RU2818684C1 - Crystalline form lnp023 - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a crystalline hydrated form of hydrochloride LNP023 (form HB), having formula (A), characterized by a powder X-ray diffraction pattern containing at least five peaks at 2-theta angles selected from (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2)° and (28.0±0.2) when measured at a temperature in range from 20 to 30 °C using Cu-Calfa_1.2 radiation with wavelength of 0.15419 nm. Method comprises steps of (i) providing LNP023 hydrochloride in solid form; (ii) suspending LNP023 hydrochloride provided in step (i), in a first solvent containing acetone and water, in a weight ratio of acetone to water from 60:40 to 90:10, and heating to a temperature in range of 30 to 56 °C to dissolve a solid to obtain a solution; (iii) cooling the solution obtained in step (ii) and adding a second solvent containing acetone and ethyl acetate in a weight ratio of acetone to ethyl acetate from 0.5:3 to 1:1, with further cooling to a temperature in the range of about 0 to 25 °C to isolate crystals in the mother solution; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother solution; (v) optionally washing the separated crystals obtained in step (iv) with a suitable solvent; and (vi) drying crystals obtained in step (iv) or (v). At step (v), a suitable organic solvent is selected from acetone and ethyl acetate.

EFFECT: obtaining crystalline hydrated form of hydrochloride LNP023 (form HB), having favorable physical and chemical properties.

7 cl, 8 dwg, 2 tbl, 5 ex

Description

TECHNICAL FIELD

Described herein is a crystalline form of LNP023 hydrochloride and a method for its preparation. Also described herein is a pharmaceutical composition containing a crystalline form of LNP023 hydrochloride and at least one pharmaceutically acceptable excipient.

The pharmaceutical composition described herein can be used to treat a disease or disorder mediated by complement activation.

BACKGROUND OF THE INVENTION

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

LNH023 hydrochloride and methods for its preparation are disclosed in W0 2015/009616, which is incorporated herein by reference in its entirety. In Example 26d of WO 2015/009616, LNP023 hydrochloride is obtained as a crystalline solid by recrystallization of the resulting amorphous material and characterized by X-ray powder diffraction. This crystalline form is referred to herein as Form A.

Different solid forms of an active pharmaceutical ingredient often have different properties. Differences in the physicochemical properties of solid forms can play a decisive role in improving pharmaceutical compositions, e.g.

pharmaceutical compositions with an improved dissolution profile, or with improved stability or shelf life, may become available due to an improved solid form of the active pharmaceutical ingredient. In addition, it is possible to improve the processing or handling of the active pharmaceutical ingredient during formulation development and manufacturing. Thus, new solid forms of the active pharmaceutical ingredient may have the desired processing properties. They may be easier to handle, better for storage, or provide better cleanup than previously known solid forms.

The crystalline "Form A" LNP023 HCl from WO 2015/009616 has certain properties that make it less suitable for large scale production process. Therefore, a more stable form of LNP023 HCl is required.

Thus, there is a need to provide a solid form of LNP023 hydrochloride that has the physicochemical properties to reliably produce a safe and effective drug product containing LNP023 hydrochloride.

SUMMARY OF THE INVENTION

The disclosure provides a crystalline hydrate form of LNP023 hydrochloride, which is also referred to hereinafter as the “HB form.” “Form NV” LNP02 3 hydrochloride has favorable physicochemical properties for a drug substance intended for use in solid oral dosage form.

Advantageous properties of the NV form of LNP023 include chemical stability, physical stability, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, compactability and wettability. As a result, these properties make the NV form suitable for large-scale production processes.

In one embodiment, the HB form is a phase-pure, highly crystalline form of LNP023 hydrochloride that is physically and chemically stable during pharmaceutical processing and storage. The NV form is a thermodynamically more stable form and potential conversion to other forms can be minimized. Form A can, under certain conditions, transform into form HB. The use of a thermodynamically stable form of a compound is highly valued because transformations, for example from Form A to Form HB, or polymorphic transformations that may occur during the production and storage of the drug substance, can be avoided if the most stable form is used. This ensures reliable bioavailability and therefore continued effectiveness of the drug product.

Abbreviations

PXRD powder x-ray diffraction

SXRD single crystal X-ray diffraction

FTIR Fourier transform infrared

ATR attenuated total reflection

DSC differential scanning calorimetry

DVS dynamic vapor sorption

TGA thermogravimetric analysis

MS mass spectrometry

NMR nuclear magnetic resonance

GC gas chromatography

KF Karl-Fischer

RH relative humidity

room temperature

weight. % weight percent

about. % volume percentage.

Definitions

For the purposes of this disclosure, the following definitions have the meanings indicated unless expressly stated otherwise:

As used herein, the term “room temperature” refers to a temperature in the range of 20 to 30°C.

As used herein, the term “measured at a temperature in the range of 20 to 30°C” refers to measurement under standard conditions. Typically, standard conditions mean a temperature in the range from 20 to 30°C, i.e. at room temperature. Standard conditions may mean a temperature of approximately 22°C.

As used herein, the term “HB form” when describing the solid form of LNP023 hydrochloride refers to the specific crystalline hydrate form of LNP023 hydrochloride, such as the monohydrate form. This form is further defined herein and in the claims.

As used herein, the term “Form A” when describing the solid form of LNP023 hydrochloride refers to the specific crystalline form of LNP023 hydrochloride as disclosed in W0 2015/009616. Form A of LNP023 hydrochloride can be characterized by a powder X-ray diffraction pattern containing peaks at 2-theta angles of (11.6±0.1)°, (15.3±0.1)°, (16.5±0.1)°, ( 20.1±0.1)° and (23.3±0.1)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

Form A is obtained according to WO 2015/009616 as follows (see example 26d):

To a solution of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl) piperidin-2-yl))benzoic acid (620 mg , 1, 467 mmol) in H ₂ O/CH ₃ CN (10/3 ml) was added 5 M aq. HCl (500 µl, 2,500 mmol). The reaction mixture was then lyophilized to obtain an amorphous compound, which was then suspended in iPrOH (300 ml). The suspension was heated to 70°C. The suspension turned into solution after 1.5 hours. The solution was then cooled to room temperature with stirring for approx. 5 hours to obtain a solid. The resulting solid was collected by filtration and dried under high vacuum at 50°C to obtain the title compound as a crystalline solid. ^1H NMR (HCl salt, 400 MHz, CD ₃ OD) δ 10.73 (br. s., 1H), 8.23 (d, J=8.44 Hz, 2H), 7.74 (d, J =8.44 Hz, 2H), 7.31-7.36 (m, 1H), 6.77 (s, 1H), 6.37 (dd, J=1.77, 3.12 Hz, 1H), 4 .33 (d, J=12.72 Hz, 1H), 4.25 (d, J=12.72 Hz, 1H), 3.79-3.85 (m, 1H), 3.76 (s, 3H), 3.51-3.67 (m, 4H), 3.37-3.44 (m, 1H), 2.51 (s, 3H), 2.21-2.29 (m, 2H) , 1.90-2.15 (m, 2H), 1.31 (t, J=6.97 Hz, 3H).

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

The term "reflection" as applied to powder X-ray diffraction as used herein means peaks in an X-ray diffraction pattern that occur at certain diffraction angles (Bragg angles) as a result of constructive interference from X-rays scattered by parallel planes of atoms in a solid material that are distributed in orderly and repeating pattern in long-range positional order. Such a solid material is classified as a crystalline material, whereas an amorphous material is defined as a solid material that lacks long-range order and exhibits only short-range order, resulting in widespread dispersion. According to the literature, long-range order, for example, extends to approximately 100-1000 atoms, while short-range order extends only to a few atoms (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term "substantially the same" with respect to powder X-ray diffraction means that variations in peak positions and relative peak intensities must be taken into account. For example, typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, for example, in the range of ±0.1° 2-theta. Thus, a peak that normally appears at 9.2° 2-theta, for example, may appear between (9.2-0.2)° and (9.2±0.2)° 2-theta, e.g. (9.2-0.1)° and (9.2±0.1)° 2-theta on most X-ray diffractometers under standard conditions. In addition, those skilled in the art will appreciate that the relative intensity of the peaks will vary depending on the apparatus, as well as depending on the degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art, and should be considered only as a qualitative measure.

The term "substantially the same" with respect to infrared spectrometry means that variations in peak positions and relative peak intensities must be taken into account. For example, typical accuracy of wavenumber values is in the range of ±4 cm ^-1 , for example, in the range of ±2 cm ^-1 . Thus, a peak at 1692 cm ^-1 , for example, may appear between (1692-4) and (1692±4) cm ^-1 , for example, between (1692-2) and (1692±2) cm ^-1 on most infrared spectrometers under standard conditions.

Peak intensities can be obtained from the corresponding figures, but one skilled in the art will appreciate that differences in peak intensities due to degree of crystallinity, sample preparation, measurement method, and other factors may also occur in infrared spectroscopy. Therefore, the intensity of the peaks should be taken only as a qualitative indicator.

The IR form of LNP023 hydrochloride described herein may be referred to herein as having graphical data "as shown in" the figure. Such data includes, for example, X-ray powder diffraction and FTIR. One skilled in the art will appreciate that factors such as changes in instrument type, sample response and directional changes, sample concentration, and sample purity may result in slight changes in such data when presented in graphical form, such as changes related to precise position and intensity of the peaks. However, comparing the graphical data in the figures herein with graphical data obtained for a different or unknown solid form, and confirming that the two sets of graphical data refer to the same crystalline form, is well known to one skilled in the art.

As used herein, the terms “solid form” or “solid state” interchangeably refer to any crystalline or amorphous phase of a compound.

As used herein, the term “amorphous” refers to the solid form of a compound that is not crystalline. An amorphous compound has no long-range order and does not exhibit a defined X-ray diffraction pattern with peaks.

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

The term "cocrystal" as used herein refers to a crystalline material containing two or more different molecular or ionic compounds in a single crystal lattice that are linked by non-ionic and non-covalent bonds, where at least two of the individual molecular or ionic compounds are solid at room temperature.

The term "hydrate" as used herein refers to a crystalline solid in which water either interacts with or fills the crystal structure, eg, is part of the crystal structure or is enclosed within the crystal (aqueous inclusions). Thus, water may be present in stoichiometric or non-stoichiometric amounts. If water is present in stoichiometric quantities, the hydrate may be indicated by adding Greek numeric prefixes. For example, a hydrate may be called a hemihydrate or a monohydrate, depending on the stoichiometry of the water/compound. The water content can be measured, for example, using Karl Fischer coulometry.

As used herein, the terms “dehydrate” or “dehydration” describe at least partial removal of water from the crystalline structure of a host molecule.

The term “solvate” as used herein refers to a crystalline solid in which one or more organic solvents are reacted with or accommodated in the crystal structure, eg, are part of the crystal structure or are included in the crystal (solvent inclusions). Thus, one or more organic solvents may be present in stoichiometric or non-stoichiometric amounts. If one or more organic solvents are present in stoichiometric amounts, the solvate may be indicated by adding Greek numeric prefixes. For example, a solvate may be called a hemisolvate or a monosolvate, depending on the stoichiometry of the solvent(s)/compound.

Solvent content can be measured, for example, using GC, NMR, SXRD or TGA/MS.

The term "isostructural solvate" as used herein refers to solvates having the same space group with slight distortions in unit cell dimensions and the same type of molecular network of the host molecule. Isostructural solvates, as defined herein, differ in the type of organic solvent(s) present as guest molecule(s).

As used herein, the terms “desolvation” or “desolvation” describe at least partial removal of an organic solvent from the crystal structure of a host molecule.

As used herein, the terms “anhydrous form” or “anhydrous” refer to a crystalline solid in which water does not interact with or is incorporated into the crystalline structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure, but may be adsorbed to the surface or absorbed into disordered regions of the crystal. Typically, the anhydrous form does not contain more than 3.0 wt. %, for example, no more than 1.0 wt. % water, based on the weight of the crystalline form.

The term "unsolvated" as used herein when referring to a crystalline solid means that no organic solvent is reacted with or incorporated into the crystalline structure. Unsolvated forms may still contain residual organic solvents that are not part of the crystal structure but may be adsorbed to the surface or absorbed into disordered regions of the crystal. In one embodiment, the unsolvated form contains no more than 3.0 wt. %, for example, no more than 1.0 wt. %. In one embodiment, the unsolvated form does not contain more than 0.5 wt. % organic solvents based on the weight of the crystalline form.

As used herein, the term "mother liquor" refers to the solution remaining after crystallization of a solid from said solution.

As used herein, the term “antisolvent” refers to liquids that reduce the solubility of LNP023 hydrochloride in a solvent.

“Predetermined amount” as used herein in relation to LNP023 hydrochloride refers to the initial amount of LNP023 hydrochloride used to prepare the pharmaceutical composition at the desired dosage of LNP023 hydrochloride.

The term "therapeutically effective amount" as used herein in relation to LNP023 hydrochloride covers the amount of LNP023 hydrochloride that produces the desired therapeutic or prophylactic effect.

As used herein, the term “non-hygroscopic” refers to a mass increase (due to water absorption) of less than 0.2% at 80% RH at 25°C, based on the weight of the compound.

The term "equilateral" as used herein in relation to crystal shapes refers to uniformly sized crystals such as cubes or spheres.

The terms "plate" or "plate-like" as used herein in reference to crystal shape refer to flat, tabular crystals having a similar width and a thickness greater than that of flakes.

The terms "flakes" or "flake-like" as used herein in reference to crystal shapes refer to thin, flat crystals having similar widths and thicknesses less than plates.

The terms "acicular" or "needle-like" as used herein in reference to crystal shape refer to pointed, thin and highly elongated crystals having similar thickness and width.

The term "columnar" or "columnar", used interchangeably herein in reference to crystal shape, refers to elongated prismatic crystals having a greater width and thickness than needles.

Such crystal habit definitions correspond to those commonly used in the art, for example, see "Polymorphism in the Pharmaceutical Industry" edited by Rolf Hilfiker (Wiley-VCH, 2006); Chapter 7, Light Microscopy (Gary Nichols).

As used herein, the term “about” means approximately, in the area, about, or about. When the term "about" is used in conjunction with a numerical interval, it modifies that interval by extending the boundaries above and below the given numerical values. In general, the term “about” is used herein to vary the numerical value above and below the stated value within a 10% variation.

As used herein, the term “substantially free from any other solid form” in relation to a composition containing a particular solid form of LNP023 hydrochloride means that the composition includes no more than 20 wt. % (weight percent), no more than 15 weight. %, no more than 10 wt. %, no more than 9 wt. %, no more than 8 wt. %, no more than 7 wt. %, no more than 6 wt. %, no more than 5 wt. %, no more than 4 wt. %, no more than 3 wt. %, no more than 2 wt. %, no more than 1 wt. %, no more than 0.5 wt. %, or maximum 0.1 wt. %, or any weight percentage from 80 to 100 wt. % of any other solid form of LNP023 hydrochloride, based on the weight of the composition.

As used herein, “substantially pure”, when used in relation to form, means a compound having a purity greater than 90 wt. %, including more than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 wt. %, and also including equal to approximately 100 wt. % of the specific solid form of LNP023 hydrochloride, based on the weight of the compound. The remaining material contains other form(s) of the compound, or reaction impurities, or processing impurities encountered during its preparation. For example, a crystalline form of LNP023 hydrochloride may be considered substantially pure if it has a purity greater than 90 wt. %, as measured by methods that are currently known and generally accepted in the art, where the remaining less than 10 wt. % of the material contains other form(s) of LNP023 hydrochloride, reaction impurities, or processing impurities.

As used herein, the term “subject” refers to a human being. By way of example, human subjects include a patient (hereinafter referred to as the patient) suffering from a disorder, such as the disorder described herein, or a normal subject.

The term "physically stable" as used herein means that a particular free base or salt form does not transform into one or more different physical forms (eg, different solid forms measured by XRPD, DSC, etc.) upon exposure to certain conditions, for example, room temperature, ambient humidity or 40°C/75% relative humidity, for a certain period of time, for example, 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or longer. In some embodiments, less than 25% of the form of the compound is converted into one or more different physical forms when exposed 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 a form of a particular compound changes into one or more different physical forms of that particular compound when exposed to given conditions. In some embodiments, an undetectable amount of a particular form of the compound is converted into one or more different physical forms of the compound.

The term "chemically stable" as used herein means that the chemical structure of a particular compound does not change into another compound (eg, decompose) when exposed to certain conditions, such as room temperature, ambient humidity, or 40°C/75% relative humidity , for a specified period of time, such as 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or longer. In some embodiments, less than 25% of the form of a particular compound is converted to one or more other compounds when exposed 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 a form of a particular compound changes into one or more other compounds when exposed to given conditions. In some embodiments, a non-detectable amount of a particular compound form is converted into one or more different physical forms of that particular compound.

As used herein, the term “pharmaceutically acceptable excipient” refers to substances that do not exhibit significant pharmacological activity at an administered dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may function, among other things, as a carrier, diluent, release agent, disintegrant, solubilizer, absorption enhancer, stabilizer or processing aid. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.

As used herein, the terms “excipient” or “diluent” refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Thinners and fillers can also serve as stabilizers.

As used herein, the term “binder” refers to substances that bind the active pharmaceutical ingredient and the pharmaceutically acceptable excipient together to maintain coherence and discrete portions.

The terms "disintegrant" or "disintegrant" as used herein refer to substances that, when added to a solid pharmaceutical composition, facilitate its breakdown or disintegration after administration and allow the active pharmaceutical ingredient to be released as efficiently as possible to ensure rapid dissolution.

The term "lubricant" as used herein refers to substances that are added to a powder mixture to prevent the compacted powder mass from sticking to equipment during the tableting or encapsulation process. They facilitate the release of the tablet from the matrix and can improve the flow of the powder.

The term "glidant" as used herein refers to substances that are used in tablet and capsule formulations to improve the compressive fluidity of the tablets and to provide an anti-caking effect.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Fig. 1 illustrates a representative PXRD form of the IR hydrochloride LNP023 described herein. The x-axis shows the scattering angle in °2-theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons per second.

Fig. 2 illustrates a comparison of a representative PXRD of Form HB of LNP023 hydrochloride described herein (bottom) and a representative PXRD of Form A of LNP023 hydrochloride from WO 2015/009616 (top). The x-axis shows the scattering angle in °2-theta. The X-ray powder diffraction pattern of Form A was shifted along the y-axis to separate the diffraction patterns for clarity. Therefore, the y-axis is arbitrary and has not been designated.

Fig. 3 illustrates a representative FTIR spectrum of the IR form of LNP023 hydrochloride described herein. The x axis shows the wave numbers in cm ^-1 , the y axis shows the relative intensity in percent transmittance.

Fig. 4 illustrates a representative DSC curve of the IR form of LNP023 hydrochloride described herein. The x-axis shows temperature in degrees Celsius (°C), and the y-axis shows heat flow rate in watts per gram (W/g) with ascending endothermic peaks.

Fig. 5 illustrates a representative TGA curve of the IR form of LNP023 hydrochloride described herein. The x-axis shows the temperature in degrees Celsius (°C), and the y-axis shows the mass (loss) of the sample in weight percent (wt%).

Fig. 6 illustrates representative DVS isotherms of the IR form of LNP023 hydrochloride described herein over the range of 0 to 95% relative humidity. The x-axis shows the relative humidity as a percentage (%) measured at a temperature of (25.0±1.0)°C, the y-axis shows the change in equilibrium mass as a percentage of weight (wt.%) relative to the weight of the sample at RH 0 %. The sorption cycle is marked with triangles, while the desorption cycle is marked with squares.

Fig. 7a and 7b illustrate scanning electron microscopy images of the IR form of LNP023 hydrochloride described herein when prepared in accordance with Example 3 (scale bar overall: 50 micrometers).

DETAILED DESCRIPTION OF THE INVENTION

Crystal form

Example embodiments:

In one embodiment, the invention relates to a crystalline hydrate form of LNP023 hydrochloride, also referred to herein as the “HB form”.

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

The IR form of LNP023 hydrochloride described herein can be characterized by analytical methods well known in the pharmaceutical industry for characterizing solids. Such methods include, but are not limited to, PXRD, SXRD, FTIR, DSC, DVS, TGA and SEM. They can be characterized by one of the above analytical methods or a combination of two or more of them. In particular, the IR form of LNP023 hydrochloride described herein may be characterized by any one of the following embodiments or a combination of two or more of the following embodiments.

Examples of PXRD embodiments:

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (9.2±0.2)° and ( 19.1±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)° and (19.1±0.2) ⁰ when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (19.1±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Calpha radiation _{1 ,2} with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 up to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)°, (21.3±0.2)° and (24.6±0. 2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0, 2)°, (21.3±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 wavelength 0 radiation ,15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0, 2)°, (19.1±0.2)°, (21.3±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalpha _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0, 2)°, (19.1±0.2)°, (21.3±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalpha _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (Form HB), characterized in that the crystalline form of LNP023 hydrochloride (Form HB) can be characterized by PXRD peaks identified at 2-theta angle values (4.6 ± 0.2) °, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6 ±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalpha _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0, 2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (21.3±0.2)° and (24 .6±0.2) when measured at temperatures ranging from 20 to 30°C using Cu-Calpha _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0, 2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21 .3±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0, 2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21 .3±0.2)°, (24.0±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Calpha radiation _{1, 2} with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0, 2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21 .3±0.2)°, (22.2±0.2)°, (24.0±0.2)° and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0, 2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21 ,3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2)° and (28.0±0.2 ) when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4.6±0.2)°, (6.8±0.2)°, ( 9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)° and (24.6±0.2)°, and at least one or more peak selected from the group consisting of (10.0±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2) °, (17.2±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0 ±0.2)° and (28.0±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-Calfa _1.2 radiation with a wavelength of 0.15419 nm.

In another embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values such as:

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

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

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (19.1±0.1)° and (24.6±0 ,1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0 ,1)° and (24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0 ,1)°, (21.3±0.1)° and (24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (12.6±0 ,1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)° and (24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)° and ( 24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)° and ( 24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (19.1±0.1)°, ( 21.3±0.1)° and (24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, ( 19.1±0.2)°, (21.3±0.2)° and (24.6±0.2)°; or

(4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0 ,2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, ( 19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)° and (24.6±0.2)°; or

(4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0 ,2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, ( 19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)° and (24.6±0. 1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, ( 19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0, 1)° and (24.6±0.1)°; or

(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0 ,2)°, (12.6±0.2)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, ( 19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0, 1)°, (24.6±0.1)° and (28.0±0.1)° at

measured at temperatures ranging from 20 to 30°C using Cu-Calfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (HB form) characterized by PXRD peaks identified at 2-theta angle values of (4(4.6±0.1)°, (6.8±0.1)° , (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)° and (24.6±0.1)°, and at least one or more peak selected from the group consisting of (10.0±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0, 1)°, (17.2±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24 .0±0.1)° and (28.0±0.1)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

The PXRD of Form HB described herein can be clearly distinguished from the PXRD of Form A from WO 2015/009616 (see also the PXRD overlay shown in FIG. 2 described herein). For example, Form HB shows characteristic peaks at (4.6±0.1) and (9.2±0.1)° 2-theta, whereas Form A shows no peaks in the same ranges. According to page 176 of WO 2015/009616, among the four most characteristic peaks of form A, one is the peak at 11.6° 2-theta. In contrast, the NV form described herein does not show a peak in the same range.

In another embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB), which can be characterized by PXRD as described in one of the embodiments above, but does not include a peak at 2-theta (11.6±0.2)° at measured at temperatures ranging from 20 to 30°C using Cu-Kalpha _1;2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB), which can be characterized by PXRD as described above, but does not include peaks at 2-theta angle values of (11.6±0.1)° 2-theta at measured at temperatures ranging from 20 to 30°C using Cu-Kalpha _1;2 radiation with a wavelength of 0.15419 nm.

In another embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB) having substantially the same PXRD as shown in FIG. 1 described herein when measured at a temperature in the range of 20 to 30°C using Cu-Kalpha _1.2 radiation with a wavelength of 0.15419 nm.

The relative intensity of the peaks, for example, as shown in FIG. 1 and shown in Table 2, can be changed to a certain extent due to the morphology of particles of the NV form. In general, the morphology of many crystalline particles tends to produce a pattern that exhibits some degree of

preferred orientation in the sample holder. This is especially evident for needle or plate crystals, where decreasing the size allows for thinner needles or plates. The preferred orientation in the sample affects the intensity of the various peaks, such that some are more intense and others are less intense than what would be expected from a completely random sample.

Examples of FTIR implementations:

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(34 52±4) cm ^-1 , (2875±4) cm ^-1 and (1692±4) cm ^-1 .

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(3452±4) cm ^-1 , (2875±4) cm ^-1 , (1692±4) cm ^-1 and (1439±4) cm ^-1 when measured at temperatures ranging from 20 to 30°C using a diamond ATR cells.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (1692±4) cm ^-1 , (1439±4) cm ^-1 and (12 4 3±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (1692±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1692±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures ranging from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures ranging from 20 to 30° With the help of an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1439 ±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 .

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm~1, (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures ranging from 20 to 30°C using an ATP diamond cell .

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures ranging from 20 up to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^{- 1} when measured at temperatures ranging from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^-1 , (1243±4) cm ^{- 1} and (767±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^-1 , (1384±4) cm ^{- 1} , (1243±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^-1 , (1384±4) cm ^{- 1} , (1243±4) cm ^-1 , (1184±4) cm ^-1 and (767±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^-1 , (1384±4) cm ^{- 1} , (1243±4) cm ^-1 , (1184±4) cm ^-1 , (1069±4) cm ^-1 and (767±4) cm ^-1 when measured at a temperature ranging from 20 to 30°C s using the ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4) cm ^-1 , (1515 ±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^-1 , (1384±4) cm ^{- 1} , (1243±4) cm ^-1 , (1184±4) cm ^-1 , (1069±4) cm ^-1 , (767±4) cm ^-1 and (739±4) cm ^-1 when measured at temperature in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (3274±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601 ±4) cm ^-1 , (1515±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^-1 , (1425±4) cm ^{- 1} , (1384±4) cm ^-1 , (1243±4) cm ^-1 , (1184±4) cm ^-1 , (1069±4) cm ^-1 , (767±4) cm ^-1 and (739± 4) cm ^-1 when measured at temperatures in the range from 2 0 to 30 ° C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (3274±4) cm ^-1 , (2933±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1709±4) cm ^-1 , (1692±4) cm ^-1 , (1658±4) cm ^-1 , (1615 ±4) cm ^-1 , (1601±4) cm ^-1 , (1515±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1439±4) cm ^{- 1} , (1425±4) cm ^-1 , (1384±4) cm ^-1 , (1243±4) cm ^-1 , (1184±4) cm ^-1 , (1069±4) cm ^-1 , (767± 4) cm ^-1 and (739±4) cm ^-1 when measured at temperatures in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±4) cm ^-1 , (2875±4) cm ^-1 , (2732±4) cm ^-1 , (1692±4) cm ^-1 , (1439±4) cm ^-1 , (1243±4) cm ^-1 and (767±4) cm ^-1 and at least one peak selected from the group consisting from (3274±4) cm ^-1 , (2933±4) cm ^-1 , (1709±4) cm ^-1 , (1658±4) cm ^-1 , (1615±4) cm ^-1 , (1601±4 ) cm ^-1 , (1515±4) cm ^-1 , (1497±4) cm ^-1 , (1461±4) cm ^-1 , (1425±4) cm ^-1 , (1384±4) cm ^-1 , (1184±4) cm ^-1 , (1069±4) cm ^-1 and (739±4) cm ^-1 when measured at temperatures ranging from 20 to 30°C using an ATP diamond cell.

In another embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers

(34 52±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 (12 4 3±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 , (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 , (1615±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 , (1615±2) cm ^-1 , (1601±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 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1439±2) cm ^-1 , (1243±2) cm ^-1 and ( 767±2) cm ^-1 ; or

(3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1709±2) cm ^-1 , (1692±2) cm ^-1 , (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1439±2) cm ^-1 , ( 1243±2) cm ^-1 and (767±2) cm ^-1 ; or

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

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

(3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1709±2) cm ^-1 , (1692±2) cm ^- !., (1658±2 ) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1461±2) cm ^-1 , (1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 and (767±2) cm ^-1 ; or

(3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1709±2) cm ^-1 , (1692±2) cm ^- !., (1658±2 ) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1461±2) cm ^-1 , (1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 , (1184±2) cm ^-1 and (767±2) cm ^-1 ; or

(3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1709±2) cm ^-1 , (1692±2) cm ^-1 , (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1461±2) cm ^-1 , ( 1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 , (1184±2) cm ^-1 , (1069±2) cm ^-1 and (767±2) cm ^-1 ; or

(3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1709±2) cm ^-1 , (1692±2) cm ^-1 , (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1461±2) cm ^-1 , ( 1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 , (1184±2) cm ^-1 , (1069±2) cm ^-1 , (767±2) cm ^-1 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, (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , ( 1461±2) cm ^-1 , (1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 , (1184±2) cm ^-1 , (1069±2) cm ^-1 , (767±2) cm ^-1 and (739±2) cm ^-1 ; 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 , (1692±2) cm ^-1 , (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2) cm ^-1 , (1515±2) cm ^-1 , ( 1497±2) cm ^-1 , (1461±2) cm ^-1 , (1439±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1243±2) cm ^-1 , (1184±2) cm ^-1 , (1069±2) cm ^-1 , (767±2) cm ^-1 and (739±2) cm ^-1 when measured at a temperature in the range from 20 to 30°C using an ATP diamond cell.

In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by the presence of an FTIR spectrum including peaks at wavenumbers (3452±2) cm ^-1 , (2875±2) cm ^-1 , (2732±2) cm ^-1 , (1692±2) cm ^-1 , (1439±2) cm ^-1 , (1243±2) cm ^-1 and (767±2) cm ^-1 and at least one peak selected from the group consisting from (3274±2) cm ^-1 , (2933±2) cm ^-1 , (1709±2) cm ^-1 , (1658±2) cm ^-1 , (1615±2) cm ^-1 , (1601±2 ) cm ^-1 , (1515±2) cm ^-1 , (1497±2) cm ^-1 , (1461±2) cm ^-1 , (1425±2) cm ^-1 , (1384±2) cm ^-1 , (1184±2) cm ^-1 , (1069±2) cm ^-1 and (739±2) cm ^-1 when measured at temperatures ranging from 20 to 30°C using an ATP diamond cell.

In yet another embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB) having substantially the same FTIR spectrum as shown in FIG. 3 described herein when measured at temperatures in the range of 20 to 30°C using an ATR diamond cell.

Illustrative Examples of DSC Embodiments:

In one embodiment, LNP023 hydrochloride (form HB) exhibits substantially the same DSC profile as shown in FIG. 4. In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB) characterized by having a DSC curve showing a broad endothermic event that ends at approximately 170°C, followed by exothermic decomposition at approximately 200°C when measured with heating rate 10 K/min. In one embodiment, a broad endothermic event that ends at a temperature of approximately 170°C is an endothermic event in the range of 35°C to 170°C when measured at a heating rate of 10 K/min.

Illustrative examples of TGA embodiments:

In one embodiment, LNP023 hydrochloride (form HB) is characterized using substantially the same thermogravimetric analysis (TGA) as shown in FIG. 5. In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB) characterized by a TGA curve demonstrating mass loss at approximately 220°C, for example between 200 and 220°C, due to loss of water and residual solvents no more than 4.5 wt. %, for example, no more than 4.3 wt. %, for example, no more than 4.0 wt. %, for example, no more than 3.8 wt. %, for example, no more than 3.4 wt. %, based on the weight of the crystalline form of the crystalline form, when heated from 30 to 300°C at a rate of 20 K/min.

Illustrative Examples of DVS Embodiments: In one embodiment, LNP023 hydrochloride (form HB) has substantially the same DVS as shown in FIG. 6. In one embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (HB form) having a weight change of no more than 4.5 wt. %, for example, no more than 4.0 wt. %, for example, no more than 3.0 wt. %, for example, no more than 2.0 wt. %, for example, no more than 1.8 wt. %, 1.6 wt. %, 1.5 wt. % or 1.4 wt. %, based on the weight of the crystalline form when measured using DVS at relative humidity in the range from 0 to 95% and temperature (25 ± 1.0) ° C.

Illustrative examples of additional embodiments:

In another embodiment, the invention relates to a crystalline form of LNP023 hydrochloride (form HB), characterized as a non-solvated form. In one embodiment, the LNP023 hydrochloride crystalline form is in a hydrated form, such as a monohydrate.

Examples of morphology

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB) characterized by a columnar or equilateral morphology.

In one embodiment, the invention provides a crystalline form of LNP023 hydrochloride (form HB) having a crystal habit that is substantially equilateral or columnar, for example, substantially equilateral. This leads to preferable flow properties compared to small acicular (needle-shaped) or lath-shaped (lobed) crystals. Such preferred crystal forms can be obtained by performing the process as set forth herein, for example, by performing a crystallization procedure involving temperature cycling followed by grinding to reduce particle size.

The resulting particles are characterized by a suitable aspect ratio. The aspect ratio ψ _A (0<ψ _A ≤1) is determined by the ratio of the minimum and maximum Feret diameter ψ _A =x _{Feret min} /x _{Feret max} . It gives an idea of the elongation of the particle, i.e. the lower the value, the more elongated the particle is. Therefore, in additional embodiments of the invention, the equilateral particles of the LNP023 hydrochloride crystalline form (HB form) have an aspect ratio (a50) greater than about 0.4, such as greater than about 0.45. In other embodiments, the equilateral HB-shaped particles have an aspect ratio of from about 0.4 to about 0.7, such as from about 0.45 to 0.6.

In further embodiments, the Xd ₀ particle size distribution of the equilateral LNP023 hydrochloride crystalline form (HB form) particles is less than about 300 μm, such as less than about 200 μm, such as less than about 150 μm. In additional embodiments of the invention, the particle size distribution of X ₉₀ is from about 30 to about 150 microns, for example from about 35 to about 130 microns, for example from about 40 to about 105 microns.

In further embodiments, the particle size distribution X ₅₀ of the equilateral particles of the HB form is from about 5 to about 100 microns, for example from about 10 to about 70 microns, for example from about 15 to about 55 microns.

In yet another embodiment of the invention, the particle size distribution X ₁₀ of the equilateral particles of the form HB is from about 0.1 to about 50 μm, for example from about 1 to about 30 μm, for example from about 2 to about 20 μm.

In a further embodiment, the equilateral particles of the NV form have a consolidated (15 kPa) bulk density of less than about 0.8 g/ml, for example, less than about 0.7 g/ml. In other embodiments, the equilateral particles of the HB form have a consolidated (15 kPa) bulk density of from about 0.4 to about 0.7 g/ml, for example, from about 0.50 to about 0.65 g/ml, for example, from about 0.55 to approximately 0.60 g/ml.

Composition

Example embodiments:

In another aspect, the invention provides a composition containing the IR form of LNP023 hydrochloride described herein, as defined in any of the embodiments described above, wherein said composition does not substantially contain any other solid form of LNP023 hydrochloride. For example, a composition containing the NV form of LNP023 hydrochloride described herein contains no more than 20 wt. %, for example, no more than 10 wt. %, for example, no more than 5, 4, 3, 2 or 1 wt. %, any other solid form of LNP023 hydrochloride, based on the weight of the composition. In one embodiment, any other solid form of LNP023 hydrochloride is Form A from WO 2015/009616 or an amorphous form. Form A of LNP023 hydrochloride shows PXRD including, among other things, a characteristic peak at 2-theta (11.6±0.1)° when measured at temperatures ranging from 20 to 30°C using Cu-Calpha _1.2 radiation with a wavelength of 0.15419 nm. Thus, the absence of this peak at 2-theta angle (11.6±0.1)° in PXRD confirms the absence of Form A of LNP023 hydrochloride in the composition.

In one embodiment, the invention provides a composition containing the IR form of LNP023 hydrochloride described herein, as defined in any of the embodiments described above, wherein said composition has a PXRD that does not contain a peak at the 2-theta angle (11.6± 0.1)° when measured at temperatures ranging from 20 to 30°C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm.

In one embodiment, the invention relates to a composition containing at least 90 wt. %, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 wt. %, and also including equal to approximately 100 wt. % amount of the LNP023 hydrochloride NV crystalline form determined in any of the embodiments described above, based on the total weight of the composition. The remaining material may contain other solid form(s) of LNP023 hydrochloride, or reaction impurities or process impurities arising during the preparation of the composition.

Way

Example embodiments:

In another aspect, the invention relates to a method for producing the IR form of LNP023 hydrochloride described herein, or a composition containing the same, as defined in any of the aspects and their respective embodiments described above, comprising:

(i) providing LNP023 hydrochloride in solid form;

(ii) suspending the LNP023 hydrochloride provided in step (i) in a first solvent containing acetone and water, and heating to dissolve the solid to obtain a solution;

(iii) cooling the solution obtained in step (ii) and adding a second solvent containing acetone or ethyl acetate, or a combination thereof, to obtain crystals in the mother liquor;

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

(v) optionally washing the isolated crystals obtained in step (iv); And

(vi) drying the crystals obtained in step (iv) or

(v).

Example of a method description:

Solid starting material LNP023 hydrochloride can be prepared in accordance with the procedure disclosed in example 26d of WO 2015/009616.

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

Optionally, in a next step, the isolated crystals can be washed with a suitable solvent, for example an organic solvent or water. Suitable organic solvents include, but are not limited to, acetone and ethyl acetate.

The resulting crystals can then be dried. Drying can be carried out at a temperature of about 70°C or less, for example about 60°C or less, for example about 50°C. Drying can also be carried out at room temperature. Drying can be carried out for a period of time ranging from about 2 to 24 hours, for example from about 4 to 16 hours, for example from about 6 to 10 hours. In one embodiment, drying can be carried out over a period of approximately 6 to 8 hours. Drying can be carried out at atmospheric pressure or under reduced pressure. In one embodiment, drying is carried out at a pressure of about 200 mbar or less, for example, about 150 mbar or less. In one embodiment, drying is carried out at a pressure of approximately 80 mbar or less. In one embodiment, drying is carried out, for example, under a vacuum of approximately 50 mbar or less.

In one embodiment, certain crystallization techniques may be used in a process to produce crystals of the HB form with improved product processability. Methods include, but are not limited to, temperature cycling or adding a second solvent over an extended period of time, for example, 12-36 hours, for example, there may be a temperature cycle. The temperature cycle can be carried out as follows: In step (iii), before adding the second solvent, the solution can be cooled to a temperature in the range of from about 0 to 25°C, for example from about 5 to 15°C, for example 10°C, and then heated to a temperature in the range of from about 30 to 45°C, for example from 30 to about 40°C, for example 35°C. This temperature cycle can be carried out at least 3 times, for example at least 6 times eg at least 8 times, eg 6 to 12 times. After the temperature cycle, a second solvent can be added. In one embodiment, the second solvent may be ethyl acetate.

The form of NV after processing, i.e. after applying certain crystallization methods as described above, consists of crystals with a well-defined morphology, this morphology results in excellent powder properties and processability, allowing the drug product containing the NV form to be formulated using standard manufacturing processes and equipment. In one embodiment, unlike Form A, which cannot be formulated in this manner, Form HB is not brittle so problems with grinding and wide particle size distribution can be minimized. In addition, the fluidity of the NV form is higher than that of Form A. Thus, the NV form, especially during development, combines high physicochemical stability and excellent powder properties. It is therefore superior to Form A and is an ideal solid form of LNP023 hydrochloride for routine production of an advanced pharmaceutical composition.

In one embodiment, the invention relates to a method for preparing the IR form of LNP023 hydrochloride described herein, or a composition containing it, as defined in any of the aspects and their respective embodiments described above, comprising as step (iii) the procedure described above

a) cooling the solution obtained in step (ii), followed by reheating the solution;

b) repeating step (a) at least 3 times and

c) adding a second solvent containing acetone, ethyl acetate, or a combination thereof.

Grinding example

Before the particles of the LNP023 hydrochloride IR form described herein are filled into capsules or otherwise subjected to further processing, they are, for example, crushed. Grinding can be carried out in order to allow the particles to be easily filled directly into capsules, in particular without the need for additional excipients.

In one embodiment, the particle size of the LNP023 hydrochloride NV form is reduced using rotary impact grinding. Rotary impact grinding can be carried out using a variety of static and rotating equipment, such as a rotary impeller beater with a static screen, a rotary impeller beater with a static screen and impactor, a rotary pin disc with a static pin disc, or a rotary pin disc with a rotating pin disc. The NV form of hydrochloride LNP023 to be crushed is transported to the rotary impact mill using appropriate powder conveying systems, such as a vibratory feeder or twin screw feeder, to adequately control the appropriate powder feed rate. The powder is then transported to the impact elements by a gas flow generated either by the rotating elements of the rotary impact mill or by a blower connected to the rotary impact mill. Particle size reduction of the NV form of LNP023 hydrochloride particles occurs through impact on rotating elements, impact on static elements, or impact between colliding NV form particles. Adequate process parameters, such as rotor rotation speed and material feed rate for obtaining an individual form of NV hydrochloride LNP023, are associated with specific parameters of the rotary impact mill equipment. The crushed product with specified physical properties is collected in a product container after separation from the transport gas using, for example, filters, cyclones. The ground product can be finally mixed using appropriate techniques, such as a diffusion mixer, to obtain adequate physical homogeneity of the manufactured batch.

Rotary impact grinding can be carried out, for example, by rotary impact grinding using a rotating pin disk with a static pin disk attachment, often described in the art as a pin mill. The scale-independent parameters of rotor speed and feed rate can be described by the rotor tip speed and the specific feed rate. The rotor speed of a particular scale of equipment is in principle related to the diameter of the pin disk of the corresponding scale of equipment by the parameter rotor tip speed for a scale-independent parameter. The feed rate of a particular scale of equipment is in principle related to the pin surface area of the corresponding scale of equipment by the specific feed rate parameter for a scale-independent parameter. The NV form of the LNP023 hydrochloride product with specified physical properties can be obtained by rotary impact grinding with the following scale-independent grinding parameters: rotor tip speed from 10 to 60 m/s, with the diameter of the external rotating pins taken into account for standardization, or specific feed speed no more approximately 4000 kg/(h⋅m ² ), while the area of the cylindrical surface of the rotating pins is taken into account for normalization.

In a scale-dependent example, the IR form of hydrochloride LNP023 can be milled using a rotary impact mill, such as model 100UPZ, Hosokawa Alpine AG, Augsburg/Germany, and a rotating pin disc with a static pin disc tooling, often described in the public domain as a pin mill. A product with desired physical properties can be obtained by carrying out the process at a rotor speed of 1800 to 10,500 rpm, for example, from 4000 to 8500 rpm, for example, at a rotor speed of 6000 rpm. The feed rate is, for example, from 1 to 22 kg/h, for example from 6 to 18 kg/h, for example, at a feed rate of 15 kg/h.

Pharmaceutical compositions and uses

Example embodiments:

In a further aspect, the invention relates to the use of the IR form of LNP023 hydrochloride described herein, or a composition containing the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, for the preparation of a pharmaceutical composition.

In a further aspect, the invention relates to a pharmaceutical composition containing the IR form of LNP023 hydrochloride or a composition containing the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, for example, in a predetermined or therapeutically effective amount, and according to at least one pharmaceutically acceptable excipient.

In one embodiment, a pharmaceutical composition comprising the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, contains LNP023 hydrochloride at a dose of no more than about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment, the pharmaceutical composition contains LNP023 hydrochloride at a dose of from about 10 mg to about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment, the pharmaceutical composition contains LNP023 hydrochloride at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg, each expressed as the anhydrous free base of LNP023.

In one embodiment, the pharmaceutical composition contains LNP023 hydrochloride at a dose of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg, each expressed as LNP023 anhydrous free base.

In one embodiment, the therapeutically effective amount of the IR form of LNP023 hydrochloride is selected from the group consisting of 1, 5, 10, 25, 50, 100 and 200 mg, based on the anhydrous free base of LNP023. In one embodiment, the therapeutically effective amount of the IR form of LNP023 hydrochloride is 100 or 200 mg. In one embodiment, the therapeutically effective amount of the IR form of LNP023 hydrochloride is 50 mg. In one embodiment, the therapeutically effective amount of the IR form of LNP023 hydrochloride is 10 mg.

At least one pharmaceutically acceptable excipient that may be included in the pharmaceutical composition described herein is, for example, selected from the group consisting of carriers, excipients, diluents, binders, disintegrants, lubricants, glidants, and combinations thereof . Suitable carriers are, for example, a dispersing liquid or a capsule. In one preferred embodiment, the pharmaceutical composition contains one pharmaceutically acceptable excipient, for example, a carrier.

In a preferred embodiment, the pharmaceutical composition containing the IR form of LNP023 hydrochloride, or the composition containing the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, is a solid dosage form for oral administration. In one embodiment, the solid oral dosage form is selected from the group consisting of tablets and capsules. In one embodiment, the oral dosage form is in the form of a tablet. In one embodiment, the oral dosage form is a capsule. In one embodiment, the capsule is size 0.

A tablet can be prepared by mixing the IR form of LNP023 hydrochloride or a composition containing the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, with at least one excipient, such as fillers, diluents, binders, disintegrants, lubricants, glidants, or combinations thereof. Optionally, a granulation step, such as dry or wet granulation, is performed before compression.

The capsule can be prepared by mixing the IR form of LNP023 hydrochloride or a composition containing the IR form of LNP023 hydrochloride, as defined in any of the aspects and their respective embodiments described above, with at least one excipient, such as fillers, diluents, binders, disintegrating agents, lubricants, glidants, or combinations thereof, and filling the mixture into capsules that are used as a carrier. Alternatively, the IR form of hydrochloride LNP023 is carefully filled into a capsule which is used as a carrier. The capsule shell may be gelatin or hydroxypropyl methylcellulose (HPMC) shell.

In one embodiment, the invention relates to a pharmaceutical composition comprising an IR form of LNP023 hydrochloride particles in a capsule, such as a size 0 capsule. In one embodiment, the IR form particles in a capsule have an aspect ratio of from 0.4 to about 0.7, e.g. 0.45 to 0.6. In one embodiment, the particles of the NV form in the capsule have a particle size distribution X ₅₀ of about 5 to about 100 microns, for example, from about 10 to about 70 microns, for example, from about 15 to about 55 microns. In one embodiment, the particles of the NV form in the capsule have a consolidated (15 kPa) bulk density of from about 0.4 to about 0.7 g/ml, for example, from about 0.50 to about 0.65 g/ml, for example, from about 0.55 to about 0.60 g/ml.

In a further aspect, the invention relates to the IR form of LNP023 hydrochloride, or a composition containing the IR form of LNP023 hydrochloride, or a pharmaceutical composition containing the same as defined in any of the above-described aspects and their respective embodiments, for use in the treatment of diseases described herein and disorders.

In yet another aspect, the invention relates to the IR form of LNP023 hydrochloride, or a composition containing the IR form of LNP023 hydrochloride, or a pharmaceutical composition containing the same as defined in any of the above-described aspects and embodiments thereof, for use in the treatment or prevention of the indications disclosed in WO 2015/009616 and WO 2019/043609, in particular for the treatment or prevention of paroxysmal nocturnal hemoglobinuria (PNH), kidney diseases caused by complement, C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy) and other nephropathies with features of glomerular deposition C3, such as MN (membranous nephropathy) and HUS (hemolytic uremic syndrome caused by E. coli), as well as atypical hemolytic uremic syndrome (aHUS).

In another aspect, the invention relates to a method of treating the diseases and disorders disclosed in WO 2015/009616 and WO 2 019/043609, each of which is incorporated herein by reference in their entirety, in a subject in need thereof. In one embodiment, the disease or disorder is selected from paroxysmal nocturnal hemoglobinuria (PNH), complement-induced kidney diseases, C3G (C3 glomerulopathy), IgAN (immunoglobulin A nephropathy), and other nephropathies with features of glomerular C3 deposition, such as MN (membranous nephropathy) and HUS (hemolytic uremic syndrome caused by E. coli), as well as atypical hemolytic uremic syndrome (aHUS). In one embodiment, the method comprises administering to a subject a therapeutically effective amount of the NV form of LNP023 hydrochloride, as described herein.

In another aspect, the invention provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a form of NV LNP023 to treat the subject.

In one embodiment, a method of treating PNH in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of no more than about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of no more than about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating PNH in a subject includes administering to the subject a form of NV LNP023 at a daily dose of from about 20 mg to about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of from about 10 mg to about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating PNH in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered to a subject at a total daily dose of about 20 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 10 mg.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered to a subject at a total daily dose of about 50 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 25 mg.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered to a subject at a total daily dose of about 100 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 50 mg.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered to a subject at a total daily dose of about 200 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 100 mg.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered to a subject at a total daily dose of about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 200 mg.

In one embodiment of a method of treating PNH, the NV form LNP023 is administered to a subject orally twice daily (b.i.d.), for example, approximately every 12 hours.

In one embodiment of a method of treating PNH, the NV form of LNP023 is administered orally twice daily (b.i.d.), for example, approximately every 12 hours, to a subject at a dose of 200 mg, expressed as LNP023 anhydrous free base.

In another aspect, the invention provides a method of treating complement-induced kidney disease C3G (C3 glomerulopathy) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a form of NV LNP023 to treat the subject.

In one embodiment, a method of treating C3G in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of no more than about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of no more than about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating C3G in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of from about 20 mg to about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of from about 10 mg to about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating C3G in a subject comprises administering to the subject an IR form of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered to a subject at a total daily dose of about 20 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 10 mg.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered to a subject at a total daily dose of about 50 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 25 mg.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered to a subject at a total daily dose of about 100 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 50 mg.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered to a subject at a total daily dose of about 200 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 100 mg.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered to a subject at a total daily dose of about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 200 mg.

In one embodiment of the C3G treatment method, the NV form LNP023 is administered to a subject orally twice daily (b.i.d.), for example, approximately every 12 hours.

In one embodiment of the C3G treatment method, the IR form of LNP023 is administered orally twice daily (b.i.d.), for example, approximately every 12 hours, to a subject at a dose of 200 mg, expressed as LNP023 anhydrous free base.

In another aspect, the invention provides a method of treating IgAN (immunoglobulin A nephropathy) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a form of NV LNP023 to treat the subject.

In one embodiment, a method of treating IgAN in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of no more than about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of no more than about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating IgAN in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of from about 20 mg to about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of from about 10 mg to about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating IgAN in a subject comprises administering to the subject an IR form of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered to a subject at a total daily dose of about 20 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 10 mg.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered to a subject at a total daily dose of about 50 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 25 mg.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered to a subject at a total daily dose of about 100 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 50 mg.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered to a subject at a total daily dose of about 200 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 100 mg.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered to a subject at a total daily dose of about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 200 mg.

In one embodiment of a method of treating IgAN, the NV form LNP023 is administered to a subject orally twice daily (b.i.d.), for example, approximately every 12 hours.

In one embodiment of a method of treating IgAN, the IR form of LNP023 is administered orally twice daily (b.i.d.), for example, approximately every 12 hours, to a subject at a dose of 200 mg, expressed as the anhydrous free base of LNP023.

In another aspect, the invention provides a method of treating MN (membranous nephropathy), for example, idiopathic MN (iMN), in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a form of NV LNP023 to treat the subject.

In one embodiment, a method of treating MN, e.g., iMN, in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of no more than about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of no more than about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating MN, e.g., iMN, in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of from about 20 mg to about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of from about 10 mg to about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating MN, e.g., iMN, in a subject includes administering to the subject a form of NV LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, based on the anhydrous free base of LNP023 . In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered to a subject at a total daily dose of about 20 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 10 mg.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered to a subject at a total daily dose of about 50 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 25 mg.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered to a subject at a total daily dose of about 100 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 50 mg.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered to a subject at a total daily dose of about 200 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 100 mg.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered to a subject at a total daily dose of about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 200 mg.

In one embodiment of a method of treating MN, the NV form LNP023 is administered to a subject orally twice daily (b.i.d.), for example, approximately every 12 hours.

In one embodiment of a method of treating MN, the IR form of LNP023 is administered orally twice daily (b.i.d.), for example, approximately every 12 hours, to a subject at a dose of 200 mg, expressed as LNP023 anhydrous free base.

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

In one embodiment, a method of treating aHUS in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of no more than about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of no more than about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating aHUS in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of from about 20 mg to about 400 mg, expressed as LNP023 anhydrous free base. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of from about 10 mg to about 200 mg, based on LNP023 anhydrous free base.

In one embodiment, a method of treating aHUS in a subject comprises administering to the subject an NV form of LNP023 at a daily dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, based on the anhydrous free base of LNP023.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered to a subject at a total daily dose of about 20 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 10 mg.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered to a subject at a total daily dose of about 50 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 25 mg.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered to a subject at a total daily dose of about 100 mg, based on the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 50 mg.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered to a subject at a total daily dose of about 200 mg, calculated as the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 100 mg.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered to a subject at a total daily dose of about 400 mg, calculated as the anhydrous free base of LNP023. In one embodiment, administration is twice daily (b.i.d.), for example, approximately every 12 hours, at a dose of approximately 200 mg.

In one embodiment of a method of treating aHUS, the NV form LNP023 is administered to a subject orally twice daily (b.i.d.), for example, approximately every 12 hours.

In one embodiment of a method of treating aHUS, the NV form of LNP023 is administered orally twice daily (b.i.d.), for example, approximately every 12 hours, to a subject at a dose of 200 mg, expressed as LNP023 anhydrous free base.

All of the above embodiments relating to methods for treating certain diseases at certain dosages are equally applicable to

the NV form of the drug LNP023 for use in the treatment of certain diseases at certain doses in accordance with the present invention;

the use of the HB form of LNP023 in the production of a medicament for the treatment of certain diseases in certain doses in accordance with the present invention;

the use of the NV form of LNP023 for the treatment of certain diseases in certain doses in accordance with the present invention; And

a pharmaceutical composition containing the HB form of LNP023 and one or more pharmaceutically acceptable carriers, for use in the treatment of certain diseases at certain doses in accordance with the present invention.

Methods for testing morphological properties

Aspect Ratio: Aspect ratio refers to the ratio of the maximum length of the crystal to its minimum width. With an aspect ratio of 1, the crystal has an isometric crystal habit. As the aspect ratio decreases below 1, the crystal habit becomes more and more plate-like. On the contrary, as the aspect ratio increases more and more above 1, the crystal approaches an acicular crystal habit. According to the disclosure, equilateral particles of the HB form have an aspect ratio a ₅₀ , for example, from about 0.4 to about 0.7.

The aspect ratio is determined by dynamic image analysis (DIA) using a QICPIC dynamic image analyzer from Sympatec GmbH, Clausthal-Zellerfeld, Germany.

Particle size distribution: Particle size distribution is measured by laser light diffraction (LLD) using a Helos instrument from Sympatec GmbH, Clausthal-Zellerfeld, Germany.

Consolidated Bulk Density: Consolidated (15 kPa) bulk density is measured using an FT4 powder rheometer (Freeman Technology).

EXAMPLES

The following non-limiting examples are illustrative of the disclosure and should not be construed as limiting in any way.

Example 1. Preparation of the NV form of LNP023 hydrochloride

The LNP023-HCl salt of form A was prepared as described in example 26d of WO 2015/009616. Suspended 9.3 g of LNP023 Form A hydrochloride in 48.1 g of a mixture of acetone and water (acetone:water = 78:22 m:m) and dissolved at approximately 50°C. The solution was cooled to 40°C and added 136 g a mixture of acetone and ethyl acetate (acetone: ethyl acetate = 1:2 m: m) for 24 hours. The suspension was cooled to 10°C to complete crystallization. The product was isolated by filtration and dried in vacuo at 50° C. to obtain 7.7 g of crystalline salt monohydrate LNP023-HCl (Form HB).

Example 2. Preparation of the NV form of LNP023 hydrochloride using seed crystals

The LNP023-HCl salt of form A was prepared as described in example 26d of WO 2015/009616. Suspended 42 g of LNP023 hydrochloride Form A in 212 g of a mixture of acetone and water (acetone:water = 80:20 m:m) and dissolved at approximately 50°C. The solution was cooled to 25° C. and 0.4 g of LNP023-HCl crystalline salt monohydrate (form HB) seed crystals obtained in Example 1 was added to initiate crystal growth. 207 g of acetone were then added over 3 hours, followed by 414 g of ethyl acetate over 6 hours. The product was isolated by filtration and dried in vacuo at 50° C. to obtain 36 g of crystalline salt monohydrate LNP023-HCl (Form HB).

Example 3: Preparation of the Designed NV Form of LNP023 Hydrochloride Using Temperature Cycling The LNP023-HCl Form A salt was prepared as described in Example 26d of WO 2015/009616. Suspend 80 g of LNP023 hydrochloride Form A in 409 g of a mixture of acetone and water (acetone: water = 78:22 m: m) and dissolve at approximately 50°C. The solution is cooled to 40°C and 0.32 g of seed crystals are added crystalline salt monohydrate LNP023-HCl (form HB) prepared in accordance with Example 1 to initiate crystal growth. Then temperature cycling was carried out by cooling to 10°C and heating to 35°C for 9 times. 1090 g of ethyl acetate was then added over 12 hours, followed by cooling to 5°C. The product was isolated by filtration and dried in vacuo at 50° C. to obtain 66 g of crystalline LNP023-HCl salt monohydrate (form HB) with columnar particles.

Example 4. Characteristics of the NV form of LNP023 hydrochloride

The title compound has the same ¹ H NMR spectrum as example 26d of WO 2015/009616.

Examples of analyzes and interpretation of results:

Powder X-ray diffraction

PXRD was performed on a Bruker D8 Advance diffractometer with Bragg-Brentano geometry, Cu-Kalfa _1.2 radiation (wavelength 0.15419 nm) with a focusing mirror and a PIXcel solid-state detector. The diffraction pattern was recorded at a tube voltage of 30 to 40 kV and a tube current of 40 mA in steps of 0.015-0.020° 2-theta with an approximate step time of at least 40 s in the angular range from 2° to 40° 2-theta in environmental conditions. Typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, for example, ±0.1° 2-theta. Thus, the diffraction peak of the NV form of LNP023 hydrochloride, which appears, for example, at 9.2° 2-theta, can appear in the range from (9.2-0.2)° to (9.2±0.2)° 2-theta, for example, (9.2-0.1)° to (9.2±0.1)° 2-theta on most X-ray diffractometers under standard conditions.

A representative diffraction pattern of the NV form of LNP023 hydrochloride is shown in FIG. 1 in this document. The corresponding list of peaks is provided in Table 2 below.

The relative intensity, as shown in Table 2, can be changed to a certain extent due to the morphology of the NW-shaped particles.

Fourier transform infrared spectroscopy

The FTIR spectrum was recorded using the attenuated total reflectance (ATR) technique on a Nicolet 6700 spectrometer with a resolution of 4 cm ^-1 at room temperature. The number of scans was 64, and the range was from 650 to 4000 wavenumbers (cm ^-1 ).

To record the spectrum, a sample was applied to the surface of the diamond in powder form using the tip of a spatula. The sample was then pressed against the diamond using a sapphire anvil and the spectrum was recorded. The spectrum of pure diamond was used as the background spectrum. Typical wavenumber accuracy is in the range of approximately ±2 cm ^-1 . Thus, the infrared peak of the IR form of LNP023 hydrochloride described herein at 3452 cm ^-1 can appear between (3452-2) and (3452±2) cm ^-1 on most infrared spectrometers under standard conditions.

A representative FTIR spectrum of the crystalline form of NV described herein is shown in FIG. 3, and the corresponding peak list is given below with typical wavenumber accuracy in the range of ±2 cm ^-1 .

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

Differential scanning calorimetry

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

A representative DSC curve is shown in FIG. 4 further and shows a broad endothermic event that ends at approximately 170°C, followed by exothermic decomposition at approximately 200°C when measured at a heating rate of 10 K/min. More precisely, the endothermic phenomenon is in the range from 35°C to 170°C.

Thermogravimetric analysis

TGA was carried out on a Mettler Toledo DSC/TGA 1 device. The sample (from 10 to 20 mg) was heated in an aluminum crucible with a volume of 100 μL, closed with an aluminum lid, from 30 to 300°C at a speed of 20 K/min. The lid was automatically pierced at the beginning of the measurement. Nitrogen was used as the purge gas (purge rate 50 ml/min).

A representative TGA curve is shown in FIG. 5 continues and shows the stage from approximately 30 to 220°C, which is associated with the loss of water (dehydration) and residual solvents. The weight during the stage was determined to be approximately 4.1%. The water content of the sample was determined to be 3.7% by coulometric Karl-Fischer titration, corresponding to 0.98 mol of water per mol of LNP023 HCl. Water determination was carried out on a Metrohin 831 KF coulometer connected to a 774 Oven sample processor, which was heated to 160°C for measurements.

Dynamic vapor sorption

Dynamic vapor sorption isotherms were recorded using a DVS Advantage device. The measurement cycle began at a relative ambient humidity (RH) of 4 0%. RH was then reduced to 0% in 10% increments. RH was then increased from 0% to 90% in 10% increments and from 90% to 95% in 5% increments in the sorption cycle and then decreased to 0% in the desorption cycle in 10% or 5% increments. Finally, the RH of the air was increased to an ambient relative humidity of 4 0% in 10% increments. The time per step was set to a minimum of 3 hours and a maximum of 6 hours. If an equilibrium state with a constant mass change of 0.002%/min for a minimum of 5 min was reached before the maximum time for all samples tested, then a sequential humidification step was applied until a maximum time of 6 h. If equilibrium was not achieved, then after a maximum time of 6 hours the next humidification stage was applied. The temperature was 25±1.0°C.

In fig. Figure 6 shows the change in the equilibrium mass (delta m in wt% - reference weight at RH 0% along the y-axis) of the NV form of LNP023 hydrochloride during the sorption cycle (marked with triangles) from 0% to 95% RH, as well as during the desorption cycle (marked squares) from 95 to 0% RH (x axis). There may be a difference in molecular weight between 40 and 95% RH of less than 0.2 wt. % and the absence of significant hysteresis between the sorption and desorption curves. Therefore, the IR form of LNP023 hydrochloride described herein can be considered non-hygroscopic. The PXRD of the NV form of LNP023 hydrochloride remains unchanged after the experiment.

Electron microscopy

Electron microscopic images were obtained using a Gemini SE 300 microscope (Zeiss) using an SE detector. As can be seen in FIG. 7a and 7b, the IR form of LNP023 hydrochloride obtained using engineering crystallization techniques, such as those shown in Example 3, contains columnar and equilateral shaped particles, which explains the excellent flow properties of the powder.

Example 5. Preparation of a pharmaceutical composition

The HB form particles obtained in Example 3 are transferred to a pin mill 100UPZ from Hosokawa Alpine AG, Augsburg/Germany. The particles are crushed at a rotor speed of 6000 rpm. and feed speed 15 kg/h.

The resulting equilateral particles in an amount of 50, 100 or 200 mg each are filled into size 0 hard gelatin capsules.

Claims (17)

1. A method for producing the crystalline hydrate form of LNP023 hydrochloride (HB form) having the following formula (A) characterized by a powder X-ray diffraction pattern containing at least five peaks at 2-theta angles selected from (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2) °, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6 ±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)° , (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2)° and (28.0±0.2) when measured at temperatures ranging from 20 to 30 °C using Cu-Kalfa _1.2 radiation with a wavelength of 0.15419 nm, where the method includes the following steps: (i) providing LNP023 hydrochloride in solid form; (ii) suspending the LNP023 hydrochloride provided in step (i) in a first solvent containing acetone and water, in a mass ratio of acetone to water from 60:40 to 90:10, and heating to a temperature ranging from 30 to 56 °C to dissolve a solid to produce a solution; (iii) cooling the solution obtained in step (ii) and adding a second solvent containing acetone and ethyl acetate in a mass ratio of acetone to ethyl acetate from 0.5:3 to 1:1, further cooling to a temperature ranging from about 0 to 25 °C to isolate crystals in the mother solution; (iv) separating at least a portion of the crystals obtained in step (iii) from the mother liquor; (v) optionally washing the isolated crystals obtained in step (iv) with a suitable solvent; And (vi) drying the crystals obtained in step (iv) or (v). 2. The method according to claim 1, including as step (iii) (a) cooling the solution obtained in step (ii), adding LNP023-HCl crystalline salt monohydrate (form HB) seed crystals, followed by reheating the solution; (b) repeating step (a) at least 3 times. 3. The method according to claim 1 or 2, in which the addition of the second solvent in step (iii) is carried out over a period of 12 to 36 hours. 4. Method according to any one of paragraphs. 1-3, wherein in step (v) a suitable solvent is selected from an organic solvent and water. 5. The method according to claim 4, in which the organic solvent is selected from acetone and ethyl acetate. 6. Method according to any one of paragraphs. 1-5, wherein in step (vi), drying of the crystals is performed at a temperature of 70 °C or less. 7. Method according to any one of paragraphs. 1-6, wherein in step (vi), drying of the crystals is performed at ambient pressure or reduced pressure.