Crystalline form H1 of 5-((3R, 5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-nitrile semihydrate

Abstract

Provided herein are crystalline polymorphs of a 5-((3R, 5S)-3-amino-5-(trifluoromethyl) piperidin-1-yl) quinoline-8-nitrile hemihydrate, and methods for preparing the same. Also disclosed are methods for preparing the polymorphs and pharmaceutical compositions comprising the polymorphs.

Description

TECHNICAL FIELD

[0001] Provided herein are crystalline polymorphs of 5-((3R, 5S)-3-amino-5- (trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate. Also disclosed are methods for preparing the polymorphs and pharmaceutical compositions comprising the polymorphs. BACKGROUND

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

[0003] Enpatoran is a potent and selective dual toll-like receptor (TLR) 7 / 8 inhibitor that is in clinical development, including for the treatment of cutaneous lupus erythematosus and systemic lupus erythematosus (CLE / SLE). The compound can be prepared according to the methods provided in WO2017 / 106607.

[0004] Polymorphism refers to the occurrence of a single compound in different crystal forms. A single compound can give rise to multiple polymorphs, each having different solid state physical properties, such as different solubility, melting point, stability, dissolution rate, and / or different X-ray diffraction peaks. Because there can be variations in the solubility and / or stability of different polymorphs, it is important to identify the presence of polymorphs of a pharmaceutical compound to provide a drug product with a predictable solubility profile. It can be necessary to investigate the solid state forms of a drug substance, including polymorphs, and determine the stability, solubility, and flow properties of each polymorph. Unfortunately, the existence of a particular polymorph and its physical properties are not predictable.

[0005] When used to treat humans, it is important that the crystalline form of a therapeutic agent, such as 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile or a salt or hydrate thereof, remains in an appropriate polymorph and chemically stable, with solubility and other physicochemical properties that are suitable over time and in various manufacturing batches of the agent. If the physical or chemical properties vary over time and / or batch, administration of a therapeutically effective dose can become problematic and can result in inconsistent dosing or ineffective treatment. Thus, it is important to select a polymorph of an agent that is stable, reproducibly manufactured, and has physicochemical properties that are advantageous for its use as a therapeutic agent.

[0006] However, the art has not been able to predict which crystalline form of an agent will have the desired combination of properties and be suitable for human administration, and how to prepare the agent in that crystalline form. SUMMARY

[0007] In one aspect, the present disclosure provides a crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate, referred to herein as Form H1. The polymorph described herein can be used to treat immune diseases, including diseases associated with TLR7 / 8, such as cutaneous lupus erythematosus and systemic lupus erythematosus (CLE / SLE).

[0008] In another aspect, the present disclosure provides a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate Form H1. One embodiment provides a pharmaceutical composition comprising Form H1 described herein and one or more pharmaceutically acceptable carriers or excipients.

[0009] In another aspect, the present disclosure provides a method of treating a disease responsive to administration of a dual toll-like receptor (TLR) 7 / 8 inhibitor by administering a pharmaceutical dosage form comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate Form H1.

[0010] Another aspect provides a method of treating a disease or disorder modulated by TLR 7 / 8, the method comprising administering to a mammal in need of such treatment an effective amount of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate Form H1. The method can comprise administering a composition comprising Form H1 alone or in combination with one or more additional polymorphs or compounds having TLR 7 / 8 inhibitory properties.

[0011] Another aspect provides the use of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate Form H1 in the manufacture of a medicament for treating an immune disease.

[0012] BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 A powder X-ray diffraction pattern of Form H1 is shown.

[0014] Figure 2 A single crystal structure of Form H1 is shown.

[0015] Figure 3 A DSC scan (5 K / min) of Form H1 is shown.

[0016] Figure 4 A TGA scan (5 K / min) of Form H1 is shown.

[0017] Figure 5Water vapor sorption isotherm (25°C) showing H1 type.

[0018] Figure 6 SEM images (magnification: left: 100x; middle: 200x; right: 500x) showing H1 type. DETAILED DESCRIPTION

[0019] As used herein, the terms "polymorph" or "polymorphic form" refer to the different crystallographic forms of a substance. The actual physical properties of a polymorph are influenced by the molecular conformation and orientation in the unit cell, which determines the particular polymorphic form of a substance. Different polymorphic forms of the same compound can have different physical, chemical, biological, and / or spectroscopic properties. For example, and without limitation, different polymorphic forms can have different stability properties. A particular polymorphic form can be more sensitive to relative humidity, heat, and / or light. In some cases, the difference in stability is caused by a change in chemical reactivity, such as, but not limited to, differential oxidation. These properties can provide for a more suitable product quality, such as a dosage form that is more resistant to discoloration when containing a particular polymorphic form.

[0020] Alternatively or additionally, a particular polymorphic form can have a different dissolution rate, providing, for example, a more desirable bioavailability. Alternatively or additionally, a particular polymorphic form can provide different compressibility and / or density properties, providing more desirable characteristics for formulation and / or product manufacturing. The mechanical properties can also differ between polymorphic forms. For example, and without limitation, a tablet having a higher proportion of a particular polymorphic form can be more resistant to breakage upon storage. Further, the different physical properties of polymorphic forms can affect their processing. For example, a particular polymorphic form can or can not form solvates, or can be more difficult to filter and / or wash.

[0021] Polymorphic forms can be detected, identified, classified, and characterized using well-known techniques, including, 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.

[0022] As used herein, the term "peak" when referring to spectra and / or data presented in a graph refers to a feature that one skilled in the art would recognize as not attributable to background noise.

[0023] In some embodiments, the application provides crystalline polymorph Form H1 of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate having one or more peaks expressed in degrees 2Θ ± 0.2° by powder X-ray diffraction (PXRD) (Cu-Kal radiation), 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.

[0024] 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.

[0025] Crystalline polymorph Form H1 of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate can be 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 every PXRD peak at 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 provided herein are measured with Cu-Kal radiation in degrees 2Θ and include ± 0.2 degrees.

[0026] Crystalline polymorph Form H1 of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate can be characterized by PXRD peaks including a peak at 13.4.

[0027] Crystalline polymorph Form H1 of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoline-8-carbonitrile hemihydrate can be characterized by PXRD peaks including peaks at 9.7 and 13.4.

[0028] 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate crystalline polymorph Form Hl can have the following characteristics: its PXRD peaks include those at 7.2, 9.7, and 13.4.

[0029] 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate crystalline polymorph Form Hl can have the following characteristics: its PXRD peaks include those at 7.2, 9.7, 13.4, and 22.2.

[0030] 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate crystalline polymorph Form Hl can have the following characteristics: its PXRD peaks include those at 7.2, 9.7, 13.4, 21.5, and 22.2.

[0031] 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate crystalline polymorph Form Hl can additionally or alternatively be characterized by single crystal X-ray diffraction. Form Hl crystallizes in the orthorhombic space group Pnnm with lattice parameters of a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A, and a = y = b = 90°. P 212121Form Hl crystallizes in the orthorhombic space group Pnnm with lattice parameters of a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A, and a = y = b = 90°.

[0032] In some aspects, the present disclosure provides compositions comprising 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl. Compositions comprising Form Hl can comprise Form Hl alone, or in combination with one or more additional polymorphs or compounds having inhibitory properties against TLR 7 / 8.

[0033] Enpatoran compositions comprising crystalline polymorph H1 can comprise any amount of H1 form. The composition can comprise less than about 1% of H1 form. The composition can comprise 1% to 100% of H1 form. The composition can comprise 50% to 100% of H1 form. The composition can comprise 80% to 100% of H1 form. The composition can comprise 90% to 100% of H1 form. The composition can comprise 5% to 99% of H1 form. The composition can comprise 10% to 95% of H1 form. The composition can comprise 15% to 95% of H1 form. The composition can comprise 1% to 80% of H1 form. The composition can comprise 1% to 75% of H1 form. The composition can comprise 1% to 70% of H1 form. The composition can comprise 1% to 65% of H1 form. The composition can comprise 1% to 60% of H1 form. The composition can comprise 1% to 55% of H1 form. The composition can comprise 1% to 50% of H1 form. The composition can comprise 1% to 25% of H1 form. The composition can comprise 1% to 20% of H1 form. The composition can comprise 1% to 15% of H1 form. The composition can comprise 1% to 10% of H1 form. The composition can comprise 1% to 5% of H1 form.

[0034] Further aspects provide a pharmaceutical composition comprising H1 form 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 vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers or excipients that can be used in a pharmaceutical composition of H1 form include any such excipient known in the art.

[0035] Pharmaceutically acceptable compositions of the present application can be orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents can also be added.

[0036] Solid dosage forms for oral administration of the H1 form of the active compound include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the H1 form of the active compound is optionally mixed with at least one inert, pharmaceutically-acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) moisturizing agents, such as glycerol and glycerol monostearate, h) respiration agents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also optionally contain buffering agents.

[0037] Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can optionally be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0038] In another aspect, the present disclosure provides a method of treating a disease responsive to administration of a dual toll-like receptor (TLR) 7 / 8 inhibitor by administering a pharmaceutical dosage form comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carboxylate hemihydrate Form H1 to a patient in need thereof. As used herein, the term "patient" or "subject" refers to an animal, preferably a mammal, most preferably a human.

[0039] Another aspect provides a method of treating a disease or disorder modulated by TLR 7 / 8, the method comprising administering to a mammal in need of such treatment an effective amount of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form H1. The method can comprise administering a composition comprising Form H1 alone or in combination with one or more additional polymorphs or compounds having TLR 7 / 8 inhibiting properties.

[0040] The present application also relates to a method of treating or preventing a disease or disorder in a subject, e.g., a TLR 7 / 8 related disease or disorder, the method comprising administering to the subject an effective amount of a composition comprising Form H1.

[0041] The disease or disorder treated or prevented by administration of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile Form H1 can be an autoimmune disease, e.g., those characterized by joint pain, anti-nuclear antibody positivity, malar rash, or discoid rash. In some aspects, the autoimmune disease is associated with the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not evidenced by symptoms in the skin, muscle tissue, and / or connective tissue in the individual. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases that can be treated or prevented by administration of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile Form H1 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 I diabetes, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, myositis, such as dermatomyositis or polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, hypopituitarism, graft versus host disease (GvHD), autoimmune skin disease, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases can also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold urticaria.

[0042] In some aspects, the autoimmune disease is selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic onset arthritis, and irritable bowel syndrome.

[0043] In other aspects, the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type I diabetes. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, the autoimmune disease is autoimmune pancreatitis (AIP). In some aspects, the autoimmune disease is glomerulonephritis. In some aspects, the autoimmune disease is pyelonephritis. In some aspects, the autoimmune disease is sclerosing cholangitis. In some aspects, the autoimmune disease is psoriasis. In some aspects, the autoimmune disease is rheumatoid disease or disorder.

[0044] In other aspects, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin disease, and multiple sclerosis. The autoimmune disease can be cutaneous lupus erythematosus and systemic lupus erythematosus (CLE / SLE). In some aspects, any of the above autoimmune diseases are TLR7 / 8 associated autoimmune diseases.

[0045] EMBODIMENT

[0046] Example 1: Preparation of Form H1

[0047] About 220 mg of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8- carbonitrile (Compound 73) prepared according to the method of WO 2017 / 106607 was suspended in 0.8 mL water at 50 °C for 2 hours. After filtration, the solid was dried at ambient conditions for 18 hours.

[0048] Example 2: NMR data for Form H1

[0049] NMR data for Form H1: 1 H NMR (500 MHz, DMSO) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.52 (dd, J = 8.6, 1.6 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.6, 4.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 3.62 - 3.50 (m, 1H), 3.51 - 3.40 (m, 1H), 3.12 (tt, J = 10.7, 4.7 Hz, 1H), 3.09 - 2.95 (m, 1H), 2.86 (t, J = 11.5 Hz, 1H), 2.47 (d, J = 11.1 Hz, 1H), 2.18 (d, J = 12.2 Hz, 1H),1.74 (s, 2H), 1.26 (q, J = 12.2 Hz, 1H).

[0050] Example 3: Crystallographic study of H1 form

[0051] Powder X-ray diffractograms were obtained by standard techniques described in Chapter 2.9.33 of the European Pharmacopoeia 6thedition and were recorded on a PANalytical X'Pert Pro MPD diffractometer using a Gobel jump table and a PIXcel3D detector. Figure 1 X-ray powder diffractograms (monochromatic Cukal radiation, l = 1.5406 A, Stoe StadiP 611 KL transmission diffractometer) were recorded and had the following peaks:

[0052] Single crystal X-ray structure data were obtained on the H1 form at 298 K (Oxford Diffraction Supernova single crystal X-ray diffractometer with a graphite monochromator and a CCD detector). The hemihydrate H1 form crystallizes in the orthorhombic space group Pnma with lattice parameters a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A and a = y = b = 90°. From the single crystal structure it can be seen that the H1 form represents a hemihydrate form. P 212121crystallizes and has lattice parameters a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A and a = y = b = 90°. From the single crystal structure it can be seen that the H1 form represents a hemihydrate form.

[0053] Example 4: Physical properties of H1 form

[0054] The H1 form is characterized by the following physical properties. The thermal behavior shows dehydration < 100 °C followed by melting of the anhydrous form A1 at ~165 °C. The TGA shows a weight loss of about 2.9% (w / w) at temperatures up to 130 °C which can clearly be attributed to the degradation of 0.5 mol water. The DSC and TGA curves are shown in Figure 3 and Figure 4 The DSC scan of the H1 form was acquired on a Mettler-Toledo DSC1 using a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min. The TGA scan of the H1 form was acquired on a Mettler-Toledo TGA 851 using a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min.

[0055] Water vapour sorption behaviour indicated a water uptake level of ~0.5% (w / w) over the full relative humidity (RH) range of 0-98% RH. According to the European Pharmacopeia standard (Section 5.11), the hemihydrate Form H1 can be classified as non-hygroscopic. Water vapour sorption isotherms (25°C) are shown in Figure 5 . Water vapour sorption isotherms were obtained on a DVS Intrinsic system from SMS.

[0056] SEM images of Form H1 prepared according to Example 1 are shown in Figure 6 (magnification: left: 100x; middle: 200x; right: 500x).

Claims

1. A crystalline polymorph of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)piperidin-1- yl)quinoline-8-carbonitrile characterized by, The powder X-ray diffraction (PXRD) has one or more peaks, wherein the peaks expressed in 2Q ± 0.2° 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.

2. The crystalline polymorph of claim 1, 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 PXRD peak expressed in 2Q ± 0.2° is 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.

3. The crystalline polymorph of claim 1, characterized by: The PXRD peaks expressed in 2Q ± 0.2° include a peak at 13.

4.

4. The crystalline polymorph of claim 1, characterized by: The PXRD peaks expressed in 2Q ± 0.2° include peaks at 9.7 and 13.

4.

5. The crystalline polymorph of claim 1, characterized by: The PXRD peaks expressed in 2Q ± 0.2° include peaks at 7.2, 9.7, and 13.

4.

6. The crystalline polymorph of claim 1, characterized by: The PXRD peaks expressed in 2Q ± 0.2° include peaks at 7.2, 9.7, 13.4, and 22.

2.

7. The crystalline polymorph of claim 1, characterized by: The PXRD peaks expressed in 2Q ± 0.2° include peaks at 7.2, 9.7, 13.4, 21.5, and 22.

2.

8. A crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile characterized by, The orthorhombic space group thereof is P 212121, lattice parameters a = 10.7499 ± 0.1 A, b = 16.4119 ± 0.1 A, c = 17.5927 ± 0.1 A, and α = γ = β = 90°.

9. A pharmaceutical composition comprising the crystalline polymorph of any one of claims 1 to 8 and one or more pharmaceutically acceptable carriers.

10. A pharmaceutical composition for use in a method of treating or preventing an autoimmune disease associated with TLR7 / 8, the composition comprising the crystalline polymorph of any one of claims 1 to 8 and one or more pharmaceutically acceptable carriers.

11. The pharmaceutical composition for use in a method of claim 10, wherein, The autoimmune disease associated with TLR7 / 8 is selected from the group 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 disease, scleroderma, Sjogren's disease, 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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