Crystal form A1 of 5-((3R, 55)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-formonitrile hydrochloride

Abstract

Provided herein is an anhydrous crystalline polymorphic form of 5-((3R, 5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl) quinoline-8-formonitrile hydrochloride salt. Also disclosed are methods of preparing the polymorphs and pharmaceutical compositions comprising the polymorphs.

Description

Technical Field

[0001] This document provides a crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile hydrochloride. Methods for preparing this polymorph and pharmaceutical compositions comprising this polymorph 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] Polymorphism refers to the presence of different crystalline forms of a compound. A single compound can produce multiple polymorphs, each with different solid-state physical properties, such as different solubilities, melting points, stability, dissolution rates, and / or different X-ray diffraction peaks. Because the solubility and / or stability of different polymorphs can vary, identifying the presence of polymorphs in pharmaceutical compounds is important for providing pharmaceutical products with predictable solubility characteristics. Studying the solid forms of drugs (including polymorphs) to determine the stability, solubility, and flowability of each polymorph can be necessary. Unfortunately, the presence of specific polymorphs and their physical properties are unpredictable.

[0005] When used for human treatment, it is important that the polymorphism of the therapeutic agent (such as 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile or its salts) maintains appropriate polymorphism and chemical stability, solubility, and other physicochemical properties over time and in different manufacturing batches of the agent. If physical or chemical properties vary over time and / or between batches, the administration of an effective therapeutic dose can become problematic and can lead to inconsistent dosing or ineffective treatment. Therefore, it is important to select a stable, reproducible polymorphic form of the agent that has 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 an anhydrous crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, referred herein as crystalline form HCl A1. The polymorph described herein can be used to treat immune disorders, including TLR7 / 8-related diseases such as cutaneous and systemic lupus erythematosus (CLE / SLE).

[0008] In another aspect, this disclosure provides a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1. Embodiments provide pharmaceutical compositions comprising the crystalline form HCl A1 described herein and one or more pharmaceutically acceptable carriers or excipients.

[0009] In another aspect, this disclosure provides a method for treating a disease by administering a pharmaceutical formulation comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1, said disease being responsive to administration of dual Toll-like receptor (TLR) 7 / 8 inhibitors.

[0010] 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 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1. The method may include administering the composition alone comprising crystalline form HCl A1, or in combination with one or more other 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-carboxynitrile crystalline form HCl A1 in the manufacture of medicaments for the treatment of immune diseases. Attached Figure Description

[0012] Figure 1 The powder X-ray diffraction pattern of HCl salt crystal form Al is shown.

[0013] Figure 2 The single-crystal structure of HCl salt Al is shown.

[0014] Figure 3 The DSC scan (5 K / min) of HCl salt crystal form A1 is shown.

[0015] Figure 4 The TGA scan (5 K / min) of HCl salt crystal form A1 is shown.

[0016] Figure 5 The water vapor adsorption isotherm (25°C) of HCl salt crystal form Al is shown. Detailed Implementation

[0017] 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, and without limitation, different polymorphic forms can have different levels of stability. Specific polymorphic forms 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, and without limitation, different oxidation processes. Such properties can provide more suitable product quality; for example, dosage forms composed of specific polymorphs are more resistant to discoloration.

[0018] Alternatively or additionally, specific polymorphic forms may have different dissolution rates, thereby providing, for example, a more desirable bioavailability. Alternatively or additionally, specific polymorphic forms may provide different compressibility and / or density properties, thereby providing more desirable characteristics for formulation and / or product manufacturing. The mechanical properties of polymorphs may also differ. For example (but not limited to), tablets containing a higher proportion of a particular polymorph may be less prone to breakage during storage. Furthermore, the different physical properties of polymorphs can affect their processing. For example, a particular polymorph may more or less form solvates, or may be more difficult to filter and / or wash.

[0019] 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.

[0020] 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.

[0021] In an embodiment, the present invention provides 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl Al, characterized in that one or more peaks in powder X-ray diffraction (PXRD) (Cu-Kα1 radiation) are expressed in degrees 2θ ±0.2°, wherein the peaks include 8.1, 11.9, 14.4, 17.0, 17.4, 18.0, 18.9, 19.8, 20.3, 20.8, 22.5, 23.6, 24.4, 25.4, 26.2, and 29.8.

[0022] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 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, or each of the following PXRD peaks: 8.1, 11.9, 14.4, 17.0, 17.4, 18.0, 18.9, 19.8, 20.3, 20.8, 22.5, 23.6, 24.4, 25.4, 26.2, and 29.8. All PXRD peaks provided herein were measured using Cu-Kα1 radiation at 2θ degrees and include ±0.2 degrees.

[0023] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by the presence of a PXRD peak at 22.5 Å.

[0024] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 14.4 and 22.5.

[0025] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 14.4, 17.0 and 22.5.

[0026] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 8.1, 14.4, 17.0 and 22.5.

[0027] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 8.1, 11.9, 14.4, 17.0 and 22.5.

[0028] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 8.1, 11.9, 14.4, 17.0, 17.4 and 22.5.

[0029] The crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 is characterized by PXRD peaks at 8.1, 11.9, 14.4, 17.0, 17.4, 22.5 and 29.8.

[0030] The crystalline polymorphs of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile HCl A1 can be characterized, additionally or alternatively, by single-crystal X-ray diffraction. The crystalline form HCl A1 is in monoclinic space group... P Crystallization in 21, lattice parameters a = 5.20215 ± 0.1 Å, b = 14.6970 ± 0.1 Å, c = 10.8135 ± 0.1 Å, and β = 90.261° (where α = γ = 90°).

[0031] In this aspect, the present disclosure provides a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1. The composition comprising crystalline form HCl A1 may contain only crystalline form HCl A1, or may be combined with one or more other polymorphs or compounds having TLR 7 / 8 inhibition properties.

[0032] Empatolan compositions containing the polymorphic polymorph HCl A1 can contain any amount of crystalline HCl A1. The composition may contain less than about 1% crystalline HCl A1. The composition may contain 1% to 100% crystalline HCl A1. The composition may contain 50% to 100% crystalline HCl A1. The composition may contain 80% to 100% crystalline HCl A1. The composition may contain 90% to 100% crystalline HCl A1. The composition may contain 5% to 99% crystalline HCl A1. The composition may contain 10% to 95% crystalline HCl A1. The composition may contain 15% to 95% crystalline HCl A1. The composition may contain 1% to 80% crystalline HCl A1. The composition may contain 1% to 75% crystalline HCl A1. The composition may contain 1% to 70% crystalline HCl A1. The composition may contain 1% to 65% crystalline HCl A1. The composition may contain 1% to 60% crystalline HCl Al. The composition may contain 1% to 55% crystalline HCl Al. The composition may contain 1% to 50% crystalline HCl Al. The composition may contain 1% to 25% crystalline HCl Al. The composition may contain 1% to 20% crystalline HCl Al. The composition may contain 1% to 15% crystalline HCl Al. The composition may contain 1% to 10% crystalline HCl Al. The composition may contain 1% to 5% crystalline HCl Al.

[0033] A further aspect provides pharmaceutical compositions comprising the crystalline form HCl A1 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 unit that does not interfere with the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers or excipients in pharmaceutical compositions of crystalline HCl A1 include any such excipients known in the art.

[0034] The pharmaceutically acceptable compositions of the present invention 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.

[0035] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In this type of solid dosage form, an active compound comprising crystalline HCl A1 is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectant, such as glycerin; d) disintegrant, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarder, such as paraffin; f) absorption accelerator, such as quaternary ammonium compounds; g) humectant, such as cetyl alcohol and glyceryl monostearate; h) adsorbent, such as kaolin or bentonite; and i) lubricant, 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.

[0036] 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.

[0037] In another aspect, this disclosure provides a method for treating a disease by administering to a patient in need a pharmaceutical formulation comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1, said 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.

[0038] 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 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1. The method may include administering the composition alone comprising crystalline form HCl A1, or in combination with one or more other polymorphs or compounds having TLR 7 / 8 inhibitory properties.

[0039] 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 an effective amount of a composition comprising crystalline HCl Al to the subject.

[0040] Diseases or conditions treated or prevented by administering a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile crystalline form HCl A1 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 the 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 HCl A1 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 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] Example

[0045] Example 1: Preparation of HCl salt crystal form Al

[0046] About 1.1 g of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carboxynitrile, prepared according to the method of WO 2017 / 106607 (compound 73), was dissolved in 7 mL of ethanol at 50 °C. 312 µL of HCl was diluted in 0.5 mL of ethanol. The two solutions were combined at 50 °C. A yellow precipitate was observed. The turbid solution was cooled to 4 °C over 7.5 hours and filtered. The solid was dried under ambient conditions in an N2 stream.

[0047] Example 2: NMR data of HCl salt crystal form A1

[0048] NMR data for HCl salt crystal form A1: 1 H NMR (500 MHz, DMSO) δ 9.08 (dd, J = 4.2, 1.6Hz, 1H), 8.57 (dd, J = 8.6, 1.6 Hz, 1H), 8.51 (s, 3H), 8.29 (d, J = 8.0 Hz, 1H), 7.73 (dd, J= 8.6, 4.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.78 – 3.72(m, 1H), 3.72 – 3.65 (m, 1H), 3.61 – 3.53 (m, 1H), 3.28 – 3.17 (m, 1H), 2.97(t, J = 11.6 Hz, 1H), 2.89 (t, J = 11.0 Hz, 1H), 2.43 (d, J = 11.9 Hz, 1H), 1.67 (q, J = 12.1 Hz, 1H).

[0049] Example 3: Crystallographic Study of HCl Salt Crystal Form A1

[0050] The powder X-ray diffraction pattern was obtained using the standard technique described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia, characterized in that... Figure 1 The X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe Stadi P 611 KL transmission diffractometer) shows the following peaks:

[0051] Single-crystal X-ray structure data of the HCl salt crystalline form Al were obtained at 298 K (Oxford Supernova single-crystal X-ray diffractometer with graphite monochromator and CCD detector). The HCl salt crystalline form Al is located in the monoclinic space group. P Crystallization in 21, lattice parameters a = 5.20215 ± 0.1 Å, b = 14.6970 ± 0.1 Å, c = 10.8135 ± 0.1 Å, and β =90.261° (where α = γ = 90°). The single-crystal structure shows that the HCl salt crystal form Al represents an anhydrous form.

[0052] Example 4: Physical properties of HCl salt crystal form Al

[0053] The HCl salt crystal form Al is characterized by the following physical properties. Thermal behavior shows no significant enthalpy change event at <300℃. TGA shows a weight loss of ~1.1% (w / w) up to 160℃ before the start. DSC and TGA curves are shown in [data missing]. Figure 3 and Figure 4DSC scans of HCl salt crystal form A1 were obtained on a Mettler-Toledo DSC1 with a heating rate of 5 K / min and a nitrogen purge gas of 50 mL / min. TGA scans of HCl salt crystal form A1 were obtained on a Mettler-Toledo TGA 851 with a heating rate of 5 K / min and a nitrogen purge gas of 50 mL / min.

[0054] Water vapor adsorption behavior was observed across the entire relative humidity (RH) range of 0-98%, with an adsorption level of ~1% (w / w). According to the European Pharmacopoeia (Section 5.11), the HCl salt crystal form A1 can be classified as non-hygroscopic to slightly hygroscopic. The water vapor adsorption isotherm (25°C) is shown... Figure 5 The water vapor adsorption isotherm was obtained on the DVS intrinsic system of the SMS.

Claims

1. A crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1- yl)quinoline-8-carbonitrile characterized by one or more peaks in powder X-ray diffraction (PXRD), wherein the peaks, expressed in degrees 2-theta ± 0.2°, comprise 8.1, 11.9, 14.4, 17.0, 17.4, 18.0, 18.9, 19.8, 20.3, 20.8, 22.5, 23.6, 24.4, 25.4, 26.2, and 29.

8.

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, or each of the following PXRD peaks, expressed in degrees 2-theta ± 0.2°: 8.1, 11.9, 14.4, 17.0, 17.4, 18.0, 18.9, 19.8, 20.3, 20.8, 22.5, 23.6, 24.4, 25.4, 26.2, and 29.

8.

3. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise a peak at 22.5, expressed in degrees 2-theta ± 0.2°.

4. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise peaks at 14.4 and 22.5, expressed in degrees 2-theta ± 0.2°.

5. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise peaks at 14.4, 17.0, and 22.5, expressed in degrees 2-theta ± 0.2°.

6. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise peaks at 8.1, 14.4, 17.0, and 22.5, expressed in degrees 2-theta ± 0.2°.

7. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise peaks at 8.1, 11.9, 14.4, 17.0, and 22.5, expressed in degrees 2-theta ± 0.2°.

8. The crystalline polymorph of claim 1, characterized by The PXRD peaks comprise peaks at 8.1, 11.9, 14.4, 17.0, 17.4, 22.5, and 29.8, expressed in degrees 2-theta ± 0.2°.

9. A crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)-piperidin-1-yl)quinoline-8-carbonitrile characterized by Monoclinic space group P 21, lattice parameters a = 5.20215 ± 0.1 A, b = 14.6970 ± 0.1 A, c = 10.8135 ± 0.1 A, and β = 90.261° (wherein a = y = 90°).

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

11. A pharmaceutical composition for use in a method of treating or preventing a TLR7 / 8 associated autoimmune disease, the composition comprising the crystalline polymorph of any one of claims 1 to 9 and one or more pharmaceutically acceptable carriers.

12. The pharmaceutical composition for use in a method of claim 11, wherein the TLR7 / 8 associated autoimmune disease is selected from the group of rheumatoid arthritis, autoimmune pancreatitis, lupus, systemic lupus erythematosus, cutaneous lupus erythematosus, type I diabetes mellitus, multiple sclerosis, anti-phospholipid 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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