Crystalline forms of 5-((3R, 5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-formonitrile

Abstract

Provided herein are crystalline forms of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)-piperidine-1-yl) quinoline-8-formonitrile having a specific morphology, and methods for preparing the same. Also disclosed are methods of making such particles and pharmaceutical compositions comprising such particles.

Description

Technical Field

[0001] This document provides the crystal form of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile with a specific morphology. Methods for preparing such particles and pharmaceutical compositions comprising such particles are also disclosed. Background Technology

[0002] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, also known as Enpatoran, is a compound having the following structure:

[0003] Empatolan is a potent and selective dual Toll-like receptor (TLR) 7 / 8 inhibitor currently in clinical development, including for the treatment of cutaneous and systemic lupus erythematosus (CLE / SLE). The compound can be prepared according to the method provided in WO 2017 / 106607.

[0004] The solid form of a particular chemical compound can vary due to polymorphism and / or particle morphology or shape. Polymorphism refers to the existence of different crystal forms (i.e., the arrangement of molecules within a crystal) of a single compound. A single compound can produce multiple polymorphic forms, each with different solid-state physical properties, such as different solubilities, melting points, stability, dissolution rates, and / or different X-ray diffraction peaks. Furthermore, crystals with the same or different polymorphic forms can exhibit different crystal habits (i.e., the external shape of the crystal particles). Studying the solid form of a drug can be necessary to determine the stability, solubility, and flowability of each form. Unfortunately, the existence of a particular form and its physical properties are unpredictable.

[0005] When used for human treatment, it is important that the crystal form of the therapeutic agent (such as 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile or its salts or hydrates) maintains appropriate chemical stability, solubility, and other physicochemical properties over time and in different batches of manufacture. If physical or chemical properties vary over time and / or between batches, the administration of an effective therapeutic dose can become problematic and may lead to inconsistent dosing or ineffective treatment. Therefore, it is important to select a stable, reproducible form of the agent that possesses advantageous properties for use as a therapeutic agent.

[0006] However, it remains impossible in the art to predict which crystal form of the reagent will have the desired combination of properties and be suitable for human administration, and how to manufacture the reagent in such a crystal form. Summary of the Invention

[0007] In one aspect, this disclosure provides isometric particles of the crystalline form of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile. As used herein, the term "particle" refers to a primary particle.

[0008] In another aspect, this disclosure provides crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile having an aspect ratio of at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0009] The granules described in this article can be used to treat immune diseases, including TLR7 / 8-related diseases such as cutaneous and systemic lupus erythematosus (CLE / SLE).

[0010] In another aspect, this disclosure provides compositions comprising the particles described herein. Embodiments provide pharmaceutical compositions comprising the particles described herein and one or more pharmaceutically acceptable carriers or excipients.

[0011] In another aspect, this disclosure provides a method for treating a disease by administering a pharmaceutical dosage form comprising the particles described herein, the disease being responsive to administration of dual Toll-like receptor (TLR) 7 / 8 inhibitors.

[0012] Another aspect provides a method for treating diseases or conditions regulated by TLR 7 / 8, comprising administering to a mammal requiring such treatment an effective amount of a composition comprising the particles described herein. The method may include administering, alone, a composition comprising the particles described herein, or in combination with one or more particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in other forms, or in combination with compounds having TLR 7 / 8 inhibitory activity.

[0013] Another aspect provides the use of the particles described herein in the manufacture of drugs for treating immune diseases.

[0014] Another aspect provides a method for preparing the particles described herein by suspending 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a solvent and / or recrystallizing from the solvent, said solvent comprising (i) one or more organic solvents and (ii) water. Attached Figure Description

[0015] Figure 1SEM images of anisotropic primary particles of Empatollan are shown (magnification: top: 100x; bottom: 200x).

[0016] Figure 2 ParticleView shows anisotropic Empatollan particles during the cooling crystallization process. TM Image (top: Tr = 53 ℃; bottom: Tr = 44 ℃).

[0017] Figure 3 SEM images of equiaxed Empatollan particles are shown (magnification: top: 50x; bottom: 200x).

[0018] Figure 4 The powder X-ray diffraction pattern of the hemihydrate crystal form H1 is shown.

[0019] Figure 5 The single crystal structure of the hemihydrate crystal form H1 is shown.

[0020] Figure 6 Microscopic images of Empatollan particles are shown (magnification: 50x).

[0021] Figure 7 Microscopic images of Empatollan particles are shown (magnification: 50x).

[0022] Figure 8 Microscopic images of the Empatollan particles are shown (magnification: Sample 5A 20x, Sample 5B 50x, Sample 5C 10x, Sample 5D 20x).

[0023] Figure 9A The aspect ratio distribution of the Empatollan particles in sample 5C was described. Figure 9B An example particle is shown. Detailed Implementation

[0024] This article provides isometric particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile. The isometric particles are generally similar in length, width and height, and include cubic particles, spherical particles and other shapes.

[0025] This disclosure also provides crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile having an aspect ratio of at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9. Aspect ratio is a parameter describing the size of the particles in different dimensions.

[0026] In some embodiments, the aspect ratio of the equiaxed particles described herein is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0027] In some embodiments, the aspect ratio is the ratio of the particle's width to its length. In some embodiments, the length is the maximum Feret diameter, and the width is the minimum Feret diameter. In some embodiments, the length is the maximum distance between any two points on the particle's periphery parallel to the principal axis, and the width is the maximum distance between any two points on the particle's periphery parallel to the secondary axis. The principal axis passes through the object's center of mass, and its direction corresponds to the minimum rotational energy of the shape. The secondary axis passes through the center of mass and is perpendicular to the principal axis.

[0028] In some embodiments, the aspect ratio is determined from a two-dimensional representation of the particle. In other embodiments, the aspect ratio is determined from a three-dimensional representation of the particle. Preferably, the aspect ratio is determined from a two-dimensional representation of the particle and corresponds to the ratio of the minimum Ferrette diameter to the maximum Ferrette diameter.

[0029] The three-dimensional shape of the particles can be determined, for example, by using X-ray microtomography (see Yin et al., Sci Rep. 2016 Apr 21:6:24763) and other 3D imaging systems, such as dynamic image analysis using two cameras (see Liu et al., Chem. Eng. J., 438 (2022) and Rajagopalan et al., Vol. 321, November 2017, pp. 479-493). The two-dimensional shape of the particles can be determined, for example, by optical microscopy. The size and morphology of the particles can also be determined by optical microscopy, for example, as described in USP, Method 776.

[0030] Methods for preparing the particles described herein and pharmaceutical compositions comprising such particles are also disclosed.

[0031] The particles described herein exhibit improved bulk properties and significantly improved manufacturability. The particles may possess one or more of the following characteristics: higher bulk density, higher flowability, improved tableting manufacturability, and / or other improved properties.

[0032] In formulation and manufacturing processes, the use of the particles provided herein can significantly improve the processing or handling of active pharmaceutical ingredients. Therefore, the particles can provide the desired processability. They are easier to handle during dosage form manufacturing, thereby improving the consistency of the API within the dosage form.

[0033] The particles disclosed herein exhibit good tableting properties, including one or more of the following: (i) low tendency to adhere to manufacturing equipment (e.g., the punch of a tableting machine), and / or (ii) good flowability for uniform and repeatable filling of the tableting die. The particles disclosed herein exhibit good flowability to achieve smooth and repeatable tableting of the drug.

[0034] Composition

[0035] The present invention also provides compositions comprising the particles described herein, such as pharmaceutical compositions further described below.

[0036] This document provides compositions comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles, wherein a majority of these particles are equiaxed. For example, in this composition, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95% of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles are equiaxed particles. In some embodiments, the average aspect ratio, mode aspect ratio, or median aspect ratio of the equiaxed particles in the composition is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0037] This document provides compositions comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles, wherein the average aspect ratio, mode aspect ratio, or median aspect ratio of the particles in the composition is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9. In some embodiments, the average aspect ratio, mode aspect ratio, or median aspect ratio is determined from a three-dimensional representation of the particles. Preferably, the average aspect ratio, mode aspect ratio, or median aspect ratio is determined from a two-dimensional representation of the particles.

[0038] The aspect ratio of each individual particle can be determined by selecting a representative number of primary particles, and then the mean, mode, or median aspect ratio can be calculated based on this.

[0039] Body properties

[0040] The 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles and the resulting compositions described herein have improved bulk properties, improved manufacturability, and other improved particle characteristics, such as flowability. The particles described herein may have one or more of the following characteristics: higher bulk density, higher flowability, improved tableting manufacturability, and / or other improved characteristics.

[0041] The bulk density of compositions containing the particles described herein may be greater than about 0.3 g / cm³. 3 Greater than approximately 0.4 g / cm 3 Greater than approximately 0.5 g / cm 3 Greater than approximately 0.55 g / cm³ 3 Greater than approximately 0.6 g / cm³ 3 Greater than approximately 0.65 g / cm³ 3 or greater than approximately 0.7 g / cm³ 3 In a further embodiment, the bulk density of the composition comprising the particles described herein is less than about 0.95 g / cm³. 3 Less than approximately 0.9 g / cm³ 3 Less than approximately 0.85 g / cm³ 3 Or less than approximately 0.8 g / cm³ 3 In some embodiments, the bulk density of the composition comprising the particles described herein is about 0.5 g / cm³. 3 To approximately 0.95 g / cm 3 Approximately 0.55 g / cm³ 3 To approximately 0.9 g / cm 3 Approximately 0.6 g / cm 3 To approximately 0.85 g / cm 3 Or approximately 0.7 g / cm 3 To approximately 0.8 g / cm 3 The bulk density of a composition can be determined as the ratio of the mass of an untamped powder sample to its volume (including the contribution of the interparticle void volume). Therefore, the bulk density depends on the density of the particles and the spatial arrangement of the particles in the sample.

[0042] As used herein, the term “about” when used in relation to a value (e.g., an upper limit of a range or reference value, such as a reference expression level for a biomarker) refers to any value reasonably close to the referenced value, for example, any value less than 10% lower or higher than the referenced value. In some implementations, “about” refers to an exact value.

[0043] The flow function coefficient (ffc) of the compositions described herein may be greater than about 4; greater than about 5; greater than about 6; greater than about 7; or greater than about 8. Powder flow is important during tableting to ensure the uniformity of API powder flow and distribution into the tableting die. This ensures uniform tablet weight and the production of tablets with consistent and repeatable properties.

[0044] The flow function coefficient (ffc) test is performed under controlled environmental conditions (i.e., 22°C and 35% relative humidity) to reduce or prevent deviations in flowability caused by hygroscopic effects. The consistency of environmental conditions (±2°C; ±5% RH) should be checked directly before starting the measurement. Measurements can be performed with n=1. Fill the bottom ring of the shear cell. Pretreatment (e.g., sieving to depolymerize) may be necessary. For very fine, blocky solids, filling the bottom ring with a sieve is advantageous. Input the test parameters (e.g., material, batch number, method) into the RST control software and follow the instructions of the RST control software during the measurement process. Measurements can be saved as an input file (.inp) for further analysis and as an output file (.out) as a PDF file of the raw data document. Additionally, a test time file (.FTD) can be saved to view the raw data. The evaluation of fffc and cohesion values ​​is determined by constructing Mohr circles using the RST-Control 95 XS software. Standard data evaluation parameters are:

[0045] In a further embodiment, the average particle size, mode, or median particle size d90 of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition described herein is less than about 600 μm, less than about 500 μm, less than about 450 μm, or less than about 400 μm. In a further embodiment, the average particle size, mode, or median particle size d90 of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition described herein is greater than about 1 μm, greater than about 10 μm, greater than about 50 μm; or greater than about 100 μm. In a further embodiment, the average particle size, mode particle size, or median particle size d90 of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition described herein is about 1 to about 600 μm, about 10 to about 500 μm, about 50 to about 450 μm, or about 100 to about 400 μm.

[0046] Methods for preparing particles

[0047] The inventors discovered that suspending or crystallizing 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in anhydrous organic solvents results in highly anisotropic particles. However, it has been found that suspending or crystallizing in water or a mixture of organic solvent and water produces more isotropic equiaxed particles. The compound has poor solubility in water, resulting in low crystallization efficiency from water and limited control over particle size distribution from aqueous suspensions. In contrast, using an organic solvent in a mixture with water to suspend or crystallize the compound allows for better control over particle size and provides a preferred particle shape.

[0048] Therefore, a method for preparing particles involves: dissolving and / or suspending 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a solvent as described below, optionally wet-milling the suspension / solution, optionally heating and cooling the suspension / solution, and separating the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles from the solvent.

[0049] The method for preparing 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles includes the following steps: (i) Preparing a suspension of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a solvent comprising water, more preferably comprising one or more organic solvents and water; (ii) Optionally, the suspension may be heated to the recrystallization temperature; (iii) Stir the suspension at ambient temperature or recrystallization temperature for a period of time; (iv) Optionally cooling the suspension; and (v) Separating 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles from the solvent.

[0050] Optionally, there may be a further wet polishing step, for example, performed directly after converting to an equiaxed habit. The wet polishing step may be performed directly after step (iii) of the method described above.

[0051] Heating the suspension promotes the partial or complete dissolution of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in the solvent. Optionally, heating can be carried out at temperatures ranging from room temperature (e.g., 25°C) to the boiling point of the solvent. In embodiments, the suspension is heated to a temperature equal to or higher than 35°C, equal to or higher than 35°C, equal to or higher than 40°C, equal to or higher than 45°C, or equal to or higher than 50°C. Preferably, stirring or other mixing is applied to the suspension during heating. The suspension is stirred at a selected recrystallization temperature for 30 minutes to a day or longer. In embodiments, the suspension is stirred for a period of time, from 30 minutes to about 24 hours, from 1 hour to 24 hours, or from 2 hours to 24 hours.

[0052] Optionally, the suspension is cooled to room temperature or lower. In embodiments, the suspension is cooled to a final temperature of room temperature to 0°C, 0°C to 10°C, or 0°C to 5°C. Preferably, the cooling temperature is reached slowly, i.e., at a rate of 1°C / min or slower, 0.5°C / min or slower, 0.4°C / min or slower, 0.3°C / min or slower, or 0.2°C / min or slower. Preferably, the suspension is stirred or otherwise mixed during cooling. The suspension may be held at the cooling temperature for a period of time before the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles are separated from the solvent. The suspension may be held at the cooling temperature for 10 minutes to 4 hours, 20 minutes to 2 hours, or 30 minutes to 1.5 hours.

[0053] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles can be separated from the solvent by any means known in the art, including, for example, filtration or centrifugation.

[0054] The solvent used to produce the granules is water, preferably in combination with one or more organic solvents. The organic solvent is miscible with at least 0.1% (v / v) water; miscible with at least 0.5% (v / v) water; miscible with at least 1% (v / v) water; or miscible with at least 2% (v / v) water.

[0055] Solvents comprising one or more organic solvents and water may contain 80 to 99.9% (v / v) of one or more organic solvents and 0.1 to 20% (v / v) of water; 85 to 99.9% (v / v) of one or more organic solvents and 0.1 to 15% (v / v) of water; 90 to 99.9% (v / v) of one or more organic solvents and 0.1 to 10% (v / v) of water; 98 to 99.9% (v / v) of one or more organic solvents and 0.1 to 2% (v / v) of water; or 99 to 99.8% (v / v) of one or more organic solvents and 0.5 to 1.5% (v / v) of water.

[0056] Organic solvents can be esters, ethers, alcohols, ketones, or combinations thereof.

[0057] Ester solvents can have the formula R 1 -OC(=O)-R 2 , where R 1 Selected from C1 to C5 alkyl or C2 to C5 alkenyl; and R 2 Selected from C1 to C5 alkyl or C2 to C5 alkenyl. Exemplary ester solvents include, but are not limited to, methyl acetate; ethyl acetate; n-propyl acetate; isopropyl acetate; n-butyl acetate; isobutyl acetate; sec-butyl acetate; tert-butyl acetate, etc.

[0058] Ether solvents can have the formula R 3 -OR 4 , where R 3 Selected from C1 to C5 alkyl or C2 to C5 alkenyl; and R 4 Selected from C1 to C5 alkyl or C2 to C5 alkenyl. Exemplary ether solvents include, but are not limited to, methyl tert-butyl ether; methyl isopropyl ether; ethyl isopropyl ether; diisopropyl ether, etc.

[0059] The alcohol solvent can be selected from C2 to C6 alcohols, glycols, and triols. Exemplary alcohol solvents include, but are not limited to, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, etc.

[0060] The ketone solvent can be selected from C3 to C6 ketones. Exemplary ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, 2-butanone, 2-pentanone, 3-pentanone, etc.

[0061] A preferred solvent for preparing 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles is a mixture comprising isopropyl acetate and water. Water may be present in the isopropyl acetate at a concentration of 0.1% to 2% (v / v); 0.5% to 2% (v / v); or 0.5% to 1.5% (v / v). In one embodiment, the solvent is isopropyl acetate containing 1% (v / v) water.

[0062] Wet milling can be used to control or reduce the size of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles and / or ensure a more uniform particle size distribution. In wet milling, particles are suspended in a liquid and passed through a wet mill. The mixture can be recycled through the wet mill until desired properties, such as particle size and / or uniformity, are obtained. The liquid used for wet milling is the solvent described herein.

[0063] Wet milling can be performed using techniques, equipment, and conditions known in the art, including, for example, planetary mills, colloid mills, media mills, ball mills, disc mills, and conical mills. Those skilled in the art will understand that various aspects of the milling process, such as milling time, milling speed (rotation speed), temperature, etc., can be modified to achieve the desired particle size and / or uniformity.

[0064] Wet milling times can range from several minutes to several hours, depending on the desired particle size. Wet milling times can range from 5 minutes to 200 minutes. In some embodiments, wet milling is performed at speeds from about 500 rpm to about 50,000 rpm, for example, from 3,000 rpm to 25,000 rpm. There are no particular limitations on the temperature of wet milling. It can be performed at low temperatures (e.g., 0°C) and high temperatures (e.g., 60°C). Preferably, wet milling is performed at temperatures below 50°C, for example, 25°C.

[0065] Polymorphic form

[0066] The 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles described herein may comprise one or more polymorphic forms of the compound. In embodiments, the polymorphic form may be the anhydrous form of the compound. More preferably, the polymorphic form of the compound is a hydrate or a hemihydrate, and most preferably a hemihydrate. In embodiments, the particles comprise different polymorphic forms of the compound. In some embodiments, the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a majority of the particles of the composition is in the hemihydrate form, such as polymorph H1 described below. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the particles have 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a hemihydrate form, such as crystal form H1.

[0067] As used herein, the term "polymorph" or "polymorphic form" refers to the different crystallographic forms of a substance. The actual physical properties of a polymorphic form are influenced by the conformation and orientation of molecules within the unit cell, which defines the specific polymorphic form of the substance. Different polymorphs of the same compound can have different physical, chemical, biological, and / or spectroscopic properties. For example (but not limited to), different polymorphic forms can have different stability. A particular polymorphic form may be more sensitive to relative humidity, heat, and / or light. In some cases, differences in stability are due to changes in chemical reactivity, such as (but not limited to) different oxidation processes. Such properties can provide a more suitable product quality, for example, dosage forms composed of a particular polymorph are more resistant to discoloration. Alternatively or additionally, a particular polymorphic form can have different dissolution rates, thereby providing, for example, a more desirable bioavailability. Polymorphs can be detected, identified, classified, and characterized using well-known techniques, such as, but not limited to, powder X-ray diffraction (PXRD), single-crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, quantitative analysis, solubility, and dissolution rate.

[0068] As used herein, when referring to data shown in spectra and / or graphs, the term "peak" refers to a feature that a person skilled in the art would not consider to be attributable to background noise.

[0069] In the embodiments, the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile of the particles is in the polymorphic form H1 of the crystalline hemihydrate as described herein.

[0070] The characteristic of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate crystal form H1 is that it contains one or more peaks in powder X-ray diffraction (PXRD) (Cu-Kα1 radiation) expressed in degrees 2θ ± 0.2°, wherein the peaks include 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9. The powder X-ray diffraction pattern can be obtained using the standard techniques described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia, and by... Figure 4 The X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe Stadi P 611 KL transmission diffractometer) was used to characterize it.

[0071] Single-crystal X-ray structure data for morphology H1 can be obtained at 298 K (Oxford Supernova single-crystal X-ray diffractometer with graphite monochromator and CCD detector). The hemihydrate morphology H1 is in orthogonal space group... P Crystallization in 212121, lattice parameters a = 10.7499 ± 0.1 Å, b = 16.4119 ± 0.1 Å, c = 17.5927 ± 0.1 Å, and α = γ= β = 90°. from Figure 5 The single crystal structure shows that crystal form H1 represents a hemihydrate form.

[0072] Crystalline form H1 is characterized by the following physical properties. Thermal behavior shows dehydration <100 °C, followed by melting of non-crystalline Al at ~165 °C. TGA shows a weight loss of ~2.9% (w / w) up to 130 °C, which can be attributed to the degradation of 0.5 moles of water. DSC scans of crystalline form H1 were obtained on a Mettler-Toledo DSC1 at a heating rate of 5 K / min, purged with nitrogen gas at a rate of 50 mL / min. TGA scans of crystalline form H1 were obtained on a Mettler-Toledo TGA 851 at a heating rate of 5 K / min, purged with nitrogen gas at a rate of 50 mL / min.

[0073] Water vapor adsorption behavior was observed across the entire relative humidity (RH) range of 0–98%, with an adsorption level of ~0.5% (w / w). According to the European Pharmacopoeia (Section 5.11), the hemihydrate crystal form H1 is classified as non-hygroscopic. Water vapor adsorption isotherms were obtained on the DVS intrinsic system of the SMS.

[0074] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate, crystal form H1, is characterized by two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or each of the following PXRD peaks: 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9. All PXRD peaks presented in this paper were measured at 2θ degrees using Cu-Kα1 radiation, including ±0.2 degrees.

[0075] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate form H1 is characterized by the presence of a PXRD peak at 13.4.

[0076] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate form H1 is characterized by PXRD peaks at 9.7 and 13.4.

[0077] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate form H1 is characterized by PXRD peaks at 7.2, 9.7 and 13.4.

[0078] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate form H1 is characterized by PXRD peaks at 7.2, 9.7, 13.4 and 22.2.

[0079] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hemihydrate form H1 is characterized by PXRD peaks at 7.2, 9.7, 13.4, 21.5 and 22.2.

[0080] The 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles with polycrystalline hemihydrate form H1 described herein offer improved physical and high chemical stability. For example, under ambient conditions, particles of form H1 offer improved stability compared to the enantiotropic behavior of certain anhydrous polycrystalline forms. Based on this high physical stability, pharmaceutical formulations of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile with polycrystalline hemihydrate form H1 may not require protective packaging materials.

[0081] Pharmaceutical Composition

[0082] A further aspect provides pharmaceutical compositions comprising the particles described herein and one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, adjuvant, excipient, or delivery system that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers or excipients that can be used in pharmaceutical compositions include any such excipients known in the art.

[0083] Pharmaceutically acceptable compositions can be administered orally in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. For oral tablets, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient can be combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may optionally be added if desired.

[0084] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the granules described herein are mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or a) fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin or bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. For capsules, tablets and pills, the dosage form may optionally contain a buffer.

[0085] Similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules, employing excipients such as lactose or lactose components and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They optionally contain light-blocking agents and may also have compositions that release the active ingredient only in one or more portions of the intestine or preferentially in one or more portions of the intestine, optionally in a sustained-release manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules, employing excipients such as lactose or lactose components and high molecular weight polyethylene glycol.

[0086] In another aspect, this disclosure provides for the use of the pharmaceutical compositions disclosed herein as medicines.

[0087] In another aspect, this disclosure provides a method for treating a disease by administering a pharmaceutical dosage form comprising the particles described herein to a patient in need, the disease being responsive to administration of dual Toll-like receptor (TLR) 7 / 8 inhibitors. As used herein, the terms “patient” or “subject” refer to an animal, preferably a mammal, and most preferably a human.

[0088] Another aspect provides a method for treating diseases or conditions regulated by TLR 7 / 8, comprising administering to a mammal requiring such treatment an effective amount of a composition comprising the particles described herein. The method may include administering, alone, a composition comprising the particles described herein, or in combination with one or more particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in other forms, or in combination with compounds having TLR 7 / 8 inhibitory activity.

[0089] This disclosure also relates to a method of treating or preventing a disease or condition (e.g., a TLR7 / 8-related disease or condition) in a subject, comprising administering to the subject an effective amount of a composition comprising the particles described herein.

[0090] Diseases or conditions treated or prevented by administering a composition containing the particles described herein can be autoimmune diseases, such as those characterized by arthralgia, positive antinuclear antibodies, malaise, or discoid rash. In some aspects, autoimmune diseases are associated with the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease does not manifest as skin, muscle tissue, and / or connective tissue symptoms in an individual. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases that can be treated or prevented by administering a composition containing 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), lupus, such as systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE), type 1 diabetes, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel syndrome (IBD), scleroderma, Sjogren's disease, vitiligo, myositis, such as dermatomyositis or polymyositis, pemphigus vulgaris, and pemphigus foliaceus. Autoimmune diseases include, but are not limited to, polyangiitis obliterans, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases can also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cryopathies.

[0091] In some respects, autoimmune diseases are selected from the following groups: arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic arthritis, and irritable bowel syndrome.

[0092] In other respects, autoimmune diseases are selected from the following groups: pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 diabetes. In some respects, autoimmune diseases are rheumatoid arthritis. In some respects, autoimmune diseases are autoimmune pancreatitis (AIP). In some respects, autoimmune diseases are glomerulonephritis. In some respects, autoimmune diseases are pyelonephritis. In some respects, autoimmune diseases are sclerosing cholangitis. In some respects, autoimmune diseases are psoriasis. In some respects, autoimmune diseases are rheumatoid diseases or conditions.

[0093] In other respects, autoimmune diseases are selected from the following group: systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin diseases, and multiple sclerosis. Autoimmune diseases can be cutaneous and systemic lupus erythematosus (CLE / SLE). In some respects, any of the above autoimmune diseases are TLR7 / 8-related autoimmune diseases.

[0094] Other implementation methods

[0095] This disclosure also provides the following embodiments E1 to E50: E1. Isometric particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile.

[0096] E2. Crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, wherein the aspect ratio of the particles is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8 or at least about 0.9.

[0097] E3. Particles as described in E1 or E2, wherein the crystal form of the particles is a hydrate or a hemihydrate, and most preferably a hemihydrate.

[0098] E4. Particles as described in E3, wherein the crystal form of the particles is a crystalline hemihydrate polymorph, the crystalline hemihydrate polymorph being characterized by one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2θ ± 0.2° and include 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9.

[0099] E5. Particles as described in E4, wherein the crystalline hemihydrate polymorph is characterized by two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or each of the following PXRD peaks: 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9.

[0100] E6. Particles as described in E4 or E5, wherein the crystalline hemihydrate polymorph is characterized by orthorhombic space group P212121 with lattice parameters a = 10.7499 ± 0.1 Å, b = 16.4119 ± 0.1 Å, c = 17.5927 ± 0.1 Å, and α = γ = β = 90°.

[0101] E7. Crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, wherein the aspect ratio of the particles is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9, and

[0102] The particle is a crystalline hemihydrate polymorph, characterized by (1) one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2θ ± 0.2° and include 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4 and 26.9, and (2) an orthogonal space group P212121 with lattice parameters a = 10.7499 ± 0.1 Å, b = 16.4119 ± 0.1 Å, c = 17.5927 ± 0.1 Å, and α = γ = β = 90°.

[0103] E8. A composition comprising particles as described in any one of E1 to E7.

[0104] E9. A composition comprising crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, wherein the average aspect ratio, mode aspect ratio, or median aspect ratio of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0105] E10. A composition comprising crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, wherein more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition are equiaxed particles. E11. The composition of any one of E8 to E10, wherein more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles in the composition are of the crystal form of any one of E3 to E6.

[0106] E12. A composition comprising crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, The composition wherein the average aspect ratio of the particles is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9, and The crystal form of particles with a content greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95% is a crystalline hemihydrate polymorph, characterized by (1) one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2θ ± 0.2° and include 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9, and (2) an orthorhombic space group P212121 with lattice parameters a = 10.7499 ± 0.1 Å, b = 16.4119 ± 0.1 Å, c = 17.5927 ± 0.1 Å, and α = γ = β = 90°.

[0107] E13. A composition comprising crystalline particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, The average aspect ratio of the particles in the composition is at least about 0.5, and The crystal form of more than about 80% of the particles is a crystalline hemihydrate polymorph, characterized by (1) one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2θ ± 0.2° and include 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4 and 26.9, and (2) an orthogonal space group P212121 with lattice parameters a = 10.7499 ± 0.1 Å, b = 16.4119 ± 0.1 Å, c = 17.5927 ± 0.1 Å, and α = γ = β = 90°.

[0108] E14. The composition of any one of E8 to E13, wherein the bulk density of the composition is greater than about 0.3 g / cm³. 3 Greater than approximately 0.4 g / cm³ 3 Greater than approximately 0.5 g / cm³ 3 Greater than approximately 0.55 g / cm³ 3 Greater than approximately 0.6 g / cm³ 3 Greater than approximately 0.65 g / cm³ 3 or greater than approximately 0.7 g / cm³ 3 .

[0109] E15. The composition of any one of E8 to E14, wherein the bulk density of the composition is less than about 0.95 g / cm³. 3 Less than approximately 0.9 g / cm³ 3 Less than approximately 0.85 g / cm³ 3 Or less than approximately 0.8 g / cm³ 3 .

[0110] E16. The composition as described in any one of E8 to E13, wherein the bulk density of the composition is about 0.5 g / cm³. 3 To approximately 0.95 g / cm 3 Approximately 0.55 g / cm³ 3 To approximately 0.9 g / cm 3 Approximately 0.6 g / cm 3 To approximately 0.85 g / cm 3 Or approximately 0.7 g / cm 3 To approximately 0.8 g / cm 3 .

[0111] E17. The composition of any one of E8 to E16, wherein the flow function coefficient (ffc) of the composition is greater than about 4; greater than about 5; greater than about 6; greater than about 7; or greater than about 8.

[0112] E18. The composition of any one of E8 to E17, wherein the average particle size, mode particle size, or median particle size d90 of the particles in the composition is less than about 600 μm, less than about 500 μm, or less than about 400 μm.

[0113] E19. The composition of any one of E8 to E17, wherein the average particle size, mode particle size, or median particle size d90 of the particles in the composition is about 50 to about 500 μm, about 100 to about 450 μm, or about 150 to about 400 μm.

[0114] E20. A composition as described in any one of E8 to E19, wherein the composition is a pharmaceutical composition and comprises one or more pharmaceutically acceptable carriers.

[0115] E21. A pharmaceutical composition as described in E20, wherein the composition is a tablet for oral administration.

[0116] E22. Use of the pharmaceutical composition as described in E20 or E21 as a medicament.

[0117] E23. The pharmaceutical composition as described in E20 or E21, in a method of treating or preventing TLR7 / 8-related autoimmune diseases.

[0118] E24. The pharmaceutical composition as described in E23, wherein the TLR7 / 8-related autoimmune disease is selected from the group consisting of: rheumatoid arthritis, autoimmune pancreatitis, lupus, systemic lupus erythematosus, cutaneous lupus erythematosus, type I diabetes, multiple sclerosis, antiphospholipid syndrome, sclerosing cholangitis, systemic arthritis, irritable bowel syndrome, scleroderma, Sjögren's syndrome, vitiligo, myositis, dermatomyositis, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease, autoimmune dermatitis, uveitis, pernicious anemia, and hypoparathyroidism.

[0119] E25. A method for preparing 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles, the method comprising the following steps: (i) Preparing a suspension of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile in a solvent comprising water and optionally, comprising water and one or more organic solvents, preferably comprising both one or more organic solvents and water; (ii) Optionally, the suspension may be heated to the recrystallization temperature; (iii) Stir the suspension at ambient temperature or recrystallization temperature for a period of time; (iv) Optionally, the suspension is wet-milled; (v) Optionally cooling the suspension; and (vi) Separate the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles from the solvent.

[0120] E26. The method as described in E25, wherein the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles are crystalline hemihydrates.

[0121] E27. The method as described in E26, wherein the crystalline hemihydrate is in polymorphic form H1.

[0122] E28. The method of any one of E25 to E27, wherein the heating in step (ii) comprises heating the suspension to a recrystallization temperature equal to or higher than 35°C, or equal to or higher than 40°C, or equal to or higher than 45°C, or equal to or higher than 50°C.

[0123] E29. The method of any one of E25 to E28, wherein step (iii) comprises stirring the suspension for a period of time, from 30 minutes to about 24 hours, from 1 hour to 24 hours, or from 2 hours to 24 hours.

[0124] E30. The method of any one of E25 to E29, wherein step (iv) comprises cooling the suspension to a temperature below room temperature to 0°C, 0°C to 10°C, or 0°C to 5°C.

[0125] E31. The method as described in E30, wherein the cooling temperature is achieved by cooling the suspension at a rate of 1°C / min or slower, at 0.5°C / min or slower, at 0.4°C / min or slower, at 0.3°C / min or slower, or at 0.2°C / min or slower.

[0126] E32. The method of any one of E25 to E31, wherein the suspension may be maintained at a cooling temperature for 10 minutes to 4 hours, 20 minutes to 2 hours, or 30 minutes to 1.5 hours.

[0127] E33. The method of any one of E25 to E32, wherein the solvent comprises one or more organic solvents and water.

[0128] E34. The method as described in E33, wherein the one or more organic solvents and water may comprise 80 to 99.9% (v / v) of one or more organic solvents and 0.1 to 20% (v / v) of water; or 85 to 99.9% (v / v) of one or more organic solvents and 0.1 to 15% (v / v) of water; or 90 to 99.9% (v / v) of one or more organic solvents and 0.1 to 10% (v / v) of water; or 98 to 99.9% (v / v) of one or more organic solvents and 0.1 to 2% (v / v) of water; or 99 to 99.8% (v / v) of one or more organic solvents and 0.5 to 1.5% (v / v) of water.

[0129] E35. The method as described in E33 or E34, wherein the one or more organic solvents are selected from esters, ethers, alcohols, ketones, or combinations thereof.

[0130] E36. The method of any one of E25 to E35, wherein more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the particles are equiaxed.

[0131] E37. The method of any one of E25 to E36, wherein the average aspect ratio, mode aspect ratio, or median aspect ratio of said particles is at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0132] E38. The method of any one of E25 to E37, wherein the bulk density of the resulting particulate composition is greater than about 0.3 g / cm³. 3 Greater than approximately 0.4 g / cm 3 Greater than approximately 0.5 g / cm 3 Greater than approximately 0.55 g / cm³ 3 Greater than approximately 0.6 g / cm³ 3 Greater than approximately 0.65 g / cm³ 3 or greater than approximately 0.7 g / cm³ 3 .

[0133] E39. The method of any one of E25 to E38, wherein the bulk density of the resulting particulate composition is less than about 0.95 g / cm³. 3 Less than approximately 0.9 g / cm³ 3 Less than approximately 0.85 g / cm³ 3 Or less than approximately 0.8 g / cm³3 .

[0134] E40. The method of any one of E25 to E39, wherein the flow function coefficient (ffc) of the resulting particulate composition is greater than about 4; or greater than about 5; or greater than about 6; or greater than about 7; or greater than about 8.

[0135] E41. The method of any one of E25 to E40, wherein the average particle size, mode particle size, or median particle size d90 of the particles in the resulting composition is less than about 600 μm, less than about 500 μm, or less than about 400 μm.

[0136] E42. The method of any one of E25 to E40, wherein the average particle size, mode particle size, or median particle size d90 of the particles in the resulting composition is about 50 to about 500 μm, about 100 to about 450 μm, or about 150 to about 400 μm.

[0137] E43. 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles, which can be obtained by any of the methods described in E25 to E42.

[0138] E44. Particles as described in E43, having the characteristics of particles as described in any one of E1 to E7.

[0139] E45. A composition comprising particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, wherein the particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile can be obtained by any one of E25 to E42.

[0140] E46. A composition as described in E45, wherein the composition is a pharmaceutical composition and comprises one or more pharmaceutically acceptable carriers.

[0141] E47. A pharmaceutical composition as described in E46, wherein the composition is a tablet for oral administration.

[0142] E48. Use of the pharmaceutical composition as described in E46 or E47 as a medicament.

[0143] E49. The pharmaceutical composition as described in E46 or E47, in a method of treating or preventing TLR7 / 8-related autoimmune diseases.

[0144] E50. The pharmaceutical composition as described in E49, wherein the TLR7 / 8-related autoimmune disease is selected from the group consisting of: rheumatoid arthritis, autoimmune pancreatitis, lupus, systemic lupus erythematosus, cutaneous lupus erythematosus, type I diabetes, multiple sclerosis, antiphospholipid syndrome, sclerosing cholangitis, systemic arthritis, irritable bowel syndrome, scleroderma, Sjögren's syndrome, vitiligo, myositis, dermatomyositis, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease, autoimmune dermatitis, uveitis, pernicious anemia, and hypoparathyroidism.

[0145] Example

[0146] Example 1: Preparation of the anisotropic form of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile

[0147] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile (API) was prepared according to the method of WO 2017 / 106607 (compound 73).

[0148] Cooling crystallization in isopropyl acetate: Approximately 35 g of API was weighed into a 400 mL reactor (equipped with a top stirrer and reflux device) at an EasyMax 402 station. The reactor was sealed with a PTFE cap and 256 g of isopropyl acetate was added. The 4-blade propeller stirrer was set to 200 rpm. The reactor was heated to 60 °C as quickly as possible, and then further heated to 75 °C at 0.5 K / min. A clear solution was observed at approximately 70 °C. The solution was cooled to 65 °C at 0.5 K / min, and then further cooled to 5 °C at 0.1 K / min. Nucleation occurred at approximately 53 °C, and the growth of fibrous particles was observed. ParticleView of anisotropic particles during cooling crystallization. TM Image as Figure 2 As shown (top: Tr = 53 ℃; bottom: Tr = 44 ℃). The suspension was filtered through a vacuum filter using a Buchner funnel and cellulose filter paper (Watman size 2). The resulting powder was dried at 40 ℃ under a stream of dry nitrogen for 24 hours.

[0149] SEM images of anisotropic primary particles are shown below. Figure 1 As shown (magnification: left: 100x; right: 200x). The bulk properties of the anisotropic particles are reported in Table 1.

[0150] Table 1

[0151] Example 2: Preparation of the anisotropic form of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile

[0152] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile (API) was prepared according to the method of WO 2017 / 106607 (compound 73).

[0153] The corresponding amounts of API were suspended in organic solvents at ambient temperature or 50 °C, as shown in Table 2. Each suspension was stirred for 1 day using a magnetic stir bar, and then separated by filtration.

[0154] Table 2

[0155] The results of sample analysis using an optical microscope are reflected in Figure 6 In the middle. For example Figure 6 As shown, it was found that suspension or crystallization in anhydrous organic solvents leads to anisotropic particles.

[0156] Example 3: Preparation of isometric particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile

[0157] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile (API) was prepared according to the method of WO 2017 / 106607 (compound 73).

[0158] Suspension in isopropyl acetate and water (1% v / v): Weigh approximately 20 g of API into a 100 mL reactor (equipped with a top stirrer and reflux device) at an EasyMax 402 station. Seal the reactor with a PTFE cap and add 105 mL of isopropyl acetate. Set the jacket temperature to 25 °C and stir the suspension at 250 rpm (4-blade propeller upward). Stir the suspension for 30 minutes, then set the stirrer to 400 rpm and stir for 90 minutes. Then cool the reactor temperature to 5 °C at 0.2 K / min. Stir the suspension at 5 °C for 30 minutes, then filter through a vacuum using a Buchner funnel and cellulose filter paper (Watman size 2). Dry the resulting powder at ambient temperature under a stream of dry nitrogen for 18 hours.

[0159] SEM images of equiaxed particles as follows Figure 3 As shown (magnification: top: 50x; bottom: 200x).

[0160] The bulk properties of the equiaxed particles prepared by this method are reported in Table 3.

[0161] Table 3

[0162] Example 4: Preparation of isometric particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile

[0163] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile (API) was prepared according to the method of WO 2017 / 106607 (compound 73).

[0164] Milligram-level suspensions in organic solvents / water: As shown in Table 4, the corresponding amounts of API were suspended in the solvents at ambient temperature and 50 °C. Each suspension was stirred for 1 day using a magnetic stir bar.

[0165] Table 4

[0166] The analysis results are reflected in Figure 7 As shown in the figure, suspension or crystallization in water or a mixture of water and an organic solvent (even in very small amounts of water) exhibits more isotropic, equiaxed particles. The compound has poor solubility in water, resulting in low crystallization efficiency and poor control over particle size distribution in the suspension. Using an organic solvent in a mixture with water allows for control over the preferred equiaxed particle size.

[0167] Example 5: Preparation of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile particles

[0168] 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile (API) was prepared according to the method of WO 2017 / 106607 (compound 73).

[0169] The API is then further processed in four different ways.

[0170] Sample 5A: The API was suspended in water and heated to 30 °C. The suspension was stirred for 18 hours and then filtered. It was dried at 70 °C under vacuum (20-50 mbar) for 35 hours.

[0171] Sample 5B: API was suspended in EtOH and 1 M K₂CO₃ solution, heated to 60 °C and stirred for 60 min. The solution was cooled to 25 °C as soon as possible and subjected to fine filtration. The solution was reheated to 60 °C, and water was added over 40 min. The suspension was stirred for 60 min and cooled to 10 °C at 1 K / min. Finally, the cooled suspension was stirred for 4 hours and filtered. The filter cake was dried at 70 °C and 320-70 mbar for 36 hours.

[0172] Sample 5C: API was slurried in I-PrOAc / water (1%) at 25 °C for 120 min, then cooled to 5 °C at 0.2 K / min, and separated into solid and liquid components by filtration.

[0173] Sample 5D: API was slurried in I-PrOAc / water (1%) at 50 °C, wet-milled under ambient conditions, and the suspension was heated to 60 °C at 0.5 K / min and held at 60 °C for 1 hour. Ostwald ripening was performed by cooling to 5 °C at 0.2 K / min, and solid / liquid separation was performed by filtration.

[0174] Then the particle size of the sample was measured.

[0175] Optical Microscopy: Particle size was determined using an optical microscope with a calibrated Leica DM. The sample was dispersed in silicone oil to ensure good particle distribution and prevent agglomeration. A portion of the dispersed sample was prepared on a microscope slide and covered with a coverslip. The particle size, i.e., the maximum and minimum Ferrette diameters, was measured using Leica Application Suite version 4.12.0 image analysis software. The aspect ratio was calculated according to the following equation: Aspect Ratio = Minimum Ferrette Diameter / Maximum Ferrette Diameter. The analysis results are shown in Table 5, and representative images are shown below. Figure 8 As shown.

[0176] Table 5

[0177] As shown in Table 5, samples 5C and 5D show that suspending API in organic solvents and water produced equiaxed particles with an average aspect ratio higher than 0.3, while samples suspending API in water or organic solvents alone resulted in columnar or needle-like particles with a low aspect ratio.

[0178] Morphologi G3: The aspect ratio of sample 5C was determined using the Morphologi G3 (Malvern) automated image analysis system (calculated as the ratio of width to length, where length is the maximum distance between any two points on the periphery of the particle parallel to the primary axis, and width is the maximum distance between any two points on the periphery of the particle parallel to the secondary axis). Approximately 19 mm... 3 The sample was dispersed on the imaging plate at a pressure of 1 bar, with an injection time of 20 ms and a sampling time of 60 s. Measurements were performed in Z-stacking mode at 5x magnification. Particle properties were determined using Morphologi software version 8.23. The following filters were applied to exclude secondary particles and underweight particles: Circularity: <0.85 Convexity: <0.90 Length: <100 µm Area in pixels: <1300 Then, the calculated major and minor diameters after volume conversion are determined as follows: D[v, 0.1]: 0.49 (the aspect ratio of 10% of volume-weighted particles is less than 0.49) D[v, 0.5]: 0.62 (50% of the volume-weighted particles have an aspect ratio less than 0.62) D[v, 0.9]: 0.83 (90% of volume-weighted particles have an aspect ratio less than 0.83) The aspect ratio distribution of the particles and an exemplary particle are shown in Figure 9. As the data shows, the aspect ratio determined by automated image analysis is consistent with the average aspect ratio (value 0.59 σ0.14) determined by optical microscopy for sample 5C.

Claims

1. A composition comprising crystalline particles of 5-((3R,5S)-3-amino-5- (trifluoromethyl)-piperidin-l-yl)quinoline-8-carbonitrile, wherein the average aspect ratio of the 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-l-yl)quinoline-8- carbonitrile particles in the composition is at least about 0.

3.

2. The composition of claim 1, wherein the majority of the particles are in the crystalline form of a hydrate or a hemihydrate.

3. The composition of claim 2, wherein the majority of the particles are crystalline hemihydrate polymorphs characterized by one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2Q ± 0.2° comprising 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.

9.

4. The composition of claim 2, wherein the majority of the particles are crystalline hemihydrate polymorphs characterized by one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks are expressed in degrees 2Q ± 0.2° comprising 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4, and 26.9, and further characterized by the orthorhombic space group P212121 with lattice parameters a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A, and a = g = b = 90°.

5. The composition of any one of claims 1 to 4, wherein the composition has a bulk density greater than about 0.3 g / cm3 3 .

6. The composition of any one of claims 1 to 5, wherein the composition has a bulk density of less than about 0.95 g / cm3 3 .

7. The composition of any one of claims 1 to 6, wherein the flow function coefficient (ffc) of the composition is greater than about 4.

8. The composition of any one of claims 1 to 7, wherein the average particle size d90 of the particles in the composition is less than about 600 pm.

9. A method of making particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)- piperidin-l-yl)quinoline-8-carbonitrile, the method comprising the steps of: (i) preparing a suspension of 5-((3R,5S)-3-amino-5-(trifluoromethyl)- piperidin-l-yl)quinoline-8-carbonitrile in a solvent comprising one or more organic solvents and water; (ii) optionally heating the suspension to a recrystallization temperature; (iii) stirring the suspension at ambient temperature or the recrystallization temperature for a period of time; (iv) optionally wet milling the suspension; (v) optionally cooling the suspension; and (vi) isolating the particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)- piperidin-l-yl)quinoline-8-carbonitrile from the solvent.

10. A composition comprising particles of 5-((3R,5S)-3-amino-5-(trifluoromethyl)- piperidin-l-yl)quinoline-8-carbonitrile obtainable by the method of claim 9.

11. The composition of claim 10, wherein the composition has the features of the composition of any one of claims 1 to 8.

12. The composition of any one of claims 1 to 8, 10 and 11, wherein the composition is a pharmaceutical composition and comprises one or more pharmaceutically acceptable carriers.

13. The pharmaceutical composition of claim 12 for use as a medicament.

14. The pharmaceutical composition of claim 12 for use in a method of treating or preventing a TLR7 / 8 associated autoimmune disease.

15. The pharmaceutical composition of claim 14, wherein the TLR7 / 8 associated autoimmune disease is selected from the group consisting of rheumatoid arthritis, autoimmune pancreatitis, lupus, systemic lupus erythematosus, cutaneous lupus erythematosus, type I diabetes mellitus, multiple sclerosis, antiphospholipid syndrome, sclerosing cholangitis, systemic onset arthritis, irritable bowel syndrome, scleroderma, Sjogren's syndrome, vitiligo, myositis, dermatomyositis, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft versus host disease, autoimmune skin disease, uveitis, pernicious anemia, and hypoparathyroidism.

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