Crystal morphology of LNP023

Abstract

This document provides the crystalline hydrate form of LNP023 hydrochloride and its manufacturing process. [Solution] A crystalline hydrate form of LNP023 hydrochloride is provided, characterized in that when measured using Cu-Kα1,2 lines with a wavelength of 0.15419 nm at a temperature in the range of 20-30°C, the powder X-ray diffraction pattern includes peaks at 2θ angles of (4.6±0.2)°, (9.2±0.2)°, and (19.1±0.2)°. Furthermore, a pharmaceutical composition is provided comprising the crystalline hydrate form of LNP023 hydrochloride and at least one excipient that is acceptable as a pharmaceutical agent. The pharmaceutical composition can be used to treat diseases and disorders mediated by complement activation.

Description

[Technical Field]

[0001] The crystalline form of LNP023 hydrochloride and its manufacturing process are described herein. A medical device comprising the crystalline form of 023 hydrochloride and at least one excipient that is acceptable as a drug. Pharmaceutical compositions are also described herein. The pharmaceutical compositions described herein are for complement activation. Therefore, it can be used to treat the disease or disorder that is being mediated. [Background technology]

[0002] LNP023 belongs to a class of complement pathway B factor inhibitors and is involved in the initial activation mechanism. It acts by inhibiting or suppressing the amplification of the complement system caused by unrelated C3 activation. Currently, paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulosis (C3G), and immunoglobulinemia are being treated. In development for the treatment or prevention of IgAN (Implantable Nephropathy) and membranous nephropathy (MN) LNP023 hydrochloride is chemically 4-((2S,4S)-(4-ethoxy-1-(( 5-Methoxy-7-methyl-1H-indole-4-yl)methyl)piperidine-2-yl It is designated as a benzoate salt and can be represented by the following chemical structure by formula (A). Cut. [ka]

[0003] LNP023 hydrochloride and its manufacturing method are incorporated herein by reference in their entirety. This is disclosed in International Publication No. 2015 / 009616. In Example 26d of Brochure No. 15 / 009616, LNP023 hydrochloride was obtained It is obtained as a crystalline solid by recrystallization of the amorphous material, and its characteristics are determined by X-ray powder diffraction. It can be attached. This crystalline form is referred to as form A in this specification.

[0004] The various solid states of active pharmaceutical ingredients often have different properties. Differences in physicochemical properties can play an important role in improving pharmaceutical compositions, for example, improved Pharmaceutical preparations having a dissolution profile, or having improved stability or shelf life, The improved solid state of the active pharmaceutical ingredient makes it usable. Furthermore, formulation and Furthermore, the processing or handling of the active ingredients of pharmaceuticals during manufacturing can be improved. The novel solid-state forms of the components have desirable processing characteristics. These are not conventionally known. Compared to solid forms, it is easier to handle, more suitable for storage, or offers superior purification. It could be possible.

[0005] International Publication No. 2015 / 009616, LNP023 HCl crystal "A The "form" has certain characteristics, and for that reason it is not very suitable for large-scale manufacturing processes. Therefore, a more stable form of LNP023 HCl is desired.

[0006] Thus, reliable manufacturing of safe and effective pharmaceuticals containing LNP023 hydrochloride is possible. It is necessary to provide a solid-state form of LNP023 hydrochloride that possesses the physicochemical properties that enable this. It has a sex. [Overview of the project] [Means for solving the problem]

[0007] This disclosure provides a crystalline hydrate form of LNP023 hydrochloride, also referred to below as the "HB form". Provided. The "HB form" of LNP023 hydrochloride is an active pharmaceutical ingredient intended for use in oral solid dosage forms. It has desirable physicochemical properties.

[0008] The advantageous properties of the HB form of LNP023 include chemical stability, physical stability, and hygroscopicity. Solubility, dissolution, morphology, crystallinity, fluidity, compressibility ) and wettability are also mentioned. As a result, these properties make the HB form suitable for large-scale manufacturing. It will be suitable for Seth.

[0009] In one embodiment, the HB form is physically and chemically stable during the pharmaceutical process and storage. This is the phase-pure, highly crystalline form of LNP023 hydrochloride. The HB form is thermodynamically more stable. It is a fixed form, and the possibility of transformation into other forms can be minimized. Form A is a specific It can be converted to the HB form under certain conditions. When the most stable form is used, the manufacturing process of the active pharmaceutical ingredient is carried out. Possible transformations during cessation and storage, such as transformation from form A to form H or polymorphism, are eliminated. As such, the use of thermodynamically stable forms of compounds is highly valued. Therefore, reliable bioavailability of pharmaceuticals, and thus consistent efficacy of pharmaceuticals. It will become 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 Steam Adsorption 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 meaning of designations: As used herein, the term "room temperature" refers to a temperature in the range of 20 to 30°C. .

[0012] As used herein, the term "measured at temperatures in the range of 20–30°C" refers to standard This refers to measurements under specific conditions. Generally, standard conditions are temperatures in the range of 20-30°C, i.e., room temperature. It means warm. Standard conditions can mean a temperature of approximately 22°C.

[0013] As used herein, the term "HB form" refers to the solid form of LNP023 hydrochloride. When explaining, we mean a specific crystalline hydrate form of LNP023 hydrochloride, such as the monohydrate form. To taste. This form is further defined herein and in the claims. .

[0014] As used herein, the term "Form A" refers to the solid form of LNP023 hydrochloride. If you wish to clarify, see LNP023 salt disclosed in International Publication No. 2015 / 009616. This refers to a specific crystalline form of an acid salt. Form A of LNP023 hydrochloride has a wavelength of 0.15419 CuKα having nm 1,2 When measured using a line, within a temperature range of 20-30°C , (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 Manufactured (see Example 26d): 4-((2S,4S)-(4-ethoxy-1) in H2O / CH3CN (10 / 3mL) -((5-methoxy-7-methyl-1H-indole-4-yl)methyl)piperidine- A solution of 2-yl benzoic acid (620 mg, 1.467 mmol) is mixed with 5M HCl aqueous solution. The solution (500 μL, 2,500 mmol) was added. The reaction mixture was then freeze-dried. An amorphous compound was obtained, and then suspended in iPrOH (300 mL). The suspension was divided into 7 It was heated to 0°C. The suspension changed to a solution after 1.5 hours. Then, the solution was stirred. The mixture was then cooled to room temperature for approximately 5 hours to obtain a solid. The obtained solid was collected by filtration and high-quality analysis was performed. The compound was dried under open air at 50°C to obtain the title compound as a crystalline solid. 1 HCl NMR 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 patterns are shown in Table 1 below.

[0017] [Table 1]

[0018] As used herein, the term "reflection" in relation to powder X-ray diffraction refers to long-range position Atoms in a solid material are distributed in a spatially ordered, regular, and repeating pattern by parallel planes. 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 nce) This means that such solid materials are classified as crystalline materials, whereas amorphous materials are used for long distances. It is defined as a solid material that lacks order, exhibits only short-range order, and therefore exhibits broad-range scattering. According to the literature, long-range order extends to, for example, more than 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] Regarding powder X-ray diffraction, the term "essentially the same" refers to the peak position and relative peak intensity. This means that a degree of variation should be taken into consideration. For example, the usual precision of the 2θ value is The range is ±0.2°²θ, for example, within the range of ±0.1°²θ. Therefore, for example, 9. The peak that typically appears at 2°2θ is (9.2-0.2) in most linear diffractometers under standard conditions. °~(9.2+0.2)°2θ, for example, (9.2-0.1)°~(9.2+0.1)° It may appear at 2θ. Furthermore, the relative peak intensity may vary between instruments, as well as the degree of crystallinity, and is preferable. Variation is caused by factors such as orientation, particle size, sample preparation, and other factors known to those skilled in the art. Those skilled in the art will understand that this should be interpreted solely as a qualitative measurement.

[0020] Regarding infrared spectrophotometrics, the term "essentially the same" refers to the peak position and the phase of the peak. This means that variations in intensity should be taken into consideration. For example, the normal precision of wave values. The range is ±4cm -1 Within a range, for example, ±2cm -1 It is within the range. Therefore, for example 1692cm -1 The peak at (1692-4) is observed in most linear diffractometers under standard conditions. ~(1692+4)cm -1 For example, (1692-2)~(1692+2)cm -1 in It may appear. Peak intensity can be derived from matching drawings, but those skilled in the art will know the degree of crystallinity. Differences in peak intensity due to sample preparation, measurement methods, and other factors can also occur in infrared spectroscopy. It should be understood that, therefore, peak intensity should be interpreted only as a qualitative measurement.

[0021] The HB form of LNP023 hydrochloride described herein is shown in the graph data in the Figures “In the Figures” These characteristics may be referenced herein. Such data include, for example, powder X-ray diffraction. Examples include FTIR. Differences include instrument type, response, sample orientation, and sample concentration. Furthermore, due to factors such as differences in sample purity, when presented in the form of a chart, such data may appear small. Those skilled in the art will know that variations, such as differences related to the exact peak position and intensity, can occur. This will be understood. However, graphics created for other or unknown solid forms Comparison of physical data and graphical data in the drawings herein, and 2-second Confirmation that the graphical data in the set pertains to the same crystal morphology is well within the knowledge of those skilled in the art. It is located there.

[0022] As used herein, the terms “solid form” or “solid state form” refer to a compound. This term synonymously refers to either a crystalline or amorphous phase.

[0023] As used herein, the term "amorphous" refers to the solid form of a compound that is not crystalline. This refers to the state of matter. Amorphous compounds lack long-range order and do not exhibit definitive X-ray diffraction peaks. It does not indicate a turn.

[0024] As used herein, the term "polymorph" refers to a crystalline form of a crystalline form that has the same chemical composition but is not crystalline. This refers to a crystalline form having a different spatial arrangement of the molecules, atoms, or ions that form it.

[0025] As used herein, the term "cocrystal" refers to a non-ionic and non-covalent bond. A crystal lattice that is associated contains two or more different molecules or ionic compounds. A crystalline material in which at least two of the individual molecules or ionic compounds are solid at room temperature. It refers to crystalline materials.

[0026] As used herein, the term “hydrate” means that water is incorporated into the crystalline structure, or To be contained by the crystal structure, for example, to be part of the crystal structure or incorporated into the crystal This refers to a crystalline solid containing water. As a result, water can exist in stoichiometric or non-theoretical quantities. When water is present in a theoretical quantity, the hydrate is given the Greek numeral prefix (Greek numer It can be referred to by adding the prefix (al). For example, hydrate is water / hydrate Depending on the stoichiometry of the compound, it may be called a hemihydrate or monohydrate. The water content is, for example, Karl It can be measured by Fischer coulometry.

[0027] As used herein, the terms “dehydrate” or “dehydrate” refer to the crystal structure of the host molecule. This indicates that at least some of the water has been removed.

[0028] As used herein, the term “solvate” refers to a mixture of one or more organic solvents. Incorporated into or housed by a crystal structure, for example, as part of a crystal structure It refers to a crystalline solid that is present or incorporated within a crystal (solvent-containing). Therefore, One or more of these organic solvents may exist in stoichiometric or non-theoretical quantities. When an organic solvent is present in a theoretical amount, the solvate is obtained by adding a Greek numeral prefix. It can be referred to as such. For example, a solvate is a semisolvate or depending on the solvent / compound stoichiometry. It may be called a monosolvate. The solvent content can be determined, for example, by GC, NMR, SXRD, or TG. It can be measured by A / MS.

[0029] The term "isostructural solvate" as used herein refers to , along with the distortion of very small unit cell dimensions and the same type of molecular network structure of the host molecule This refers to solvates having the same space group. Isomorphic solvates as defined herein are guest components The types of organic solvents present as children are different.

[0030] As used herein, the terms “solvation” or “desolvation” refer to the crystallization of a host molecule. The structure indicates that at least a portion of the organic solvent is removed.

[0031] As used herein, the terms “anhydrous form” or “anhydrous substance” refer to a crystalline structure in which water is incorporated. This refers to a crystalline solid that does not contain water or whose crystal structure does not contain water. The anhydrous form may still contain residual water that is not part of the crystalline structure, but is absorbed onto the surface of the crystal. It can be attached or absorbed into disordered regions of the crystal. Typically, the anhydrous form is the weight of the crystalline form. In contrast, it does not contain more than 3.0% by weight of water, for example, it does not contain more than 1.0% by weight of water. do not have.

[0032] When referring to crystalline solids, the term "non-solvated" as used herein means The organic solvent is not incorporated into the crystal structure, or is not contained by the crystal structure. This means that the non-solvated form still contains residual organic solvents that are not part of the crystalline structure. However, it can be obtained, but it can be adsorbed on the surface of the crystal or absorbed into disordered regions of the crystal. One embodiment In this context, the non-solvated form does not contain more than 3.0% by weight of organic solvents, for example, 1.0% by weight. It does not contain organic solvents exceeding a certain percentage. In one embodiment, the non-solvated form is the crystalline form. It does not contain more than 0.5% by weight of organic solvents.

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

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

[0035] With respect to LNP023 hydrochloride, the term “predetermined amount” as used herein refers to LN Pharmaceutical composition of P023 hydrochloride with desired dosage strength This refers to the initial amount of LNP023 hydrochloride used in the manufacture of the product.

[0036] With respect to LNP023 hydrochloride, the term “therapeutic effective dose” as used herein refers to It contains an amount of LNP023 hydrochloride that produces the desired therapeutic or prophylactic effect.

[0037] As used herein, the term "non-hygroscopic" refers to a compound with a relative humidity of 80% relative to its weight. A percentage (%) indicates a mass increase of less than 0.2% at 25°C (due to water absorption).

[0038] Regarding crystal shape, the term "equant" as used herein refers to the cubic crystal system. This refers to an equi-dimensional crystal, such as a cube or sphere. do.

[0039] With respect to crystal shape, the terms “plate” or “plate-like” as used herein refer to flakes. It refers to a flat, plate-like crystal that is thicker than, but has a similar area and width.

[0040] Regarding crystal shape, the terms "flake" or "flaked" as used herein This refers to a thin, flat crystal that is thinner than a plate and has a similar area and width.

[0041] With respect to crystal shape, the terms “needle” or “needle-shaped” as used herein are similar in width. It refers to a needle-shaped, thin, and very elongated crystal that has both width and shape.

[0042] Regarding the crystal shape, the terms "cylindrical" or "cylindrical" as used synonymously in this specification refer to... The term refers to an elongated, columnar crystal that is wider and thicker than a needle.

[0043] Such definitions of crystal habits are consistent with those commonly used in the art, for example, “Poly morphism in the Pharmaceutical Industry” edited by Rolf Hilfiker(Wiley-VCH,2006) ;Chapter 7,Light Microscopy(Gary Nichols Please refer to ).

[0044] As used herein, the term "approximately" means a rough estimate or a rough estimate within a general range. To taste. When the term "approximately" is used in conjunction with a numerical range, it means that the number exceeds the stated number, and The range is modified by broadening the boundary below it. Generally, the term "approximately" is used. This is used to modify numbers that exceed a specified value and fall below a specified value with a 10% fluctuation. Used in specifications.

[0045] With regard to compositions comprising a specific solid form of LNP023 hydrochloride, the term used herein is " The phrase "substantially contains no other solid forms" means that the composition contains LNP023 hydrochloride Any other solid form of the composition, up to 20% by weight (percentage by 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 Weight %, up to 6% weight, up to 5% weight, up to 4% weight, up to 3% weight, up to 2 By weight %, up to 1% by weight, up to 0.5% by weight, or up to 0.1% by weight, or 80 This means it contains any of the following weight percentages: ~100% by weight.

[0046] When used in relation to form, “substantially pure” as used herein refers to a compound For the weight of LNP023 hydrochloride, more than 90% by weight of a specific solid form, for example Amounts exceeding 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight Furthermore, it means a compound having a purity equal to approximately 100% by weight. The remaining material is the compound. This includes other forms of or reaction or processing impurities resulting from their manufacture. For example, L The crystalline form of NP023 hydrochloride is known in the art at this time and is acceptable. It is substantially pure, as measured by various means, having a purity of over 90% by weight. It is considered that the remaining less than 10% of the material is other forms of LNP023 hydrochloride, reaction impurities or Contains processed impurities.

[0047] As used herein, the term “subject” is intended to mean a human being. The target human subjects are, for example, human patients (referred to as patients) with diseases, such as those described herein. It means to be found out, or to be a normal target.

[0048] As used herein, the term “physically stable” means that a particular free base or salt form is , specified period, for example 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 For months, 12 months, 18 months, 24 months, or longer, under specified conditions, such as room temperature, temperature When subjected to ambient humidity or 40°C / 75% relative humidity, one or more different physical forms ( For example, not changing into a different solid form (as measured by XRPD, DSC, etc.) This means that, in some embodiments, less than 25% of the compound's form is fragmented under the specified conditions. When this occurs, it transforms into one or more different physical forms. In some embodiments, Approximately 20%, approximately 15%, approximately 10%, approximately 5%, and approximately 3% of the form of the specific compound. Less than, less than about 1%, less than about 0.5% change into one or more different physical forms of that particular compound when subjected to specified conditions. In some embodiments, a detectable amount of a particular form of the compound does not change into one or more different physical forms of the compound. .

[0049] As used herein, the term "chemically stable" means that the chemical structure of a particular compound does not change into other compounds (e.g., does not decompose) when subjected to specified conditions, such as room temperature, ambient humidity or 40 °C / relative humidity 75% for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or more. In some embodiments, less than 25% of the form of a particular compound changes 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 about 5%, less than about 3%, less than about 1%, less than about 0.5% of the form of a particular compound changes into one or more other compounds when subjected to specified conditions. In some embodiments, a detectable amount of the form of a particular compound does not change into one or more different physical forms of that particular compound. .

[0050] As used herein, the term "pharmaceutically acceptable excipient" means a substance that does not exhibit significant pharmacological activity at a given dosage and is added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients can particularly function as vehicles, diluents, release agents, disintegrants, solubilizing modifiers, absorption enhancers, stabilizers or manufacturing aids. Excipients include fillers (diluents), binders, disintegrants. or manufacturing aids. ​​​​​​​​​​​​​Examples include lubricants and glidants.

[0051] As used herein, the terms “filler” or “diluent” refer to the active ingredients of the pharmacopoeia before delivery. This refers to a substance used to dilute a substance. Diluents and fillers act as stabilizers. It can also accomplish that.

[0052] As used herein, the term “binder” refers to a binder that maintains cohesiveness and separate parts. Therefore, it refers to a substance that binds together the active ingredient of a pharmaceutical and the excipients that are acceptable as pharmaceuticals. ru.

[0053] The term "disintegrant" or "disintegrant" as used herein refers to a disintegrant agent. The term "integrating agent" refers to an agent that, when added to a solid pharmaceutical composition, To promote its breakdown or disintegration after administration, and to release the active pharmaceutical ingredient as efficiently as possible, It refers to a substance that enables rapid dissolution.

[0054] As used herein, the term “lubricant” refers to a lubricant used during the tableting or encapsulation process. This refers to a substance added to the powder blend to prevent clumps of compressed powder from sticking to the equipment. The lubricant can help eject the tablet from the die and improve the powder flow.

[0055] As used herein, the term “fluidizer” refers to an agent that improves fluidity during tablet compression. In order to do so, and to produce an anti-caking effect. Therefore, it refers to substances used in tablet and capsule formulations. [Brief explanation of the drawing]

[0056] [Figure 1]A typical PXRD of the HB form of LNP023 hydrochloride described herein is illustrated. The x-axis represents the scattering angle at 2θ degrees, and the y-axis represents the intensity of the scattered X-ray beam in terms of the number of detected photons per second. [Figure 2] This specification provides an example of a comparison between a representative PXRD (bottom) of the HB form of LNP023 hydrochloride described herein and a representative PXRD (top) of the A form of LNP023 hydrochloride described in International Publication No. 2015 / 009616. The x-axis represents the scattering angle at 2θ degrees. The powder X-ray diffraction pattern of the A form is shifted along the y-axis, and the diffraction pattern has been separated for clarity. Therefore, the y-axis is arbitrary and unlabeled. [Figure 3] The following are representative FTIR spectra of the HB form of LNP023 hydrochloride as described herein. The x-axis represents the wavenumber at cm⁻¹, and the y-axis represents the relative intensity in transmittance percentage. [Figure 4] A typical DSC curve for the HB form of LNP023 hydrochloride described herein is shown. The x-axis represents temperature in degrees Celsius (°C), and the y-axis represents heat flow in watts / g (W / g) along with a rising endothermic peak. [Figure 5] A typical TGA curve for the HB form of LNP023 hydrochloride described herein is shown. The x-axis represents temperature in degrees Celsius (°C), and the y-axis represents the mass (loss) of the sample in weight percentage (W%). [Figure 6] Representative DVS isotherms of the HB form of LNP023 hydrochloride described herein are shown in the range of relative humidity from 0 to 95%. The x-axis represents the relative humidity in percent (%) measured at a temperature of (25.0 ± 1.0) °C, and the y-axis represents the equilibrium mass change in wt% (weight) relative to the sample weight at 0% relative humidity. Adsorption cycles are marked with triangles, and desorption cycles are marked with squares. [Figure 7] Figure 7: Figures 7a and 7b illustrate scanning electron microscope images of the HB form of LNP023 hydrochloride described herein, prepared according to Example 3 (total bar scale: 50 micrometers). [Modes for carrying out the invention]

[0057] Crystal form Illustration of embodiments: In one embodiment, the present invention relates to a crystalline hydrate of LNP 023 hydrochloride, also referred to herein as the "HB form". 023 hydrochloride monohydrate.

[0058] LNP 023 hydrochloride can be represented by the following chemical structure according to formula (A).

Chemical formula

[0059] The HB form of LNP 023 hydrochloride described herein can be characterized by analytical methods well known in the pharmaceutical industry with respect to the characterization of solids. Such methods include, but are not limited to, PXRD, SXRD, FTIR, DSC, DVS, TGA, and SEM. It can be characterized by one of the aforementioned analytical methods or a combination of two or more thereof. In particular, the HB form of LNP 023 hydrochloride described herein can be characterized by any one of the following embodiments or a combination of two or more of the following embodiments. In particular, the HB form of LNP 023 hydrochloride described herein can be characterized by any one of the following embodiments or a combination of two or more of the following embodiments. 、PXRD, SXRD, FTIR, DSC, DVS, TGA and SEM are included. It can be characterized by one of the aforementioned analytical methods or a combination of two or more thereof. In particular, the HB form of LNP 023 hydrochloride described herein can be characterized by any one of the following embodiments or a combination of two or more of the following embodiments. characterized by one of the aforementioned analytical methods or a combination of two or more thereof. In particular, the HB form of LNP 023 hydrochloride described herein can be characterized by any one of the following embodiments or a combination of two or more of the following embodiments. 付けられ得る。特に、本明細書に記載のLNP023塩酸塩のHB形態は、以下の実施形 態のいずれか一つによって、又は以下の実施形態の2つ以上の組み合わせによって特徴付 けられ得る。

[0060] Illustration of PXRD embodiments: In one embodiment, the present invention relates to a crystal form (HB form) of LNP 02 hydrochloride characterized by PXRD peaks identified at 2θ angles of (4.6 ± 0.2)°, (9.2 ± 0.2)°, and (19.1 ± 0.2)° when measured at a temperature in the range of 20 - 30 °C using a Cu-Kα line having a wavelength of 0.15419 nm. 1,2 line using a Cu-Kα line having a wavelength of 0.15419 nm and measured at a temperature in the range of 20 - 30 °C, the PXRD peaks identified at 2θ angles of (4.6 ± 0.2)°, (9.<x 2 ± 0.2)°, and (19.1 ± 0.2)°. よって特徴付けられ得る、LNP023塩酸塩の結晶形態(HB形態)に関する。

[0061] In one embodiment, the present invention relates to a Cu-Kα line having a wavelength of 0.15419 nm 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 peak. Regarding form.

[0062] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 concerns the crystalline form (HB form) of the trihydrochloride salt.

[0063] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C, the values ​​are (4.6±0.2)° and (6.8°C). (±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2) Characterized by PXRD peaks identified at 2θ angles of ° and (24.6±0.2)°. This concerns the crystalline form (HB form) of LNP023 hydrochloride, which can be detected.

[0064] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (4.6±0.2)°, (6. 8±0.2°, (9.2±0.2°), (12.2±0.2°), (19.1±0.2° P is identified at 2θ angles of )°, (21.3±0.2)°, and (24.6±0.2)°. The crystalline form (HB form) of LNP023 hydrochloride can be characterized by the XRD peak. To relate to.

[0065] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 Characterized by a PXRD peak identified at a 2θ angle of (24.6±0.2)°. This concerns the crystalline form (HB form) of LNP023 hydrochloride.

[0066] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 pins identified at 2θ angles of 21.3±0.2° and (24.6±0.2°) This relates to the crystalline form (HB form) of LNP023 hydrochloride, which can be characterized by the following:

[0067] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 pins identified at 2θ angles of 21.3±0.2° and (24.6±0.2°) This relates to the crystalline form (HB form) of LNP023 hydrochloride, which can be characterized by the following:

[0068] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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°)° The crystalline form of LNP023 hydrochloride can be characterized by the PXRD peak identified at a certain degree. Regarding the state (HB morphology).

[0069] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 Characterized by a PXRD peak identified at a 2θ angle of 0.6±0.2°, LN This concerns the crystalline form (HB form) of P023 hydrochloride.

[0070] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 PXRD peaks identified at 2θ angles of ±0.2° and (24.6±0.2°)° are This relates to the crystalline form (HB form) of LNP023 hydrochloride, which can be characterized as follows.

[0071] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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 Identified at 2θ angles of ±0.2°, (24.0±0.2°), and (24.6±0.2°). The crystalline form of LNP023 hydrochloride (HB form) is characterized by the PXRD peak. Regarding )

[0072] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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°. This concerns the crystalline form (HB form) of hydrochloride salts.

[0073] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (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) Characterized by PXRD peaks identified at 2θ angles of )° and (28.0±0.2)°. This concerns the crystalline form (HB form) of LNP023 hydrochloride.

[0074] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​are (4.6±0.2)°, (6. 8±0.2°, (9.2±0.2°), (12.2±0.2°), (19.1±0.2° The PXRD peak is identified at )° and (24.6±0.2)° 2θ angles, and (1 0.0±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6± 0.2°, (17.2±0.2)°, (20.7±0.2)°, (21.3±0.2) From °, (22.2±0.2)°, (24.0±0.2)°, and (28.0±0.2) LNP02 is characterized by at least one more peak selected from the group. This concerns the crystalline form (HB form) of the trihydrochloride salt.

[0075] In another embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 When measured using a line, at a temperature range of 20-30°C, the values ​​are (4.6±0.1)°, (9 (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)°; also 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)°; also 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 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 (0.7±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 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 (0.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0 Identified at 2θ angles of 0.1°, (24.6±0.1)°, and (28.0±0.1)°. The crystalline form (HB form) of LNP023 hydrochloride is characterized by the PXRD peak. To relate to.

[0076] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature range of 20-30°C using this method, the values ​​were (4.6±0.1)°, (6. 8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1 The PXRD peak is identified at )° 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 is characterized by at least one more peak selected from the group. Regarding the crystalline form (HB form) of hydrochloride salts.

[0077] The PXRD in HB form described herein is from the International Publication No. 2015 / 009616 brochure. It can be clearly distinguished from the A-form of Lett's PXRD (as shown in Figure 2 of this specification). (See also the superposition of PXRDs). The HB form is, for example, (4.6±0.1) and While form A shows an intrinsic peak at (9.2±0.1)°2θ, form A shows a peak in the same range. It does not show the mark. According to page 176 of the international publication no. 2015 / 009616 If so, one of the four most characteristic peaks of form A is the peak at 11.6°2θ. In contrast, the HB form described in the specification does not show a peak in the same range.

[0078] In another embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 When measured using a line at a temperature in the range of 20-30°C, as described in one of the embodiments above. It has a PXRD, but does not contain a peak at a 2θ angle of (11.6±0.2)°. This concerns the crystalline form (HB form) of LNP023 hydrochloride, which can be used as a characteristic feature.

[0079] In one embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 line When measured at a temperature in the range of 20-30°C using the above-mentioned PXRD, ( LNP0 can be characterized by not including a peak at a 2θ angle of 11.6±0.1)°2θ. Regarding the crystalline form (HB form) of hydrochloride salts.

[0080] In another embodiment, the present invention relates to Cu-Kα having a wavelength of 0.15419 nm. 1,2 When measured using a line at a temperature range of 20-30°C, the result is shown in Figure 1 of this specification. LNP023 hydrochloride may be characterized by having essentially the same PXRD as PXRD. Regarding the crystal morphology (HB morphology).

[0081] For example, the relative intensities of the peaks shown in Figure 1 and listed in Table 2 represent the actual morphology of the HB form. The morphology can be subject to some degree of variation. Generally, the morphology of many crystal grains is The sample holder tends to produce test specimens that exhibit a certain degree of favorable orientation. When reducing the isz yields fine needles or small plates, this is particularly true for needle-shaped or plate-shaped crystals. It is clear. The preferred orientation in the sample affects the intensity of various peaks, and As a result, some samples had higher intensities than would have been expected from completely random samples, while others had lower intensities. ru.

[0082] Example of an FTIR embodiment: In one embodiment, the present invention relates to (3452±4)cm -1 , (2875±4)cm - 1 , and (1692±4)cm -1 The FTIR spectrum has a peak at the wavenumber. This invention relates to the crystalline form (HB form) of LNP023 hydrochloride salt, characterized by the following features.

[0083] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (3452±4)cm -1 , (2875±4)cm -1 , (1 692±4)cm -1 , and (1439±4)cm -1FTIR, which includes a peak at the wavenumber Regarding the crystalline form (HB form) of LNP023 hydrochloride, characterized by having a spectrum. ru.

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

[0085] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 It is characterized by having an FTIR spectrum that includes a peak at a certain wavenumber. This concerns the crystalline form (HB form) of LNP023 hydrochloride.

[0086] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 peak at wavenumber This invention relates to the crystalline form (HB form) of LNP023 hydrochloride, characterized by the presence of cleavage.

[0087] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 It is characterized by having an FTIR spectrum that includes a peak at a certain wavenumber. This concerns the crystalline form (HB form) of LNP023 hydrochloride.

[0088] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 including peak at wavenumber This relates to the crystalline form (HB form) of LNP023 hydrochloride, characterized by having a rut.

[0089] In one embodiment, the present invention is (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 ± ٤) cm -1 of the wave number, and has an FTIR spectrum characterized by including peaks. It relates to the crystalline form (HB form) of LNP023 hydrochloride.

[0090] In one embodiment, the present invention uses a diamond ATR cell at a temperature in the range of 20 to 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 of the wave number, and has an FTIR spectrum characterized by including peaks. It relates to the crystalline form (HB form) of LNP023 hydrochloride. [[ID=]76]

[0091] In one embodiment, the present invention uses a diamond ATR cell and has a range of 20 to 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 peaks at a wavenumber of (767 ± 4) cm -1 in the FTIR spectrum characterized by a crystalline form (HB form) of LNP023 hydrochloride.

[0092] [[ID=4**]] In one embodiment, the present invention uses a diamond ATR cell and has a range of 20 to 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 peaks at a wavenumber of (767 ± 4) cm -1 in the FTIR spectrum The crystalline form of LNP023 hydrochloride, characterized by having an FTIR spectrum including ( Regarding the HB morphology.

[0093] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 is characterized by having an FTIR spectrum that includes a peak at a wavenumber. This concerns the crystalline form (HB form) of P023 hydrochloride.

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

[0095] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 is at this wavenumber The crystalline form of LNP023 hydrochloride, characterized by having an FTIR spectrum (H Regarding Form B)

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

[0097] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 It has an FTIR spectrum that includes a peak at a certain wavenumber. This invention relates to the crystalline form (HB form) of LNP023 hydrochloride salt, characterized by the following features.

[0098] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 Includes a peak at wavenumber The crystalline form (HB form) of LNP023 hydrochloride, characterized by having an FTIR spectrum. Regarding (state).

[0099] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (3452±4)cm -1 , (3274±4)cm -1 , (2 933±4)cm -1 , (2875±4)cm -1 (2732±4)cm -1 , (17 0.9±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 is characterized by having an FTIR spectrum that includes a peak at a wavenumber. This concerns the crystalline form (HB form) of the trihydrochloride salt.

[0100] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (3452±4)cm -1 , (2875±4)cm-1 , (2 732±4)cm -1 (1692±4)cm -1 (1439±4)cm -1 , (12 43±4)cm -1 and (767±4)cm -1 The peak at wavenumber and (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 At least one more peak selected from the group consisting of and The crystalline form of LNP023 hydrochloride is characterized by having an FTIR spectrum including ( Regarding the HB morphology.

[0101] In another embodiment, the present invention uses a diamond ATR cell in the range of 20-30°C. When measured at the following temperature: (3452±2)cm -1 , (2875±2)cm -1 , and (1692±2)cm -1 , or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , and (1439±2)cm-1 ; or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , ( 1439±2)cm -1 and (1243±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , ( 1439±2)cm -1 , (1243±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1692±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 and ( 767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 439±2)cm -1 , (1243±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm-1 , (1439±2)cm -1 , (1243±2)cm -1 and (7 67±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1439±2)cm -1 , (12 43±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 39±2)cm -1 , (1243±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm-1 , (14 97±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 and (76 7±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (124 3±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1243±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1, (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 and (767 ±2 cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184 ±2 cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1, ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184 ±2 cm -1 , (1069±2)cm -1 and (767±2)cm -1 ; or (3452±2)cm -1 , (2875±2)cm -1 (2732±2)cm -1 , ( 1709±2)cm -1 , (1692±2)cm -1 (1658±2)cm -1 , (1 615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (14 97±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (142 5±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184 ±2 cm -1 , (1069±2)cm -1 (767±2)cm -1 and (739±2 )cm -1 ; or (3452±2)cm-1 、 (3274 ± 2) cm -1 、 (2875 ± 2) cm -1 、 ([[]] 2732 ± 2) cm -1 、 (1709 ± 2) cm -1 、 (1692 ± 2) cm -1 、 (1 "658 ± 2) cm -1 、 (1615 ± 2) cm -1 、 (1601 ± 2) cm -1 、 (15 15 ± 2) cm -1 、 (1497 ± 2) cm -1 、 (1461 ± 2) cm -1 、 (143 9 ± 2) cm -1 、 (1425 ± 2) cm -1 、 (1384 ± 2) cm -1 、 (1243 ± 2) cm -1 、 (1184 ± 2) cm -1 、 (1069 ± 2) cm -1 、 (767 ± 2 ) cm -1 and (739 ± 2) cm -1 ; or (3452 ± 2) cm -1 、 (3274 ± 2) cm -1 、 (2933 ± 2) cm -1 、 ([[]] 2875 ± 2) cm -1 、 (2732 ± 2) cm -1 、 (1709 ± 2) cm -1 、 (1 692 ± 2) cm -1 、 (1658 ± 2) cm -1 [[ID=​​​​​​​​​​​​​​​​​​​​-1 , (1243±2)cm -1 , (1184±2)cm -1 , (1069± 2)cm -1 (767±2)cm -1 and (739±2)cm -1 The wavenumber includes a peak The crystalline form of LNP023 hydrochloride, characterized by having an FTIR spectrum (HB Regarding form.

[0102] In one embodiment, the present invention uses a diamond ATR cell to control temperatures in the range of 20 to 30°C. When measured by temperature, (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 The peak at wavenumber and (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 The crystalline form of LNP023 hydrochloride, characterized by having an FTIR spectrum containing the following Regarding (HB form).

[0103] In yet another embodiment, the present invention uses a diamond ATR cell to range 20~ When measured at a temperature of 30°C, the FT is essentially the same as that shown in Figure 3 of this specification. A crystalline form (HB form) of LNP023 hydrochloride characterized by having an IR spectrum. Regarding.

[0104] Example of a DSC embodiment: In one embodiment, LNP023 hydrochloride (HB form) is essentially the same as shown in Figure 4. It may be characterized by having the same DSC profile. In one embodiment, the present invention is When measured at a heating rate of 10K / min, it shows a broad endothermic phenomenon ending at approximately 170°C, followed by... LNP023 hydrochloric acid is characterized by having a DSC curve that shows exothermic decomposition at approximately 200°C. This relates to the crystalline form (HB form) of salt. In one embodiment, a broad absorption fermentation process terminates at approximately 170°C. When measured at a heating rate of 10 K / min, the thermal phenomenon is an endothermic phenomenon in the range of 35°C to 170°C. be.

[0105] Example of a TGA embodiment: In one embodiment, LNP023 hydrochloride (HB form) is essentially the same as shown in Figure 5. The same thermogravimetric analysis (TGA) may be used to characterize the results. In one embodiment, the present invention is When heated to 30-300°C at a speed of 20K / min, due to the loss of water and residual solvent... , relative to the weight of the crystalline form, 4.5% by weight or less, for example, 4.3% by weight or less, for example, 4.0 Less than or equal to a certain percentage by weight, for example, less than or equal to 3.8% by weight, for example, less than or equal to 3.4% by weight, at approximately 220°C, for example An LNP characterized by having a TGA curve showing mass loss at temperatures of 200-220°C. Regarding the crystalline form (HB form) of hydrochloride salt 023.

[0106] Example of a DVS embodiment: In one embodiment, LNP023 hydrochloride (HB form) is essentially the same as shown in Figure 6. The same DVS may be characterized by one embodiment, relative humidity 0-9 When measured by DVS at 5% and a temperature of (25±1.0)°C, relative to the weight of the crystalline form For example, 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 (HB form) of LNP023 hydrochloride characterized by exhibiting a mass change of less than 1% by weight. Regarding (state).

[0107] Further embodiment examples: In another embodiment, the present invention is characterized by being in a non-solvated form. This relates to the crystalline form (HB form) of hydrochloride salts. In one embodiment, the crystalline form of LNP023 hydrochloride salt The crystal form is a hydrated form, such as a monohydrate form.

[0108] An example of morphology In one embodiment, the present invention relates to a cylindrical or cubic (equant) morphology. This relates to the crystalline form (HB form) of LNP023 hydrochloride, characterized by exhibiting the following features.

[0109] In one embodiment, the present invention is essentially cubic or cylindrical, and for example, the shape is Regarding the crystal morphology (HB morphology) of LNP023 hydrochloride, which has a qualitatively cubic crystal habit. This results in a preferred form, in contrast to small needle-shaped or thin blade-shaped crystals. Bulk and fluidity are generated. Such a preferred crystal shape is obtained, for example, through temperature cycling. When crystallization engineering techniques are performed, followed by grinding to reduce the particle size, the following is described herein. It is obtained by carrying out the process described above.

[0110] The resulting particles are characterized by an appropriate aspect ratio. ratio ψ A (0<ψ A ≤1) is defined by the ratio of the minimum value to the maximum value, and the Ferret diameter (Fer (et diameter)ψ A =x Feret min / x Feret max That is the case. This provides an indicator of particle elongation; in other words, the smaller the value, the longer the particle. Therefore, in a further embodiment, the crystalline form (HB form) of LNP023 hydrochloride is cubic. Crystalline particles have an aspect ratio (a50) greater than approximately 0.4, for example, greater than approximately 0.45. It has. In other embodiments, the cubic crystalline particles of the HB form are about 0.4 to about 0.7, for example. For example, it has an aspect ratio of approximately 0.45 to 0.6.

[0111] In a further embodiment, the crystalline form (HB form) of LNP023 hydrochloride is cubic grains. Child particle size distribution X 90 This refers to particles less than approximately 300 μm, for example less than approximately 200 μm, for example approximately 150 μm. It is less than m. In a further embodiment, particle size distribution X 90 This is approximately 30 to 150 μm, for example. For example, the thickness is approximately 35 to 130 μm, or for instance, approximately 40 to 105 μm.

[0112] In a further embodiment, the particle size distribution X of cubic particles in HB form 50 It is approximately 5 to approximately 1 This is 00 μm, for example, approximately 10 to 70 μm, or for example, approximately 15 to 55 μm.

[0113] In a further embodiment, the particle size distribution X of cubic particles in HB form 10 It is approximately 0.1~ This ranges from approximately 50 μm, for example, from approximately 1 to 30 μm, or from approximately 2 to 20 μm.

[0114] In further embodiments, the cubic crystalline particles in HB form are less than about 0.8 g / ml, for example It has a compressed (15kPa) bulk density of less than approximately 0.7 g / ml. In other embodiments, The cubic crystalline particles in the HB form are approximately 0.4 to 0.7 g / ml, for example, approximately 0.50 to 0 0.65 g / ml, for example, a compressed (15 kPa) bulk density of approximately 0.55 to 0.60 g / ml. It has.

[0115] composition Example of an embodiment: In other embodiments, the present invention is defined as any one of the embodiments described above. A composition comprising the HB form of LNP023 hydrochloride as described above, wherein LNP023 hydrochloride is also This relates to compositions that do not essentially contain any of the solid forms described herein. For example, the compositions described herein A composition containing the HB form of LNP023 hydrochloride is composed of LNP023 salt in proportion to the weight of the composition. Up to 20% by weight of any other solid form of the salt, for example, up to 10% by weight, for example Contains 5, 4, 3, 2, or 1% by weight in large quantities. In one embodiment, other components of LNP023 hydrochloride Either solid form is type A as described in International Publication No. 2015 / 009616. It is amorphous or non-crystalline. Among the A forms of LNP023 hydrochloride, the wavelength is 0.15419 nm. Cu-Kα 1,2 When measured using a line, within a temperature range of 20-30°C, ( The PXRD shows an intrinsic peak at a 2θ angle of 11.6±0.1°. Therefore, P Since this peak does not exist at a 2θ angle of (11.6±0.1)° in XRD, It was confirmed that the A form of LNP023 hydrochloride was not present in the composition.

[0116] In one embodiment, the present invention is defined as any one of the embodiments described above. A composition comprising the HB form of LNP023 hydrochloride as described in the book, with a wavelength of 0.15419n CuKα with m 1,2 When measured using a line, within a temperature range of 20-30°C, This relates to a 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 is used with respect to the total weight of the composition, any of the embodiments described above. At least 90% by weight of the HB crystalline form of LNP023 hydrochloride, for example, a small amount At least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99% by weight, further This relates to a composition containing approximately 100% by weight of [the substance]. The remaining material is LNP023 hydrochloride. It may contain other solid forms or reaction or processing impurities resulting from the manufacture of the composition. .

[0118] process Example of an embodiment: In other aspects, the present invention relates to the HB form of LNP023 hydrochloride as described herein, or LNP023 hydrochloride as defined in any one of the above embodiments and its corresponding embodiments A process for producing a composition containing the HB form, (i) A step of providing LNP023 hydrochloride in solid form; (ii) In a first solvent containing acetone and water, add the LNP023 hydrochloride provided in step (i) A process of suspending the solid, heating it, and dissolving the solid to provide a solution; (iii) Cool the solution obtained in step (ii) and add acetone, ethyl acetate, or a combination thereof. A step of adding a second solvent containing the mixture to provide crystals in the mother liquor; (iv) A step of separating at least a portion of the crystals obtained in step (iii) from the mother liquor; (v) A step of optionally washing the isolated crystals obtained in step (iv); and (vi) A step of drying the crystals obtained in step (iv) or (v); Regarding processes that include this.

[0119] Example of the process: Solid LNP023 hydrochloride starting material is described in International Publication No. 2015 / 009616. It can be manufactured 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. 1. The solvent may include other organic solvents. In one embodiment, acetone and water are suspended It may be the only solvent present in the solution. The concentration of LNP023 hydrochloride in the suspension is, for example, approximately 0.07~0.30 g / g, for example, about 0.10~0.25 g / g, for example, about 0.15~0 The range is 0.20 g / g, for example, the concentration is approximately 0.20 g / g. In one embodiment... In this case, the ratio of acetone to water (g / g) is, for example, 60:40 to 90:10, for example, 65: 45-85:15, for example, 75:25-80:20. In one embodiment, process ( ii) Heating is performed at a high temperature, for example, in the range of approximately 30-56°C, for example, approximately 45-55°C. This can be done at ambient temperature. Heating may involve stirring, agitation, mixing, shaking, or vibration, but is not limited to these methods. By any type of motion of a solid material suspended in a solvent, such as ultrasonic processing or wet grinding. This can be achieved. Once the solid material is dissolved, the solution can be heated to approximately 20-50°C, for example, approximately It can be cooled to a temperature in the range of 35-45°C and contains acetone, ethyl acetate, or a combination thereof. A second solvent containing [the specified substance] may be added. The second solvent may contain further organic solvents or water. In terms of form, acetone and ethyl acetate are the only solvents added in step (iii). When both acetone and ethyl acetate are used as the second solvent, they are acetone and ethyl acetate. It can be added as a solvent mixture of biethyl acetate, or it can be added sequentially. In this state, when added sequentially, acetone is added first, followed by ethyl acetate. It is added. The concentration of LNP023 hydrochloride is, for example, about 0.04~0.15 g / g, for example, about This ranges from 0.05 to 0.10 g / g, and for example, from approximately 0.05 to 0.07 g / g. If so, its concentration is approximately 0.06 g / g. The ratio of acetone to ethyl acetate (g / g) is, for example, The ratio is 0.5:3 to 1:1, for example, 1:2. In one embodiment, the suspension is further about 0 The crystallization process is completed when the temperature is cooled to a range of approximately 5-15°C, for example, 10°C, rather than being reduced to around 25°C. It is possible. If the HB form is obtained in an essentially pure form, at least a portion of the crystal is the mother liquor or They can be separated by filtration, centrifugation, solvent evaporation, or decantation. By conventional methods such as filtration or centrifugation, the crystals are separated from the mother liquor. This is possible. In one embodiment, the crystals can be separated from the mother liquor by filtration.

[0121] Optionally, in a further step, the isolated crystals are placed in a suitable solvent, such as an organic solvent. Alternatively, it can be washed with water. Suitable organic solvents are, but are not limited to, acetone and ethyl acetate. include.

[0122] Next, the obtained crystals can be dried. Drying should be done at a temperature of approximately 70°C or lower, for example, approximately 60°C. The process can be carried out at temperatures below 50°C, for example, around 50°C. Drying can also be done at approximately room temperature. Drying takes approximately 2 to 24 hours, for example, 4 to 16 hours, or for example, 6 to 10 hours. It can crack. In one embodiment, drying may be carried out for a period of about 6 to 8 hours. Drying is carried out in the surroundings. This can be carried out under pressure or under reduced pressure. In one embodiment, drying is performed at approximately 200 mbar. The following is carried out at a pressure of approximately 150 mbar or less. In one embodiment, drying is performed. The drying is carried out at a pressure of approximately 80 mbar or less. In one embodiment, drying is performed at, for example, approximately 50 mbar. It is performed under a vacuum of less than ar.

[0123] In one embodiment, a specific crystallization technique is applied to the process to improve product processability. HB-type crystals can be obtained. The technique is not limited to temperature cycling, Alternatively, the process may involve adding a second solvent over a long period, for example, 12 to 36 hours, and undergoing temperature cycling. This is possible. The temperature cycle may be carried out as follows: In step (iii), the second melt Before adding the medium, dissolve it at a temperature of approximately 0-25°C, for example, in the range of approximately 5-15°C, for example, 10°C. The liquid may be cooled, then to a temperature in the range of approximately 30-45°C, for example, approximately 30-40°C, for example It may be heated to 35°C. This temperature cycle may be repeated at least three times, for example, at least six times. For example, this can be done at least 8 times, for example, 6 to 12 times. After the temperature cycle, the second solvent is added. This may be possible. In one embodiment, the second solvent may be ethyl acetate.

[0124] The HB form after engineering, that is, after applying the specific crystallization technique described above, is clear It consists of crystals having a morphology, and due to the morphology, it has excellent powder properties and Processability is achieved, and pharmaceutical formulations including HB form are made using standard manufacturing processes and equipment (fo This enables engineering (mmulation). In one embodiment, engineering can be performed using this method. In contrast to form A, which cannot be crushed, form HB is not brittle, and therefore does not shatter easily. Problems related to particle size distribution can be minimized. Furthermore, the fluidity of the HB form is A type. It is superior to the standard form. Therefore, especially when engineered, the HB form is superior. It possesses both refined powder properties and high physicochemical stability. Therefore, it is superior to form A. LNP023 hydrochloride is excellent and ideal for the standard manufacturing of improved pharmaceutical compositions. It is in a solid state.

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

[0126] Demonstration of pulverization The HB form particles of LNP023 hydrochloride described herein are filled into capsules or For example, grinding before further processing by another method, especially if further excipients are required. To enable easy direct filling of particles into capsules without the need for crushing, It is possible to do so.

[0127] In one embodiment, the particle size of the HB form of LNP023 hydrochloride is determined by rotor impact micro It is reduced using a rotor. Rotor impact mills use different stationary and rotating tool elements, for example. For example, a rotating wing beater with a stationary screen, a stationary screen and an impact element. A rotating wing beater equipped with a stationary pin disk, or a rotating pin disk equipped with a rotating pin disk. This can be done using a rotating pin disk equipped with pin disks. The LNP to be crushed The HB form of 023 hydrochloride is suitable for appropriate powder transport to ensure proper control of the supply rate of the associated powder. The system, for example, a vibratory feeder or a twin-screw feeder, allows for rotor impact milling. It is transported inside the tub. By the rotating element of the rotor impact mill, or the rotor impact The gas flow generated by the blower connected to the tomill further infuses the powder. Transported to the pact tool element. Reduction of particle size of LNP023 hydrochloride particles in HB form. This occurs due to impacts on rotating elements, impacts on stationary elements, or between colliding HB morphological particles. This is done by impact. The physical properties of the HB form of LNP023 hydrochloride are adjusted. Appropriate process parameters such as rotor speed and feed rate are important for rotor impact. This relates to specific equipment parameters, such as filters and cyclones used for transporting gases. After separation, the pulverized product with the adjusted physical properties is collected in the product container. The pulverized product is then blended using appropriate technology, such as a diffusion blender. Appropriate physical uniformity is achieved in the manufactured batch.

[0128] A rotor impact mill, for example, can be used as a pin mill. A pin disk with a stationary pin disk tool, which is often described in this technical field. This can be done using rotation. The scale-independent parameters of rotor speed and feed rate are: This can be described by the rotor tip speed and the specific feed rate. The rotor speed at a fixed instrument scale is, in principle, a scale-independent parameter. The parameter rotor tip speed is related to the pin disk diameter of the associated device scale. The supply rate for a particular device scale is, in principle, a scale-independent parameter. The parameter-specific supply rate is related to the pin surface area of ​​the associated device scale. Using a rotor impact mill with scale-independent grinding parameters, the adjusted material The HB form product of LNP023 hydrochloride with the following properties is obtained: diameter of the external rotating pin However, while normalization is taken into account, the rotor tip speed is 10-60 m / s, or rotational pit. The surface area of ​​the cylindrical pin is approximately 4,000 kg / (h·) when normalization is taken into account. m 2 A specific supply rate up to ).

[0129] In a scale-dependent example, the HB form of LNP023 hydrochloride is in Model 100UPZ. Hosokawa Alpine AG, Augsburg / Germany Using rotor impact mills such as those made in Germany, and in the public domain. Using a rotating pin disk with a stationary pin disk tool, often described as a pin mill It can be used to crush. Rotor speed 1,800~10,500 rpm, for example 4 A process using a rotor speed of 6,000 rpm, for example, between 0,000 and 8,500 rpm. By manipulating this, a product with adjusted physical properties is obtained. The supply rate is For example, 1-22 kg / hour, for example, 6-18 kg / hour, for example, supply speed 15 kg / hour be.

[0130] Pharmaceutical composition and use Example of an embodiment: In a further aspect, the present invention relates to the LN described herein for manufacturing a pharmaceutical composition. The HB form of P023 hydrochloride, or any one of the above embodiments and corresponding embodiments thereof This relates to the use of compositions containing the HB form of LNP023 hydrochloride as defined.

[0131] In yet another embodiment, the present invention provides, for example, LNP0 in a predetermined amount or a therapeutically effective amount. A pharmaceutical composition containing the HB form of 23 hydrochloride, or the above-described embodiment and its corresponding embodiment The HB form of LNP023 hydrochloride, defined as either one of the following, and at least one other drug. This relates to a composition containing an excipient that is permissible.

[0132] In one embodiment, the embodiments described above and any one of the corresponding embodiments are defined as follows: A pharmaceutical composition containing the HB form of LNP023 hydrochloride is provided as an anhydrous LNP023 free base. The calculated dosage includes LNP023 hydrochloride up to approximately 200 mg.

[0133] In that embodiment, the pharmaceutical composition was calculated as anhydrous LNP023 free base, It contains LNP023 hydrochloride in doses ranging from approximately 10 mg to 200 mg.

[0134] In this embodiment, the pharmaceutical composition is calculated as anhydrous LNP023 free base. The dosages were approximately 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. It contains LNP023 hydrochloride.

[0135] In this embodiment, the pharmaceutical composition is calculated as anhydrous LNP023 free base. LNP0 was administered in doses of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Contains 23 hydrochloride.

[0136] In one embodiment, the therapeutically effective amount of LNP023 hydrochloride in HB form is anhydrous LNP02 Consists of 1, 5, 10, 25, 50, 100, and 200 mg of free bases. Selected from the group. In one embodiment, the therapeutically effective amount of the HB form of LNP023 hydrochloride is It is 100 or 200 mg. In one embodiment, the HB form of LNP023 hydrochloride is used for therapeutic purposes. The effective dose 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 agent that may be included in the pharmaceutical composition described herein is acceptable. Additives include, for example, excipients, fillers, diluents, binders, disintegrants, lubricants, fluidizers, and so on. A suitable excipient is selected from the group consisting of combinations of the following. In a preferred embodiment, the pharmaceutical composition contains an acceptable additive as one agent. Additives, such as excipients.

[0138] In a preferred embodiment, a pharmaceutical composition comprising the HB form of LNP023 hydrochloride, or H of LNP023 hydrochloride as defined in any one of the embodiments described above and its corresponding embodiments The composition containing form B is an oral solid dosage form. In one embodiment, the oral solid dosage form is a tab. Selected from the group consisting of tablets and capsules. In one embodiment, the oral dosage form is a tablet. It takes the form of a ret. In one embodiment, the oral dosage form is a capsule. And the capsule is a size 0 capsule.

[0139] The tablet is in the HB form of LNP023 hydrochloride, or the above-described embodiment and its corresponding implementation. A composition containing the HB form of LNP023 hydrochloride defined in any one of the forms, Each contains one type of excipient, such as a filler, diluent, binder, disintegrant, lubricant, fluidizer, or so It can be prepared by a combination and mixing of these. Optionally, dry or wet granulation can be performed. Granulation processes such as sizing are carried out before compression.

[0140] The capsule contains LNP023 hydrochloride in HB form, or the above-described embodiment and its corresponding implementation. A composition comprising the HB form of LNP023 hydrochloride, defined as any one of the states, at least Also, one type of excipient, such as a filler, diluent, binder, disintegrant, lubricant, fluidizer or the same By combining and mixing the blend and filling it into capsules used as an excipient, It can be prepared in this way. Alternatively, the HB form of LNP023 hydrochloride can be used as an excipient. The capsules used are filled neat. The capsule shell is made of gelatin cereal. It may be a gel or a hydroxypropyl methylcellulose (HPMC) shell.

[0141] In one embodiment, the present invention provides a capsule such as a size 0 capsule containing LNP02 The present invention relates to a pharmaceutical composition containing HB morphological particles of 3-hydrochloride salt. In one embodiment, within a capsule HB morphological particles have an aspect ratio of 0.4 to approximately 0.7, for example, 0.45 to 0.6. In the embodiment, the HB morphological particles inside the capsule are about 5 to about 100 μm, for example, about 10 Particle size distribution X of approximately 70 μm, for example, approximately 15 to approximately 55 μm 50 It has in one embodiment. The HB morphological particles inside the capsule are approximately 0.4 to 0.7 mg / ml, for example, approximately 0.50 to 0.7 mg / ml. 0.65 g / ml, for example, approximately 0.55 to 0.60 g / ml compressed (15 kPa) bulk It has a degree.

[0142] In a further embodiment, the present invention is used for the treatment of diseases and disorders described herein. LNP023 hydrochloride in HB form, or a composition containing LNP023 hydrochloride in HB form, LNP023 hydrochloride as defined in any one of the above embodiments and its corresponding embodiments This relates to pharmaceutical compositions containing the HB form.

[0143] In yet another embodiment, the present invention is described in the pamphlet International Publication No. 2015 / 009616. Treatment of indications disclosed in brochure international publication No. 2019 / 043609 Specifically for prevention, paroxysmal nocturnal hemoglobinuria in complement-induced renal disease C3G (C3 glomerulosis) Glomerular C3 precipitation in conditions such as PNH, IgAN (immunoglobulin A nephropathy), and MN (membranous nephropathy) Other nephropathy with evidence of infection, and HUS (E. coli-induced hemolytic uremic syndrome) (group), and used for the treatment or prevention of atypical hemolytic uremic syndrome (aHUS), LNP023 hydrochloride in HB form, or a composition containing LNP023 hydrochloride in HB form, LNP023 hydrochloride as defined in any one of the above embodiments and its corresponding embodiments This relates to pharmaceutical compositions containing the HB form.

[0144] In other embodiments, the entirety of the present invention is incorporated herein by reference, each by reference. International Publication No. 2015 / 009616 and International Publication No. 2019 / 0436 Methods for treating the diseases and disorders disclosed in Pamphlet No. 09, for those who need them. Regarding this matter, in one embodiment, the disease or disorder is complement-induced renal disease C3G (C3 glomerulospinal disease). Paroxysmal nocturnal hemoglobinuria (PNH), IgAN (immunoglobulin A nephropathy), and MN (muscular dystrophy) Other nephropathy with evidence of glomerular C3 deposition, such as membranous nephropathy, HUS (E. coli). i) Select from induced hemolytic uremic syndrome and atypical hemolytic uremic syndrome (aHUS). In one embodiment, this method is used to obtain HB of LNP023 hydrochloride as described herein. This includes administering the substance to the target in a therapeutically effective dose.

[0145] In another embodiment, the present invention relates to paroxysmal nocturnal hemoglobinuria (PNH) as necessary for treating A method of treatment in elephants, in which the HB form of LNP023 hydrochloride is administered to the target in a therapeutically effective dose. The present invention relates to a method that includes administering a drug to treat a subject.

[0146] In one embodiment, a method for treating PNH in a subject involves anhydrous LNP023 free salt The subject was administered the HB form of LNP023 at a daily dose of up to approximately 400 mg, which was calculated as the baseline. This includes, in one embodiment, administration is twice daily (bid), for example. Approximately every 12 hours, in doses up to approximately 200 mg calculated as anhydrous LNP023 free base. This is the administration of [the substance].

[0147] In one embodiment, a method for treating PNH in a subject involves anhydrous LNP023 free salt Based on the calculation, the target daily dose is approximately 20 mg to 400 mg, and the HB form of LNP023 is used. This includes administering the substance. In one embodiment, the administration is twice a day (bid) For example, approximately every 12 hours, approximately 10 mg to approximately 2 mg of anhydrous LNP023 free base is calculated. The dosage is 00 mg.

[0148] In one embodiment, a method for treating PNH in a subject involves anhydrous LNP023 free salt The base amounts calculated are approximately 20 mg, 50 mg, 100 mg, 200 mg, or 4 This includes administering the HB form of LNP023 to the subject at a daily dose of 00 mg. In one embodiment, The administration is twice a day (bid), for example, every 12 hours, with anhydrous LNP0 Approximately 10 mg, 25 mg, 50 mg, and 100 mg of 23 free bases are calculated, and This is administered at a dose of approximately 200 mg.

[0149] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP The subject is administered a total daily dose of approximately 20 mg, calculated as O23 free base. (One embodiment) In this case, the administration is twice a day (bid), for example, every 12 hours, with a dose of approximately 10 It is administered in mg.

[0150] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP The subject is administered a total daily dose of approximately 50 mg, calculated as O23 free base. (One embodiment) In this case, the administration is twice a day (bid), for example, every 12 hours, with a dose of approximately 25 It is administered in mg.

[0151] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 100 mg, calculated as 023 free base. In this state, the administration is twice a day (bid), for example, every 12 hours, with a dose of approximately 5 The dosage is 0 mg.

[0152] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 200 mg, calculated as 023 free base. In this state, the administration is twice a day (bid), for example, every 12 hours, with a dose of approximately 1 The dosage is 00mg.

[0153] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 400 mg, calculated as 023 free base. In this state, the administration is twice a day (bid), for example, approximately every 12 hours, with a dose of approximately 2 The dosage is 00mg.

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

[0155] In one embodiment of a method for treating PNH, the HB form of LNP023 is anhydrous LNP A dose of 200 mg calculated as O23 free base, twice a day (bid), for example It is administered orally to the subjects approximately every 12 hours.

[0156] In another embodiment, the present invention addresses complement-related kidney disease C3G (C3 glomerulosis), A method of treatment for subjects in need, wherein the HB form of LNP023 is administered in a therapeutically effective amount. The present invention relates to a method that includes administering a substance to a subject, thereby treating the subject.

[0157] In one embodiment, a method for treating C3G in a subject involves the HB form of LNP023. This is calculated as anhydrous LNP023 free base and administered to the target at a maximum daily dose of 400 mg. This includes. In one embodiment, the dose is calculated as anhydrous LNP023 free base. Dosage up to 200 mg twice daily (bid), for example, every 12 hours. That is the case.

[0158] In one embodiment, a method for treating C3G in a subject involves the HB form of LNP023. This was calculated as anhydrous LNP023 free base, and the target was a daily dose of approximately 20 mg to 400 mg. This includes administering. In one embodiment, the administration is performed using anhydrous LNP023 free base. The calculated dose is approximately 10 to 200 mg, taken twice a day (bid), for example, about 1 It is administered every two hours.

[0159] In one embodiment, a method for treating C3G in a subject involves the HB form of LNP023. Calculated as anhydrous LNP023 free base, approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately This includes administering the drug to the subject at a daily dose of 200 mg or approximately 400 mg. In one embodiment, The dosage is calculated as anhydrous LNP023 free base, approximately 10 mg and approximately 25 mg. , in doses of approximately 50 mg, approximately 100 mg, or approximately 200 mg, twice daily (bid) For example, administration is done approximately every 12 hours.

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

[0161] In one embodiment of a method for treating C3G, the HB form of LNP023 is anhydrous LNP The subject is administered a total daily dose of approximately 50 mg, calculated as O23 free base. (One embodiment) In this case, the administration is at a dose of approximately 25 mg twice a day (bid), for example, approximately 1 It is administered every two hours.

[0162] In one embodiment of a method for treating C3G, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 100 mg, calculated as 023 free base. In this state, the administration is approximately 50 mg twice a day (bid), for example, approximately It is administered every 12 hours.

[0163] In one embodiment of a method for treating C3G, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 200 mg, calculated as 023 free base. In this state, the administration is at a dose of approximately 100 mg twice a day (bid), for example. The medication is administered approximately every 12 hours.

[0164] In one embodiment of a method for treating C3G, the HB form of LNP023 is anhydrous LNP The target is administered a total daily dose of approximately 400 mg, calculated as 023 free base. In this state, the administration is at a dose of approximately 200 mg twice a day (bid), for example. The medication is administered approximately every 12 hours.

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

[0166] In one embodiment of a method for treating C3G, the HB form of LNP023 is anhydrous LNP A dose of approximately 200 mg of O23 free base is taken twice a day (bid), for example. It is administered orally to the subjects approximately every 12 hours.

[0167] In another embodiment, the present invention relates to IgAN (immunoglobulin A nephropathy) and the need for it. A method of treatment for a subject, comprising administering the HB form of LNP023 to the subject in a therapeutically effective dose. and methods that include treating the subject thereby.

[0168] In one embodiment, a method for treating IgAN involves releasing anhydrous LNP023. The HB form of LNP023 is administered at a daily dose of up to approximately 400 mg, calculated as a base. This includes the following: In one embodiment, the administration is calculated as anhydrous LNP023 free base. The prescribed dose is up to approximately 200 mg, twice a day (bid), for example, every 12 hours. This is the administration of [the substance].

[0169] In one embodiment, a method for treating IgAN involves releasing anhydrous LNP023. The HB form of LNP023 is used in daily doses ranging from approximately 20 to 400 mg, calculated as a base. This includes administering to elephants. In one embodiment, the administration is performed using anhydrous LNP023 free base. A dose of approximately 10 to 200 mg, calculated as follows, twice a day (bid), for example, approximately It is administered every 12 hours.

[0170] In one embodiment, a method for treating IgAN involves releasing anhydrous LNP023. Approximately 20 mg, 50 mg, 100 mg, 200 mg, or 4 mg of bases are calculated. This includes administering LNP023 in its HB form at a daily dose of 00 mg. In one embodiment, In this case, the administration is approximately 10 mg, approximately 25 mg, calculated as anhydrous LNP023 free base. g, approximately 50 mg, approximately 100 mg, or approximately 200 mg, twice daily (bid) For example, administration is done approximately every 12 hours.

[0171] In one embodiment of a method for treating IgAN, the HB form of LNP023 is anhydrous LN The target population is administered a total daily dose of approximately 20 mg, calculated as P023 free base. In this state, the administration is approximately 10 mg twice a day (bid), for example, approximately 12 It is administered hourly.

[0172] In one embodiment of a method for treating IgAN, the HB form of LNP023 is anhydrous LN The target population is administered a total daily dose of approximately 50 mg, calculated as P023 free base. In this state, the administration is approximately 25 mg twice a day (bid), for example, about 12 It is administered hourly.

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

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

[0175] In one embodiment of a method for treating IgAN, the HB form of LNP023 is anhydrous LN The subjects are administered a total daily dose of approximately 400 mg, calculated as P023 free base. In terms of form, the administration is in doses of approximately 200 mg twice a day (bid), for example, approximately It is administered every 12 hours.

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

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

[0178] In another embodiment, the present invention relates to membranous nephropathy (MN), for example, idiopathic MN (iMN), A method of treatment for subjects in need, wherein the HB form of LNP023 is used in a therapeutically effective amount The present invention relates to a method that involves administering a substance to a subject, thereby treating the subject.

[0179] In one embodiment, a method for treating MN, for example iMN, in a subject is anhydrous LNP The target group was LNP023 HB at a daily dose of up to approximately 400 mg, calculated as free base 023. This includes administering the form. In one embodiment, the administration is anhydrous LNP023 free salt A daily dose of up to approximately 200 mg calculated as a base, twice a day (bid), for example, approximately It is administered every 12 hours.

[0180] In one embodiment, a method for treating MN, for example iMN, in a subject is anhydrous LNP The target group was LNP023 at a daily dose of approximately 20 to 400 mg, calculated as free base O23. This includes administering the HB form. In one embodiment, the administration is performed using anhydrous LNP023. A dose of approximately 10 to 200 mg calculated as a separate base, twice a day (bid), for example. For example, it is administered approximately every 12 hours.

[0181] In one embodiment, a method for treating MN, for example iMN, in a subject is anhydrous LNP Approximately 20 mg, 50 mg, 100 mg, and 200 mg of O23 free bases are calculated. or administering the HB form of LNP023 to the subject at a daily dose of approximately 400 mg. In this embodiment, the dose is approximately 10 mg, calculated as anhydrous LNP023 free base. , doses of approximately 25 mg, approximately 50 mg, approximately 100 mg, or approximately 200 mg, twice a day (b. For example, administration is done approximately every 12 hours.

[0182] In one embodiment of a method for treating MN, the HB form of LNP023 is anhydrous LNP0 In one embodiment, the subject is administered a total daily dose of approximately 20 mg, calculated as 23 free bases. The administration is approximately 10 mg twice a day (bid), for example, every 12 hours. Each dose is administered individually.

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

[0184] In one embodiment of a method for treating MN, the HB form of LNP023 is anhydrous LNP0 The total daily dose, calculated as 23 free bases, is approximately 100 mg and administered to the subject. In one embodiment, The administration is approximately 50 mg twice a day (bid), for example, at approximately 12:00 It is administered intermittently.

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

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

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

[0188] In one embodiment of a method for treating MN, the HB form of LNP023 is anhydrous LNP0 The dose calculated as 23 free bases is 200 mg, taken twice a day (bid), for example, approximately The medication is administered orally to the subjects every 12 hours.

[0189] In other embodiments, the present invention relates to atypical hemolytic uremic syndrome (aHUS) as necessary. A method of treating a target, wherein the HB form of LNP023 is administered to the target in a therapeutically effective dose. The present invention relates to a method that includes administering a drug, thereby treating a subject.

[0190] In one embodiment, a method for treating aHUS in a subject involves releasing anhydrous LNP023. The subject is administered LNP023 in its HB form at a daily dose of approximately 400 mg, calculated as a base. This includes the following: In one embodiment, the administration is calculated as anhydrous LNP023 free base. The prescribed dose is up to approximately 200 mg, twice a day (bid), for example, every 12 hours. This is the administration of [the substance].

[0191] In one embodiment, a method for treating aHUS in a subject involves releasing anhydrous LNP023. The daily dose, calculated as base, is approximately 20 to 400 mg, and the target is LNP023 in HB form. This includes administering anhydrous LNP023 free base and A dose of approximately 10 to 200 mg is calculated and administered twice a day (bid), for example, approximately 1 It is administered every two hours.

[0192] In one embodiment, a method for treating aHUS in a subject involves releasing anhydrous LNP023. Approximately 20 mg, 50 mg, 100 mg, 200 mg, or 4 mg of bases are calculated. One embodiment includes administering the HB form of LNP023 to the subject at a daily dose of 00 mg. In this case, the administration was approximately 10 mg, calculated as anhydrous LNP023 free base, and approximately 25 Doses of mg, approximately 50 mg, approximately 100 mg, or approximately 200 mg, twice a day (bid For example, administration is done approximately every 12 hours.

[0193] In one embodiment of a method for treating aHUS, the HB form of LNP023 is anhydrous LN The target population is administered a total daily dose of approximately 20 mg, calculated as P023 free base. In this state, the administration is approximately 10 mg twice a day (bid), for example, approximately 12 It is administered hourly.

[0194] In one embodiment of a method for treating aHUS, the HB form of LNP023 is anhydrous LN The target population is administered a total daily dose of approximately 50 mg, calculated as P023 free base. In this state, the administration is approximately 25 mg twice a day (bid), for example, about 12 It is administered hourly.

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

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

[0197] In one embodiment of a method for treating aHUS, the HB form of LNP023 is anhydrous LN The subjects are administered a total daily dose of approximately 400 mg, calculated as P023 free base. In terms of form, the administration is in doses of approximately 200 mg twice a day (bid), for example, approximately It is administered every 12 hours.

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

[0199] In one embodiment of a method for treating aHUS, the HB form of LNP023 is anhydrous LN A dose of 200 mg calculated as P023 free base, twice daily (bid), for example. For example, it is administered orally to the subject approximately every 12 hours.

[0200] All of the aforementioned embodiments relating to a method for treating a specific disease at a specific dose are: The HB form of LNP023 used in the treatment of a specific disease at a specific dose according to the present invention; In the manufacture of a drug for treating a specific disease at a specific dose according to the present invention, L Use of the HB form of NP023; HB form of LNP023 for treating a specific disease at a specific dose according to the present invention The use of voice; and The HB form of LNP023, used in the treatment of a specific disease at a specific dose according to the present invention. A pharmaceutical composition comprising a carrier that is acceptable as one or more types of pharmaceutical agents; It is equally applicable to the following.

[0201] Methods for testing morphological properties Aspect ratio: The aspect ratio refers to the ratio of the maximum length to the minimum width of a crystal. At an aspect ratio of 1, the crystal exhibits isometric habit. As the aspect ratio decreases below 1... Therefore, it becomes more plate-like than crystal habit. On the other hand, as the aspect ratio increases beyond 1, The crystals approach an acicular crystal habit. According to this disclosure, cubic particles in HB form are, for example, about 0.4 Aspect ratio a of approximately 0.7 50 It has.

[0202] Sympatec GmbH,Clausthal-Zellerfeld,Germ Dynamic image analysis using a commercially available QICPIC dynamic image analyzer (Dynam The aspect ratio is determined by the Image Analysis (DIA) method. ru.

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

[0204] Compressed bulk density: Compressed bulk density (15kPa) is FT4 (Freeman Techno). It is measured using a powder rheometer. [Examples]

[0205] The following non-limiting embodiments are illustrative of the scope of this disclosure and are limiting in any way. It should not be interpreted in that way.

[0206] Example 1: Preparation of the HB form of LNP023 hydrochloride As described in Example 26d of International Publication No. 2015 / 009616, A Form LNP023-HCl salt was obtained. 9.3 g of form A of LNP023 hydrochloride was mixed with acetone. Suspend in a mixture of acetone and water (48.1g, 78:22 m:m) and dissolve at approximately 50°C. It was dissolved. The solution was cooled to 40°C, and 136g of a mixture of acetone and ethyl acetate (acetone) Ethyl acetate (1:2 m:m) was added within 24 hours. The suspension was cooled to 10°C. Crystallization was completed. The product was isolated by filtration and 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 International Publication No. 2015 / 009616, A Form LNP023-HCl salt was obtained. 42 g of form A of LNP023 hydrochloride was mixed with acetone and Suspend in 212g of a water mixture (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 obtained. Crystal growth was initiated by adding 0.4 g of hydrate (HB form) seed. Subsequently, acetone was added. 207g of ethyl acetate was added within 3 hours, followed by 414g of ethyl acetate within 6 hours. The product was isolated by filtration and dried under vacuum at 50°C to obtain crystalline LNP023-HC. 36 g of 1 salt monohydrate (HB form) was obtained.

[0208] Example 3: Engineered LNP0 using temperature cycling Preparation of HB form of hydrochloride 23 As described in Example 26d of International Publication No. 2015 / 009616, A Form LNP023-HCl salt was obtained. 80 g of form A of LNP023 hydrochloride was mixed with acetone and Suspend in 409g of a water mixture (acetone:water = 78:22 m:m) and dissolve at approximately 50°C. The solution was cooled to 40°C, and the crystalline LNP023-HCl salt obtained according to Example 1 was obtained. 0.32 g of hydrate (HB form) seed was added to initiate crystal growth. Then, 10 The temperature cycle was performed 9 times by cooling to °C and heating to 35°C. Then, 1 Within 2 hours, 1090 g of ethyl acetate was added, followed by cooling to 5°C. The product was filtered. It was isolated and dried under vacuum at 50°C to obtain crystalline LNP023- containing cylindrical particles. 66 g of HCl salt monohydrate (HB form) was obtained.

[0209] Example 4: Characterization of the HB form of LNP023 hydrochloride The title compound is the same as Example 26d in International Publication No. 2015 / 009616. character 1 The 1H NMR spectrum is evaluated.

[0210] Illustrations of the analysis and interpretation of the results: Powder X-ray diffraction Along with a focusing mirror and a solid-state PIXcel detector, the Bragg-Brentano geometry What kind of Bruker D8 Advance diffractometer does it have? Cu-Kα 1,2 line (wavelength 0 PXRD was performed using 0.15419 nm. Under ambient conditions, angles of 2° to 40°2θ were measured. Within the range of degrees, with an approximate process time of at least 40 seconds, 0.015~0.020°2θ Applying a step size, the diffuser was measured at a tube voltage of 30-40kV and a tube current of 40mA. The togram was recorded. The typical precision of the 2θ value is ±0.2°2θ, for example, ±0.1°2 It is within the range of θ. Therefore, for example, the HB of LNP023 hydrochloride that appears at 9.2°2θ The diffraction peak of the morphology is (9.2-0.2)°~(9°) in most X-ray diffractometers under standard conditions. (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 that way.

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

[0212] [Table 2]

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

[0214] Fourier transform infrared spectroscopy At room temperature, 4cm -1 Using a Nicolet6700 spectrometer with high resolution, attenuation The FTIR spectrum was recorded using total internal reflection (ATR) technique. The number of scans was 64. The range is 650 to 4000 wavenumbers (cm²). -1 ) was. Record the spectrum. Therefore, the sample on the tip of the spatula was applied in powder form to the surface of the diamond. Then, saf The sample is pressed onto a diamond using a phial anvil, and the spectrum is recorded. The spectrum of a clean diamond was used as the background spectrum. The typical accuracy of the wave value is approximately ±2 cm. -1 It is within the range. Therefore, as described herein The listed LNP023 hydrochloride HB form is 3452 cm -1 The infrared peak is observed under standard conditions. Most infrared spectrometers show (3452-2)~(3452+2) cm -1 It can appear in between. Figure 3 shows a typical FTIR spectrum of the crystalline form HB described herein, and the corresponding P A list of the workpieces is provided below, and the general accuracy of the wavenumber is ±2cm. -1 It 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 using a TA Discovery DSC2500 instrument. The aluminum was perforated. In a Tzero aluminum dish with a nium lid, the sample (2.7 mg) was heated at a rate of 10°K / The mixture was heated from 30 to 300°C in minutes. Nitrogen (purge rate 50 mL / min) was used as the purge gas. I 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 A broad endothermic phenomenon ends at 170°C, followed by exothermic decomposition at approximately 200°C. More precisely, The endothermic phenomenon occurs within the range of 35°C to 170°C.

[0217] thermogravimetric analysis TGA was performed using the Mettler Toledo DSC / TGA1 instrument. Dispense the sample (10-20 mg) in a 100 μL aluminum dish sealed with a lid at a speed of 20 K / min. The sample was heated from 30°C to 300°C. A hole was automatically made in the lid at the start of the measurement. A purge gas (with a purge rate of 50 mL / min) was used.

[0218] A typical TGA curve is shown in Figure 5 below. Due to the loss of water (dehydration) and residual solvent, approximately The process is described as taking place at 30-220°C. The mass during the process was determined to be approximately 4.1%. The water content of 3.7% was determined by Karl Fischer coulometric titration, LNP023H 1 mole of Cl is equivalent to 0.98 moles of water. It is heated to 160°C for measurement, 7 Metrohm 83 connected to 74 Oven Sample Processor The water was selected using a 1KF energy meter.

[0219] Dynamic vapor sorption Dynamic vapor sorption isotherms were recorded using the DVS Advantage instrument. The measurement cycle was repeated. The experiment started at an ambient relative humidity (RH) of 40%. Subsequently, the RH was reduced to 0% in a 10% process. Subsequently, during the sorption cycle, RH increased from 0% to 90% in the 10% process, and then to 5% The process increased from 90% to 95%, followed by a 10% and 5% increase in the detachment cycle. Each was reduced to 0%. Finally, in the 10% process, RH was increased to 40% of the ambient relative humidity. The time per test was set to a minimum of 3 hours and a maximum of 6 hours. Then, before the maximum time, the system is brought to equilibrium for at least 5 minutes with a constant mass change of 0.002% / min. If equilibrium is not reached, a continuous humidity process is applied up to the maximum time of 6 hours prior. The continuous humidity process was applied after a maximum of 6 hours. The temperature was 25±1.0℃. Ta.

[0220] Figure 6 shows the sorption cycles from RH 0% to 95% (marked with triangles), as well as RH 95%. H of LNP023 hydrochloride during desorption cycles (marked with squares) at ~0% (on the x-axis) The equilibrium mass change of form B (delta m (weight %) - reference weight at 0% relative humidity on the y axis) is shown. The mass difference at relative humidity levels of 40-95% is less than 0.2% by weight, and between the sorption and desorption curves... No significant hysteresis was observed. Therefore, LNP023 hydrochloride as described herein is not applicable. The HB form of LNP023 hydrochloride can be identified as non-hygroscopic. The PXRD remained unchanged after the experiment.

[0221] Electron microscopy Using an SE detector with a Gemini SE300 (Zeiss) microscope, electron microscopy Images were taken. As can be seen from Figures 7a and 7b, for example, the engineer shown in Example 3 The HB morphology of LNP023 hydrochloride obtained by crystallization technology consists of cylindrical and cubic grains. It contains, which explains the excellent fluidity of the powder.

[0222] Example 5: Preparation of a pharmaceutical composition The HB morphological particles obtained in Example 3 were produced by Hosokawa Alpine AG, Auc Commercially available 100UPZ pins from Augsburg, Germany. The particles are transferred to a mill. The particles are ground at a rotor speed of 6,000 rpm and a feed rate of 15 kg / hour. do.

[0223] The obtained cubic particles were placed in 50 and 100 size 0 hard gelatin capsules, respectively. Alternatively, it is filled in 200 mg quantities.

Claims

1. The following formula (A) 【Chemistry 1】 A crystalline hydrate form of LNP023 hydrochloride having a wavelength of 0.15419 nm Cu-Kα １，２ When measured using a line, within a temperature range of 20-30°C, (4.6 Pee at 2θ angles of ±0.2°, (9.2±0.2°), and (19.1±0.2°) A crystalline hydrate form characterized by having a powder X-ray diffraction pattern containing q.

2. Cu-Kα with a wavelength of 0.15419 nm １，２ Using lines, temperature range 20-30°C When measured in degrees, at a 2θ angle of (6.8 ± 0.2)° or (24.6 ± 0.2)° The powder X-ray diffraction pattern having one or more peaks, as described in claim 1. The crystalline hydrate form shown.

3. When measured using a diamond ATR cell at temperatures in the range of 20 to 30°C, (3 452±2)cm －１ 、(2875±2)cm －１ 、(1692±2)cm －１ 、(14 39 ± 2 cm －１ and (1243 ± 2) cm －１ Fourier transform containing the peak at wavenumber The crystalline hydrate form according to claim 1 or 2, characterized by having an infrared spectrum.

4. When measured at a heating rate of 10 K / min, the endothermic phenomenon is included in the range of 35°C to 170°C. The method according to any one of claims 1 to 3, characterized by having a differential scanning calorimetry curve. Crystalline hydrate form.

5. When heated from 30°C to 300°C at a heating rate of 20 K / min, the weight of the crystalline form is In contrast, the thermogravimetric analysis curve showing mass loss of 4.5% by weight or less at temperatures of 200-220°C. A crystalline hydrate form according to any one of claims 1 to 4, characterized by having the above characteristics.

6. Measured by dynamic vapor sorption at relative humidity in the range of 0–95% and temperature (25±1.0)°C. In some cases, the mass change is 4.5% by weight or less relative to the weight of the crystalline form at 0% relative humidity. The crystalline hydrate form according to any one of claims 1 to 5, characterized in that

7. The crystalline hydrate according to any one of claims 1 to 6, wherein the hydrate form is a monohydrate. form.

8. The shape is essentially cubic or cylindrical, and for example, it has a crystal habit that is essentially cubic. The crystalline hydrate form according to any one of claims 1 to 7.

9. A composition comprising the crystalline hydrate form described in any one of claims 1 to 8, wherein the set For the weight of the product, add up to 20% by weight of any other physical form of LNP023 hydrochloride. A composition containing %, 10% by weight, 5% by weight, 2% by weight, or 1% by weight.

10. The other physical form of LNP023 hydrochloride is Cu- having a wavelength of 0.15419 nm Kα １，２ When measured using a line, within a temperature range of 20-30°C, (11.6 ± 0. 1)°, (15.3±0.1)°, (16.5±0.1)°, (20.1±0.1)° and It is characterized by having a powder X-ray diffraction pattern that includes a peak at a 2θ angle of (23.3 ± 0.1)°. The composition according to claim 9, characterized by form A.

11. A crystalline hydrate form defined in any one of claims 1 to 8 for the manufacture of a pharmaceutical composition The state, or use of the composition as defined in claim 9 or 10.

12. The crystalline hydrate form according to any one of claims 1 to 8, or according to claim 9 or 10 The composition described above comprises at least one excipient that is optionally acceptable as a pharmaceutical agent. A pharmaceutical composition.

13. The pharmaceutical composition according to claim 12, wherein the oral solid dosage form is, for example, a capsule.

14. Claim 12 or 1 includes a crystalline hydrate form having an aspect ratio of approximately 0.4 to approximately 0.

7. The pharmaceutical composition described in 3.

15. A particle size distribution X of about 10 to about 70 μm ５０ comprising a crystalline hydrate form having, from claim 12 A pharmaceutical composition according to any one of item 14.

16. Crystalline hydrate form with a compressed (15 kPa) bulk density of approximately 0.50 to 0.65 g / ml A pharmaceutical composition according to any one of claims 12 to 15, comprising the state.

17. LNP023 is calculated as anhydrous LNP023 free base, and is available in doses up to approximately 200 mg. A pharmaceutical composition according to any one of claims 12 to 16, comprising a hydrochloride salt.

18. LNP023 free base is calculated as anhydrous LNP023 in doses of approximately 10 mg to approximately 200 mg. The pharmaceutical composition according to claim 17, comprising P023 hydrochloride.

19. These are calculated as anhydrous LNP023 free bases, approximately 10 mg, approximately 25 mg, and approximately 5 mg respectively. Claim 1, comprising LNP023 hydrochloride in a dose of 0 mg, about 100 mg, or about 200 mg. The pharmaceutical composition described in 7.

20. These are calculated as anhydrous LNP023 free base in amounts of 10 mg, 25 mg, and 50 mg, respectively. The claim 17, comprising LNP023 hydrochloride in a dose of 100 mg or 200 mg. Pharmaceutical composition.

21. A crystalline hydrate form according to any one of claims 1 to 8, used as a drug, or The composition according to claim 9 or 10, or the composition according to any one of claims 12 to 20 Pharmaceutical composition.

22. Paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulosis), IgAN (immunoglobulin disease) (N1) Nephropathy, Membranous Nephropathy (MN), Hemolytic Uremic Syndrome (HUS) (Group), age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, jaundice Spotted edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate Partial uveitis, birdshot chorioretinitis, sympathetic ophthalmitis, ocular scarring pemphigoid (ocul) (Ar dicatatricial pemphigoid), ocular pemphigus, non-arteritic ischemic Optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome. Syndrome, traumatic brain injury, Parkinson's disease, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplantation Graft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory diseases, autoimmunity Disease-related inflammation, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion state, myocardial infarction , balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, aterostomy Mesenteric artery sclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or disease Bloodymptomatic syndrome, immune complex diseases and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (S) LE, SLE nephritis, proliferative glomerulonephritis, hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, Nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, lung Embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction , hypersensitivity pneumonitis, parasitic diseases, Goodpasture syndrome, pulmonary vasculitis, microimmunity (Pauc i-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, obesity Asthma, arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, Acquired partial lipoatrophy (Barraquer-Simons Syndrome), blood Liquid dialysis, ANCA-associated vasculitis, cryoglobulinemia, systemic lupus erythematosus, lupus Central nervous system diseases such as matodes, psoriasis, multiple sclerosis, transplants, and Alzheimer's disease, and Other neurodegenerative diseases, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, membranoproliferative gland Gulmonary nephritis, vesicular skin disease, ocular pemphigoid (ocular cicatricial pem) Used for the treatment or prevention of diseases or disorders selected from phigoids and MPGNII. The crystalline hydrate form described in any one of claims 1 to 8, or claim 9 or 10 The composition described in the above, or the pharmaceutical composition described in any one of claims 12 to 20.

23. The crystalline hydrate form according to any one of claims 1 to 8, or according to claim 9 or 10 A process for producing the composition described: (i) A step of providing LNP023 hydrochloride in solid form; (ii) A first solvent containing acetone and water, the LNP023 hydrochloride provided in step (i) A step of suspending the solid, heating it, and dissolving the solid to provide a solution; (iii) Cool the solution obtained in step (ii) and add acetone, ethyl acetate, or a combination thereof. A step of adding a second solvent containing the mixture to provide crystals in the mother liquor; (iv) A step of separating at least a portion of the crystals obtained in step (iii) from the mother liquor; (v) A step of optionally washing the isolated crystals obtained in step (iv); and (vi) A step of drying the crystals obtained in step (iv) or (v); A process that includes this.

24. As step (iii), (a) A step of cooling the solution obtained in step (ii), and then reheating the solution once again. ； (b) A step of repeating step (a) at least three times; and (c) Adding a second solvent containing acetone, ethyl acetate, or a combination thereof; The process according to claim 23, including the process described in claim 23.

25. A method for treating a disease or disorder in a person who needs it, according to claims 1 to 8 The crystalline hydrate form described in any one of the claims, or the composition described in claim 9 or 10, The method comprising administering the pharmaceutical composition described in any one of claims 12 to 20 to a target. Law.

26. The aforementioned disease or disorder is paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulosis), I γAN (Immunoglobulin A nephropathy), MN (Membranous nephropathy), HUS (E. coli) (Induced hemolytic uremic syndrome), age-related macular degeneration, geographic atrophy, diabetic retinopathy, uvea Inflammation, pigmentary retinitis, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt's disease - Koyanagi-Harada disease, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmitis, ocular scarring Pemphigoid ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological diseases Diseases treated include: multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, and hematological conditions. Dialysis complications, hyperacute allograft rejection, xenograft rejection, intermittent IL-2 therapy Kin-2 induced toxicity, inflammatory diseases, autoimmune inflammation, Crohn's disease, adult-onset respiratory distress syndrome Group, myocarditis, post-ischemia-reperfusion state, myocardial infarction, balloon angioplasty, cardiopulmonary bypass or kidney Post-pump syndrome in bypasses, atherosclerosis, hemodialysis, renal ischemia, aorta Post-reconstruction mesenteric artery reperfusion, infection or sepsis, immune complex disease and autoimmune disease, chronic conditions Rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative glomerulonephritis, hepatic fibrosis , hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, Chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, Pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture - syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex related Inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, asthma, arthritis, autoimmune heart disease, multiple Sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, acquired partial lipodystrophy, hemodialysis, ANCA Associated vasculitis, cryoglobulinemia, systemic lupus erythematosus, lupus erythematosus, psoriasis Multiple sclerosis, transplantation, central nervous system diseases such as Alzheimer's disease, and other neurodegenerative diseases atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, membranoproliferative glomerulonephritis, vesicular form The method according to claim 25, selected from adult dermatodermatitis, ocular pemphigoid, and MPGNII.

27. The crystalline hydrate form according to any one of claims 1 to 8, or according to claim 9 or 10 A process for producing a pharmaceutical composition containing the composition described.

28. The aforementioned disease or disorder is paroxysmal nocturnal hemoglobinuria (PNH), C3G (C3 glomerulosis), I γAN (immunoglobulin A nephropathy), MN (membranous nephropathy), for example, idiopathic MN (iMN), and The method according to claim 26, selected from aHUS (atypical hemolytic uremic syndrome).

29. The crystalline hydrate form of LNP023 is calculated as anhydrous LNP023 free base. The method according to claim 28, wherein the subject is administered a daily dose of up to approximately 400 mg.

30. The crystalline hydrate form of LNP023 is calculated as anhydrous LNP023 free base. The method according to claim 28, wherein the subject is administered a daily dose of approximately 10 mg to approximately 400 mg.

31. The crystalline hydrate form of LNP023 was calculated as anhydrous LNP023 free base. Daily doses of approximately 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg are used. The method according to claim 28, wherein the amount is administered to the subject.

32. The crystalline hydrate form of LNP023 was calculated as anhydrous LNP023 free base. The above-mentioned treatment is administered in daily doses of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. The method according to claim 28, administered to an elephant.

33. The crystalline hydrate form of LNP023 is, for example, administered to the subject twice a day (b.i.d.). The method according to any one of claims 28 to 32, administered orally.

Images