ( Glomerular C3 deposition in conditions such as 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 provides the methods and systems described herein, each of which is incorporated 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 Pamphlet No. 09 in a subject in need thereof In one embodiment, the disease or disorder is complement-induced kidney disease C3G (C3 glomerulonephritis). Paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN), and MN Other nephropathies with evidence of glomerular C3 deposition, such as membranous nephropathy (HUS), HUS (E. coli), li) Induced hemolytic uremic syndrome (IHS) and atypical hemolytic uremic syndrome (aHUS) In one embodiment, the method comprises administering to the patient a HBV of LNP023 hydrochloride as described herein. The method includes administering a therapeutically effective amount of the formulation to a subject.

[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 salt Subjects will be administered the HB form of LNP023 at a daily dose of up to approximately 400 mg, calculated as 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 salt 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 every 12 hours, about 10 mg to about 2 mg calculated as anhydrous LNP023 free base It is administered at a dose of 00mg.

[0148] In one embodiment, the method of treating PNH in a subject includes administering anhydrous LNP023 free salt Calculated as a group, about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 4 In one embodiment, the method comprises administering the HB form of LNP023 to a subject at a daily dose of 1000 mg. In this 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 for treating PNH, the HB form of LNP023 is anhydrous LNP 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 It is administered in mg.

[0150] In one embodiment of the method for treating PNH, 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 twice daily (bid), for example, about every 12 hours, at a dose of about 25 It is administered in mg.

[0151] In one embodiment of the method for treating PNH, 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 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 for treating PNH, 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), for example, about every 12 hours, at a dose of about 1 The dose is 00mg.

[0153] In one embodiment of the method for treating PNH, 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), 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 for treating PNH, the HB form of LNP023 is anhydrous LNP 023 200 mg calculated as the free base, twice daily (bid), e.g. The compound is administered orally to the subject approximately every 12 hours.

[0156] In another aspect, the present invention provides a method for treating complement-mediated kidney disease C3G (C3 glomerulopathy) by its A method of treating a subject in need thereof, comprising administering 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 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. twice daily (bid), e.g., about every 12 hours, at doses up to 200 mg is.

[0158] In one embodiment, the method of treating C3G in a subject includes administering 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 anhydrous free base. At a dose of about 10 to about 200 mg calculated based on the It is given every two hours.

[0159] In one embodiment, the method of treating C3G in a subject includes administering the HB form of LNP023. calculated as anhydrous LNP023 free base, 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 dose is approximately 10 mg, approximately 25 mg, calculated as anhydrous LNP023 free base. , at doses of about 50 mg, about 100 mg, or about 200 mg twice daily (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 a subject at a daily dose of about 20 mg calculated as the free base. In this case, the administration is twice daily (bid), for example about 12 hours, at a dose of about 10 mg. It is administered 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 twice daily (bid), for example about 1 hour, at a dose of about 25 mg. 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 twice daily (bid), for example about 50 mg, at a dose of 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, e.g. 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 administered orally to the subject approximately every 12 hours.

[0167] In another embodiment, the present invention provides a method for treating IgAN (immunoglobulin A nephropathy) in a person 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 receive 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 an anhydrous LNP023 free base. Doses of up to about 200 mg given 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 measured at a daily dose of approximately 20 to 400 mg calculated as the base. In one embodiment, the administration comprises administering to an elephant anhydrous LNP023 free base. twice a day (bid), for example, at a dose of 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 the base In one embodiment, the method comprises administering to a subject the HB form of LNP023 at a daily dose of 1000 mg. In this case, the dose 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 for treating IgAN, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 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 administered hourly.

[0172] In one embodiment of the method for treating IgAN, the HB form of LNP023 is P023 is administered to subjects at a total daily dose of approximately 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 administered hourly.

[0173] In one embodiment of the method for treating IgAN, the HB form of LNP023 is Subjects will be administered a total daily dose of approximately 100 mg calculated as the P023 free base. In this form, 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 for treating IgAN, the HB form of LNP023 is Subjects will be administered a total daily dose of approximately 200 mg calculated as the P023 free base. In this form, 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 for treating IgAN, the HB form of LNP023 is Subjects will be administered a total daily dose of approximately 400 mg calculated as the P023 free base. In this form, the administration is at a dose of about 200 mg twice a day (bid), for example 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, administered orally to a subject about every 12 hours.

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

[0178] In another aspect, the present invention provides a method for treating MN (membranous nephropathy), such as idiopathic MN (iMN), 1. A 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 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. A daily dose of up to about 200 mg calculated on a base, 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. The subjects were administered LNP023 at a daily dose of approximately 20 to approximately 400 mg calculated as the 023 free base. In one embodiment, the administration comprises administering an anhydrous LNP023 free base. 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 the HB form of LNP023 to a subject 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 a day (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 In one embodiment, the subject is administered a total daily dose of about 20 mg calculated as the 23 free base. The administration is at a dose of about 10 mg twice a day (bid), for example, about 12 hours. It is administered every 2 days.

[0183] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 In one embodiment, the subject is administered a total daily dose of about 50 mg calculated as the 23 free base. The administration is at a dose of about 25 mg twice a day (bid), for example, about 12 hours. It is administered every 2 days.

[0184] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 In one embodiment, 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 every so often.

[0185] In one embodiment of the method of treating MN, the HB form of LNP023 is anhydrous LNP0 In one embodiment, 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 administered hourly.

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

[0187] In one embodiment of the method of treating MN, the HB form of LNP023 is administered twice daily (b .id), which is administered orally to the subject, for example, approximately 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 treating a subject, comprising administering to the subject a therapeutically effective amount of the HB form of LNP023. and administering to the subject a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, acetaminophen, benzophenone, benzodiazepine ...

[0190] In one embodiment, the method of treating aHUS in a subject includes administering anhydrous LNP023 free Subjects will receive 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 an anhydrous LNP023 free base. Doses of up to about 200 mg given 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 approximately 20 to approximately 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 the base 00mg daily dose of the HB form of LNP023 to a subject. In this case, the dose 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 subjects at a total daily dose of approximately 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 administered hourly.

[0194] 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 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 administered hourly.

[0195] 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 100 mg calculated as the P023 free base. In this form, 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 Subjects will be administered a total daily dose of approximately 200 mg calculated as the P023 free base. In this form, 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 the P023 free base. In this form, the administration is at a dose of about 200 mg twice a day (bid), for example 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, administered orally 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 administered orally to the subject approximately 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 specific disease at a specific dose according to the present invention Use of the HB form of NP023; The HB form of LNP023 for treating specific diseases at specific doses according to the present invention. Use of forms; and HB form of LNP023 used in the treatment of specific diseases at specific doses according to the present invention and one or more pharmaceutically acceptable carriers; is equally applicable to

[0201] Test methods for morphological properties Aspect ratio: The aspect ratio refers to the ratio between the maximum length of a crystal and 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, cubic particles of HB morphology are, for example, about 0.4 ~Aspect ratio a of about 0.7 50 It has.

[0202] Sympatec GmbH,Clausthal-Zellerfeld,Germ Dynamic image analysis was performed using the commercially available QICPIC dynamic image analyzer (Dynamics). The aspect ratio was determined by the Digital Image Analysis (DIA) 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. [Example]

[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, A Form A of LNP023 hydrochloride was obtained. 9.3 g of Form A of LNP023 hydrochloride was dissolved in acetone. The mixture was suspended in 48.1 g of acetone and water (acetone:water = 78:22 m:m) and heated to about 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 the product was dried 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, A Form A of LNP023 hydrochloride was obtained by dissolving 42 g of LNP023 hydrochloride in acetone. Suspend in 212 g of a mixture of acetone and water (acetone:water = 80:20 m:m) and dissolve 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, A Form A of LNP023 hydrochloride was obtained by dissolving 80 g of LNP023 hydrochloride 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. The temperature was cycled nine 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 filtered off. and dried at 50°C under vacuum to give crystalline LNP023- 66 g of HCl salt monohydrate (HB form) were 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 model Bruker D8 Advance diffractometer with Cu-Kα 1,2 line (wavelength 0 PXRD was performed using a chromatogram of 15419 nm at ambient conditions from 2° to 40° 2θ. Within the range of 0.015 to 0.020° 2θ, with an approximate process time of at least 40 seconds Applying a step size, the diffractometer was operated at a tube voltage of 30 to 40 kV and a tube current of 40 mA. The typical accuracy of the 2θ values ​​is ±0.2° 2θ, e.g., ±0.1° 2θ. Therefore, for example, the HB of LNP023 hydrochloride appears at 9.2° 2θ. The diffraction peaks of this form range from (9.2-0.2)° to (9 0.2+0.2)°2θ, for example, in the range of (9.2-0.1)° to (9.2+0.1)°2θ It can appear in.

[0211] A representative diffractogram of the HB form of LNP023 hydrochloride is shown in Figure 1 herein. 1. A list of the corresponding peaks is given in Table 2 below.

[0212] [Table 2]

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

[0214] Fourier transform infrared spectroscopy At room temperature, 4 cm -1 Attenuation using a Nicolet 6700 spectrometer with resolution FTIR spectra were recorded using the attenuated total reflectance (ATR) technique with 64 scans. and the range is 650 to 4000 wavenumbers (cm -1 ) 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 with a fire anvil and the spectrum was recorded. The spectrum of clean diamond was used as the background spectrum. The typical accuracy of the wave number is about ±2cm. -1 Therefore, the range of The HB form of LNP023 hydrochloride is shown at 3452 cm -1 The infrared peak at 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 Figure 3, with corresponding peaks. A list of frequencies 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. The sample (2.7 mg) was heated at a rate of 10°K / °C in a Tzero aluminum pan with an aluminum lid. The mixture was heated from 30 to 300°C in minutes. 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, and when measured at a heating rate of 10 K / min, approximately It shows a broad endothermic event ending at 170°C followed by an exothermic decomposition at about 200°C. The endothermic phenomenon occurs within the range of 35℃ to 170℃.

[0217] thermogravimetric analysis TGA was performed on a Mettler Toledo DSC / TGA1 instrument. Samples (10-20 mg) were placed in 100 μL aluminum pans closed with lids at a rate of 20 K / min. The flask was heated from 30°C to 300°C by a nitrogen atmosphere. 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 approximately 100% TGA due to loss of water (dehydration) and residual solvent. The process is shown as 30 to 220°C. The mass during the process was determined to be about 4.1%. Water content of 3.7% was determined by Karl Fischer coulometric titration. 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 carried out 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, RH was increased from 0% to 90% in 10% steps, and 5% The desorption cycle was increased from 90% to 95% in steps, followed by 10%, 5% steps, and so on. Finally, the RH was increased in 10% steps to 40% ambient relative humidity. 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, successive humidity steps were applied before the maximum time of 6 hours. 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 sorption cycle from 0% to 95% RH (marked with triangles) as well as the sorption cycle from 95% RH. H of LNP023 hydrochloride during the desorption cycle (marked by a square) at ~0% (on the x-axis). Figure 2 shows the equilibrium mass change (delta m (wt%) - reference weight at 0% relative humidity) of the B-form on the y-axis. 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 salts 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 was performed on a Gemini SE300 (Zeiss) microscope using an SE detector. As can be seen from Figures 7a and 7b, the engineered The HB form of LNP023 hydrochloride obtained by the rheological 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 manufactured by Hosokawa Alpine AG, Auk 100UPZ pin available 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 and 100°C, respectively. or filled in 200 mg doses.

Claims

1. The following formula (A) 【Chemistry 1】 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 represented by the formula: A crystalline hydrate having a powder X-ray diffraction pattern containing peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.6±0.2)°, (17.2±0.2)°, (20.7±0.2)°, and (24.0±0.2)°.

2. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at at least one 2θ angle selected from (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (24.0±0.2)°, (24.6±0.2)°, and (10.0±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (21.3±0.2)°, (22.2±0.2)°, and (28.0±0.2)°, when measured using a 2θ angle measuring 10.0°C.

3. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

4. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

5. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

6. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

7. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

8. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

9. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

10. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

11. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, and (24.6±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

12. Cu-Kα with a wavelength of 0.15419 nm １，２ 2. The crystalline hydrate of claim 1, having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2)°, and (28.0±0.2)°, when measured at temperatures in the range 20-30°C using a 1000 Hz X-ray diffraction pattern.

13. (3452±2) cm when measured using a diamond ATR cell at temperatures in the range 20-30°C －１ , (2875±2)cm －１ , (1692±2)cm －１ , (1439±2)cm －１ and (1243±2) cm －１ The crystalline hydrate according to any one of claims 1 to 12, having a Fourier transform infrared spectrum comprising a peak at a wave number of

14. (3452±4) cm when measured using a diamond ATR cell at temperatures in the range 20-30°C. －１ , (3274±4)cm －１ , (2933±4)cm －１ , (2875±4)cm －１ , (2732±4)cm －１ , (1709±4)cm －１ , (1692±4)cm －１ , (1658±4)cm －１ , (1615±4)cm －１ , (1601±4)cm －１ , (1515±4)cm －１ , (1497±4)cm －１ , (1461±4)cm －１ , (1439±4)cm －１ , (1425±4)cm －１ , (1384±4)cm －１ , (1243±4)cm －１ , (1184±4)cm －１ , (1069±4)cm －１ , (767±4) cm －１ and (739±4) cm －１ The crystalline hydrate according to any one of claims 1 to 12, having a Fourier transform infrared spectrum comprising a peak at a wave number of

15. 15. The crystalline hydrate according to any one of claims 1 to 14, having a differential scanning calorimetry curve comprising an endothermic event in the range of 35°C to 170°C when measured at a heating rate of 10 K / min.

16. 16. A crystalline hydrate according to any one of claims 1 to 15, having a thermogravimetric analysis curve which, when heated from 30°C to 300°C at a heating rate of 20 K / min, exhibits a mass loss at temperatures between 200 and 220°C of not more than 4.5% by weight, relative to the weight of the crystalline hydrate.

17. 17. The crystalline hydrate of any one of claims 1 to 16, which exhibits a mass change of 4.5 wt. % or less when measured by dynamic vapor sorption at a relative humidity in the range of 0 to 95% and a temperature of (25±1.0)°C, relative to the weight of the crystalline hydrate at 0% relative humidity.

18. The crystalline hydrate according to any one of claims 1 to 17, wherein the hydrate is a monohydrate.

19. A crystalline hydrate according to any one of claims 1 to 18, having a crystal habit that is essentially cubic or cylindrical in shape.

20. 20. A composition comprising the crystalline hydrate of any one of claims 1 to 19, comprising up to 20%, 10%, 5%, 2% or 1% by weight of any other physical form of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride represented by formula (A).

21. The other physical form of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride represented by formula (A) is a Cu-Kα １，２ 21. The composition of claim 20, wherein the composition is Form A having a powder X-ray diffraction pattern comprising peaks at 2θ angles of (11.6±0.1)°, (15.3±0.1)°, (16.5±0.1)°, (20.1±0.1)°, and (23.3±0.1)°, when measured at a temperature in the range 20-30°C using X-ray diffraction.

22. Use of the crystalline hydrate according to any one of claims 1 to 19 or the composition according to claim 20 or 21 for the preparation of a pharmaceutical composition.

23. A pharmaceutical composition comprising the crystalline hydrate of any one of claims 1 to 19 or the composition of claim 20 or 21, and optionally at least one pharmaceutically acceptable excipient.

24. 24. The pharmaceutical composition of claim 23, which is an oral solid dosage form.

25. The pharmaceutical composition according to claim 23 or 24, wherein the crystalline hydrate is a crystalline hydrate having an aspect ratio of 0.4 to 0.

7.

26. The crystalline hydrate has a particle size distribution X of 10 to 70 μm. ５０ The pharmaceutical composition according to any one of claims 23 to 25, which is a crystalline hydrate having the formula:

27. 27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the crystalline hydrate is a crystalline hydrate having a compacted (15 kPa) bulk density of 0.50 to 0.65 g / ml.

28. 28. The pharmaceutical composition of any one of claims 23 to 27, comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride of formula (A) in a dosage of up to 200 mg calculated as the anhydrous free base of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride of formula (A).

29. 29. The pharmaceutical composition of claim 28, comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride of formula (A) in a dosage of 10 mg to 200 mg, calculated as the anhydrous free base of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride of formula (A).

30. 29. The pharmaceutical composition of claim 28, comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride represented by formula (A) in a dosage of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg, each calculated as the anhydrous free base of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride represented by formula (A).

31. A pharmaceutical composition according to any one of claims 23 to 30 for use as a medicament.

32. Paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), HUS (E. coli-induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid pemphigoid), ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex disease, rheumatoid arthritis, systemic lupus erythematosus Systemic Lupus Erythematosus (SLE), Systemic Lupus Erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, arthritis, autoimmune heart disease, inflammatory bowel disease, ischemia-reperfusion injury, acquired partial lipodystrophy (Barraquer-Simons syndrome) The pharmaceutical composition according to any one of claims 23 to 30, for use in the treatment or prevention of a disease or disorder selected from the group consisting of atypical hemolytic uremic syndrome (AHS), ANCA-associated vasculitis, cryoglobulinemia, psoriasis, atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis, bullous skin diseases, and MPGNII.

33. The pharmaceutical composition according to any one of claims 23 to 32, wherein the disease or disorder is selected from paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), MN (membranous nephropathy), and aHUS (atypical hemolytic uremic syndrome).

34. 34. The pharmaceutical composition of claim 33 for use in the treatment or prevention of paroxysmal nocturnal hemoglobinuria (PNH).

35. 34. The pharmaceutical composition of claim 33 for use in the treatment or prevention of C3G (C3 glomerulopathy).

36. 34. The pharmaceutical composition of claim 33 for use in the treatment or prevention of IgAN (immunoglobulin A nephropathy).

37. 34. The pharmaceutical composition of claim 33 for use in the treatment or prevention of MN (membranous nephropathy).

38. 34. The pharmaceutical composition of claim 33 for use in the treatment or prevention of aHUS (atypical hemolytic uremic syndrome).

39. 39. The pharmaceutical composition of any one of claims 33 to 38, wherein the crystalline hydrate of the compound of formula (A) is administered to a subject in a daily dose of up to 400 mg, calculated as the anhydrous free base of the compound of formula (A).

40. 39. The pharmaceutical composition of any one of claims 33 to 38, wherein the crystalline hydrate of the compound of formula (A) is administered to a subject at a daily dose of 10 mg to 400 mg, calculated as the anhydrous free base of the compound of formula (A).

41. 39. The pharmaceutical composition of any one of claims 33 to 38, wherein the crystalline hydrate of the compound of formula (A) is administered to a subject at a daily dose of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg, each calculated as the anhydrous free base of the compound of formula (A).

42. 39. The pharmaceutical composition of any of claims 33 to 38, wherein the crystalline hydrate of compound of formula (A) is administered to a subject twice daily (bid).

43. A method for producing a pharmaceutical composition comprising the crystalline hydrate of any one of claims 1 to 19, or the composition of claim 20 or 21.

44. A method for producing a crystalline hydrate according to any one of claims 1 to 19 or a composition according to claim 20 or 21, comprising: (i) providing 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride represented by formula (A) in solid form; (ii) suspending 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride of formula (A) provided in step (i) in a first solvent comprising acetone and water and heating to dissolve the solid and provide a solution; (iii) cooling the solution obtained in step (ii) and adding a second solvent comprising acetone, ethyl acetate, or a combination thereof to provide crystals in the mother liquor; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor; (v) optionally washing the isolated crystals obtained in step (iv); and (vi) drying the crystals obtained in step (iv) or (v); A manufacturing method comprising:

45. The step (iii) (a) cooling the solution obtained in step (ii) and then heating 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; 45. The method of claim 44, comprising:

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