Crystalline forms of LTA4H inhibitors

Abstract

The present application relates to various crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, as well as compositions, preparation methods, and methods of using the same. In some embodiments, these crystalline forms also contain water ("hydrates"). These substances can be used to treat diseases and conditions that are typically improved by inhibiting LTA4H. Such diseases and conditions can include inflammatory and autoimmune disorders as well as inflammation of the lungs and respiratory tract.

Description

Technical Field

[0001] The present disclosure generally relates to crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. The present disclosure also generally relates to pharmaceutical compositions comprising these crystalline forms, as well as methods for obtaining such crystalline forms and methods of using such crystalline forms in the treatment of diseases and conditions that are typically ameliorated by inhibiting LTA4H. Such diseases and conditions may include inflammatory and autoimmune disorders as well as inflammation of the lungs and respiratory tract. Background Art

[0002] (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid was first disclosed as an HCl salt in WO2015 / 092740, filed December 18, 2014, which is incorporated by reference in its entirety, and is an LTA4H inhibitor having the structure of the following formula (I):

[0003]

[0004] Compounds of formula (I) are useful for treating diseases and conditions that are typically ameliorated by inhibition of LTA4H. Such diseases and conditions include inflammatory and autoimmune disorders and inflammation of the lungs and airways.

[0005] Therefore, compounds of formula (I) can be used to treat the following diseases or conditions: acute or chronic inflammation, allergic reactions, allergic reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury and chronic obstructive pulmonary disease, inflammatory bowel disease (including ulcerative colitis, Crohn's disease and postoperative trauma), gastrointestinal ulcers, neutrophilic skin diseases (including but not limited to pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), acne and neutrophilic urticaria), immune complex-mediated glomerulonephritis, autoimmune diseases (including insulin-dependent diabetes, polymyalgia, leukemia, leukemia and necrosis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and postoperative trauma), gastrointestinal ulcers, neutrophilic skin diseases (including but not limited to pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), acne and neutrophilic urticaria), immune complex-mediated glomerulonephritis, autoimmune diseases (including insulin-dependent diabetes, polymyalgia ...necrosis and necrosis), inflammatory bowel disease (including polymyalgia, polymyalgia, necrosis and necrosis), inflammatory bowel disease (including polymyalgia, polymyalg The present invention relates to a variety of diseases and conditions including: arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, vasculitis (including but not limited to cutaneous vasculitis, Behcet's disease and Henoch-Schonlein purpura), cardiovascular disorders (including but not limited to hypertension, atherosclerosis, aneurysm, critical lower limb ischemia, peripheral arterial occlusive disease, pulmonary hypertension and Raynaud's syndrome), sepsis, inflammatory and neuropathic pain (including arthritis pain), periodontal disease (including gingivitis), ear infections, migraines, benign prostatic hyperplasia, Sjögren's syndrome and cancer (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumors and colorectal cancer).

[0006] Compounds of formula (I) are particularly useful for treating acute or chronic inflammation, especially autoinflammatory disorders, such as sterile neutrophilic inflammatory disorders, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), neutrophilic skin diseases (including pyoderma gangrenosum and acne), vasculitis, rheumatoid arthritis, gout and cardiovascular disease.

[0007] The solid state form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. Where the same composition of matter crystallizes with different lattice arrangements, crystalline forms occur, resulting in different thermodynamic properties and stability specific to a particular crystalline form. Crystal forms may also include different hydrates or solvates of the same compound. In deciding which form is preferred, many properties of the form are compared and the preferred form is selected based on many physical property variables. It is entirely possible that in some cases, where certain aspects such as ease of preparation, stability, etc. are considered to be critical, a form may be preferred. In other cases, different forms may be preferred for greater dissolution rates and / or superior bioavailability.

[0008] Therefore, the ability of a chemical substance to crystallize in more than one crystalline form can have a profound impact on the shelf life, solubility, formulation characteristics, and processing characteristics of a drug. In addition, the action of a drug may be affected by the polymorphism of the drug molecule. Different polymorphs may have different uptake rates in the body, resulting in lower or higher biological activity than desired. In extreme cases, undesirable polymorphs may even show toxicity. The appearance of unknown crystalline forms during the manufacturing process may have a significant impact.

[0009] It is also not possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which polymorphs will display such desirable properties. Summary of the invention

[0010] The present disclosure provides a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in a free form (i.e., non-salt form). In a specific embodiment, the free form further comprises water (referred to herein as a hydrate).

[0011] Therefore, the present disclosure provides a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in free form.

[0012] The present disclosure further provides a crystalline form of a hydrate of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0013] Examples of these crystalline forms include those designated herein as Form B and Form H. B The names used herein to identify a particular form (e.g., "Form B" or "Form H") are B "Type") should not be considered as limiting to any other material having similar or identical physical and chemical characteristics, but rather it should be understood that these designations are merely identifiers that should be interpreted in light of the characteristic information also presented herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 An illustrative XRPD spectrum of the free form of the compound of Formula (I), designated herein as Form B, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0015] Figure 2 An illustrative DSC of the free form of the compound of formula (I), designated herein as Form B, is provided.

[0016] Figure 3 An illustrative TGA of the free form of the compound of formula (I), designated herein as Form B, is provided.

[0017] Figure 4 Provided are hydrate forms of compounds of formula (I) (designated herein as H B An illustrative XRPD spectrum of a PEG-100 (PEG-100), showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0018] Figure 5 Provided are hydrate forms of compounds of formula (I) (designated herein as H B Illustrative DSC of (type).

[0019] Figure 6 Provided are hydrate forms of compounds of formula (I) (designated herein as H B Illustrative TGA of (type).

[0020] Type B and H are listed in Tables 1 and 2 below, respectively. BA more detailed list of XRPD peaks for each of the forms is provided, wherein relative intensity % (I / I0 x 100) is also provided. It should be understood that due to, for example, instrumental variations (including differences between instruments), there is inherent variability in the values ​​measured in degrees 2θ (°2θ) in the X-ray powder diffraction spectrum or X-ray powder diffraction pattern. Similarly, it should be understood that there is a variability of up to ± 0.2°2θ in the XRPD peak measurements, but such peaks will still be considered to represent a specific solid state form of the crystalline material described herein. It should also be understood that due to, for example, sample preparation and / or storage and / or environmental conditions, other measurements from XRPD experiments and DSC / TGA experiments (such as relative intensity and water content) may vary, but these measurements will still be considered to represent a specific solid state form of the crystalline material described herein. DETAILED DESCRIPTION

[0021] definition

[0022] As used herein, the terms "about" and "substantially" indicate that for features such as endotherms, endothermic peaks, exothermic peaks, baseline shifts, etc., their values ​​can vary. With respect to X-ray diffraction peak positions, "about" or "substantially" means taking into account typical peak position and intensity variability. For example, it will be appreciated by those skilled in the art that peak positions (2θ) can show variability between certain devices, typically up to 0.2°. Occasionally, the variability may be higher than 0.2°, depending on differences in device calibration. In addition, it will be appreciated by those skilled in the art that relative peak intensity will show variability between devices as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be measured only as a qualitative measure. For DSC, the observed temperature change will depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermograms can vary by ±5°C (and are still considered to be the characteristics of the specific crystalline forms described herein). When used in the context of other features such as weight percentage (% by weight), reaction temperature, the term "about" indicates a variance of ±5%.

[0023] The terms "crystalline form(s)" or "crystalline modification(s)" or "polymorph(s)" or "polymorph(s)" will be used interchangeably herein. "Polymorph(s)" as used herein refers to crystalline forms having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that form the crystal.

[0024] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not display a defined X-ray diffraction pattern.

[0025] As used herein, "substantially phase pure," when used with respect to any crystalline form of a compound of Formula (I), means a compound having a phase purity of greater than about 90% by weight, including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including equal to about 100% by weight of the compound of Formula (I). The term "phase pure" or "phase purity" herein refers to the phase homogeneity with respect to a particular solid state form of a compound of Formula (I) and does not necessarily imply a high degree of chemical purity in the absence of an explicit statement thereof. Phase purity can be determined according to methods known in the art, for example, by quantitative phase analysis using XRPD using one or more approaches known in the art, for example, by external standard methods, direct comparison of line (peak) features (which are attributed to different phases in a particular spectrum), or by internal standard methods. However, the presence of amorphous material can complicate XRPD quantification of phase purity. Thus, other methods that can be used to determine phase purity include, for example, solid-state NMR spectroscopy, Raman and / or infrared spectroscopy. Those skilled in the art will readily understand these methods, and how to employ these additional (or alternative) methods to determine phase purity.

[0026] As used herein, "substantially chemically pure," when used with respect to any crystalline form of a compound of Formula (I), means a compound having a chemical purity of greater than about 90% by weight based on the weight of the salt (on anhydrous basis), including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99% by weight, and also including a chemical purity of the compound of Formula (I) equal to about 100% by weight. The remaining materials typically include other compounds (such as, for example, other stereoisomers of the compound of Formula (I)), reaction impurities, starting materials, reagents, by-products, and / or other processing impurities resulting from the preparation and / or isolation and / or purification of a particular crystalline form. For example, if it has been determined that a crystalline form of a compound of formula (I) has a chemical purity greater than about 90% by weight as measured by standard and generally accepted methods known in the art, it can be considered to be substantially chemically pure, with the remaining less than about 10% by weight constituting other materials, such as other stereoisomers of the compound of formula (I), reaction impurities, starting materials, reagents, by-products, and / or processing impurities. Chemical purity can be determined according to methods known in the art, for example, high performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods, as well as how to employ these additional (or alternative) methods to determine chemical purity.

[0027] As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound of formula (I). The term "seed" can also be used as a verb to describe the following behavior: introducing one or more crystals of a crystalline compound of formula (I) into an environment (including but not limited to, for example, a solution, a mixture, a suspension, or a dispersion), thereby resulting in the formation of more crystals of a crystalline compound of formula (I).

[0028] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, is effective in (1) at least partially alleviating, inhibiting, preventing and / or ameliorating (i) a condition, disorder or disease mediated by LTA4H, or (ii) associated with LTA4H activity, or (iii) characterized by the activity (normal or abnormal) of LTA4H; or (2) reducing or inhibiting LTA4H activity; or (3) reducing or inhibiting LTA4H expression. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective in at least partially reducing or inhibiting LTA4H activity; or partially or completely reducing or inhibiting LTA4H expression.

[0029] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. The subject refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

[0030] As used herein, the terms "a", "an", "the" and similar terms used in the context of the invention (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0031] All methods described herein can be performed in any suitable order, unless otherwise specified herein or otherwise clearly contradicted by context. The application of any and all examples or exemplary language (such as "for example") provided herein is only intended to better illustrate the present invention, without limiting the scope of the present invention otherwise claimed.

[0032] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom or disorder, or a disease, or a significant decrease in the baseline activity of a biological activity or process.

[0033] As used herein, the terms "treat, treating or treatment" of any disease or condition, in one embodiment, refers to alleviating the disease or condition (i.e., slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treat, treating or treatment" refers to alleviating or reducing at least one physical parameter, including those that cannot be discerned by the patient. In still another embodiment, "treat, treating or treatment" refers to regulating the disease or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In one embodiment, "treat or treating" refers to delaying the progression of a disease or condition.

[0034] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or condition refers to prophylactic treatment of the disease or condition; or delaying the onset of the disease or condition.

[0035] As used herein, a subject is "in need of" or "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0036] The term "comprising" encompasses "including" as well as "consisting of;" for example, a composition comprising X may consist only of X, or may include additionally, such as X and Y.

[0037] As used herein, the term "combination" refers to a fixed combination in a dosage unit form, or a combined administration, wherein the crystalline form of the compound of formula (I) and the combination partner (i.e., immunotherapeutic agent) can be administered independently at the same time or separately at time intervals, particularly when these time intervals allow the combination partner to show cooperation, such as a synergistic effect. The individual components can be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration.

[0038] The terms "co-administration" or "combined administration" and the like as used herein are intended to encompass administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or administered at the same time.

[0039] As used herein, the terms "drug combination" and "combination product" are used interchangeably and refer to a fixed combination in a dosage unit form or a non-fixed combination or kit for combined administration, wherein two or more therapeutic agents can be administered independently at the same time or separately at time intervals, particularly when these time intervals allow the combination partners to show cooperation, such as synergistic effects. The term "fixed combination" means a crystalline form of a compound of formula (I) and a combination partner (i.e., an immunotherapeutic agent) that are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means a crystalline form of a compound of formula (I) and a combination partner (i.e., an immunotherapeutic agent) that are administered to a patient simultaneously, in parallel or sequentially as separate entities (without a specific time limit), wherein such administration provides therapeutically effective levels of two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more therapeutic agents. In a preferred embodiment, the drug combination is a non-fixed combination.

[0040] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat LTA4H-related diseases as described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple containers or in separate containers (e.g., tablets, capsules, powders, and liquids) of each active ingredient. The powder and / or liquid can be reconstituted or diluted to a desired dose before administration. In addition, such administration also encompasses the use of each type of therapeutic agent at approximately the same time or in different time sequences. In either case, the treatment regimen will provide a beneficial effect of the drug combination in terms of treating the conditions or disorders described herein.

[0041] Crystal form and use

[0042] The present disclosure relates to a crystalline form of the free form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid (a compound of formula (I)), which is described and characterized herein.

[0043] The present invention also relates to a crystalline form of a hydrate of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. More specifically, the present invention relates to a crystalline form of a monohydrate of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid, which is described and characterized herein.

[0044] In one embodiment, the present disclosure provides a crystalline form (Form B) of the free form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid having an X-ray powder diffraction (XRPD) pattern comprising a representative peak at 24.1±0.2°2θ, in terms of °2θ, measured at a temperature of about 25°C. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 22.6±0.2°2θ and 26.3±0.2°2θ. In one aspect of the foregoing embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 11.3±0.2°2θ, 12.8±0.2°2θ, 19.7±0.2°2θ, 25.1±0.2°2θ, and 28.5±0.2°2θ, measured at a temperature of about 25°C. Thus, the XRPD pattern of the crystalline form of the free form of the compound of Formula (I) may include one, two, three, or four representative peaks selected from 11.3±0.2°2θ, 12.8±0.2°2θ, 19.7±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, and 28.5±0.2°2θ measured at a temperature of about 25°C. In another embodiment, the crystalline form of the free form of the compound of Formula (I) has an XRPD pattern which may further include one or more additional representative peaks selected from 11.3±0.2°2θ, 12.8±0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ, measured at a temperature of about 25°C. Thus, the XRPD pattern of the crystalline form of the free form of the compound of Formula (I) may include one or more (e.g., one, two, three, four, five or six) representative peaks selected from 11.3±0.2°2θ, 12.8±0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ, measured at a temperature of about 25°C.The XRPD pattern of the crystalline form of the free form of the compound of Formula (I) may include one or more (e.g., one, two, three, four, five or six) representative peaks measured at a temperature of about 25°C and selected from the peaks disclosed in Table 1.

[0045] In another aspect of the above embodiment, the crystalline form of the free form of the compound of formula (I) is characterized by comprising four or more 2θ values ​​selected from the group consisting of: The X-ray powder diffraction pattern of 24.4±0.2°2θ is as follows: 11.3±0.2°2θ, 12.8±0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ.

[0046] In another aspect of the above embodiment, the crystalline form of the free form of the compound of formula (I) is characterized by comprising five or more 2θ values ​​selected from the group consisting of: The x-ray powder diffraction pattern of 24.4±0.2°2θ is as follows: 11.3±0.2°2θ, 12.8±0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ.

[0047] In still another aspect of the above embodiment, the crystalline form of the free form of the compound of formula (I) has substantially Figure 1 It is understood that the water content of Form B can be in the range of about 0% to about 1% and still be considered a crystalline form having an XRPD pattern including one, two, three, four, five or six representative peaks described above or in Table 1. The water content of Form B is 0.1% as determined by Karl-Fischer titration.

[0048] The crystalline form of the free form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid can be thermally characterized. In one embodiment, the crystalline form of the free form of the compound of Formula (I) has a thermal profile as measured by differential scanning calorimetry (DSC) with a heating rate of 10°C / min, including a single endothermic peak starting at about 197.4°C (corresponding to melting upon decomposition).

[0049] In another embodiment, the crystalline form of the free form of the compound of Formula (I) has substantially Figure 2 DSC thermogram shown. It will be appreciated that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on instrument parameters and therefore the same material may have thermograms that appear substantially different from one another when data is generated on two different instruments.

[0050] In another embodiment, the crystalline form of the free form of the compound of formula (I) has Figure 3 Essentially the same thermogravimetric analysis (TGA) graphs are shown. At 150°C, the weight loss by TGA is about 0.32%.

[0051] In still another embodiment, Form B is substantially phase pure.

[0052] In still another embodiment, the present invention relates to a method for preparing Form B of the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid, the method comprising the following steps:

[0053] a) Reducing the H of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid B The type is suspended in alcohol or a water / alcohol mixture to form a suspension mixture;

[0054] b) heating and stirring the suspension mixture to a temperature above 50° C.;

[0055] c) cooling the solution to room temperature to form a suspension mixture;

[0056] d) collecting Form B from the suspended mixture.

[0057] In yet another embodiment, the method comprises reacting (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid with H B The type was suspended in methanol or a water / methanol mixture or a water / 1-propanol mixture.

[0058] In yet another embodiment, the method comprises reacting (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid with H B type was suspended in methanol.

[0059] In yet another embodiment, the method comprises reacting (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid with H B The type was suspended in a water / 1-propanol mixture, wherein the water / 1-propanol ratio was 30 / 70% by weight.

[0060] In yet another embodiment, the method comprises reacting (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid with H B The type is suspended in a water / methanol mixture, wherein the water / methanol ratio is from 1:2 to 1:9 volume to volume (v / v). Preferably, the water / methanol ratio is selected from 1:2; 1:4 and 1:9 (v / v). More preferably, the water / methanol ratio is 1:2 v / v.

[0061] In still another embodiment, the temperature used in step b) of the method is preferably above 60° C., most preferably above 70° C. In another aspect of the embodiment, the stirring in step b) is more than 24 h, preferably more than 30 h.

[0062] In still another embodiment, the present invention is directed to a process for preparing Form B of compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid, wherein in step d), collecting Form B from the suspension is carried out by filtration.

[0063] In still another embodiment, the present invention is directed to a process for preparing Form B of compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid, wherein in step d), collecting Form B from the suspension is carried out by distillation.

[0064] The present invention further provides a crystalline form (H) of a hydrate of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid. BIn another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 22.1±0.2°2θ, 23.8±0.2°2θ, and 28.7±0.2°2θ, measured at a temperature of about 25°C.

[0065] Alternatively, the XRPD pattern of the crystalline form of the hydrate of the compound of Formula (I) may include one, two, three, or four representative peaks selected from 22.1±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ, and 28.7±0.2°2θ measured at a temperature of about 25°C.

[0066] In another embodiment, the crystalline form of the hydrate of the compound of formula (I) has an XRPD pattern, which may further include one or more additional representative peaks selected from 13.4±0.2°2θ, 20.8±0.2°2θ, 26.1±0.2°2θ, and 33.8±0.2°2θ. Therefore, the XRPD pattern of the crystalline form of the hydrate of the compound of formula (I) may include one, two, three, four, five or six representative peaks selected from 13.4±0.2°2θ, 20.8±0.2°2θ, 22.1±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ, 26.1±0.2°2θ, 28.7±0.2°2θ, and 33.8±0.2°2θ. The XRPD pattern of the crystalline form of the free form of the compound of Formula (I) may include one or more (e.g., one, two, three, four, five or six) representative peaks measured at a temperature of about 25°C and selected from the peaks disclosed in Table 2.

[0067] In another embodiment, the hydrate form is characterized by comprising four or more 2θ values ​​selected from the group consisting of: An x-ray powder diffraction pattern of the present invention, the group consisting of: 13.4±0.2°, 20.8±0.2°, 22.1±0.2°, 23.5±0.2°, 23.5±0.2°, 23.8±0.2, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ and 38.7±0.2°2θ.

[0068] In another embodiment, the hydrate form is characterized by comprising five or more 2θ values ​​selected from the group consisting of: An x-ray powder diffraction pattern of the present invention, the group consisting of: 13.4±0.2°, 20.8±0.2°, 22.1±0.2°, 23.5±0.2°, 23.5±0.2°, 23.8±0.2, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ and 38.7±0.2°2θ.

[0069] In yet another embodiment, the crystalline form of the hydrate of the compound of formula (I) has substantially Figure 4 The XRPD diagram shown. It should be understood that H B The water content of the hydrated form can be in the range of about 2% to about 6% and still be considered a hydrate having an XRPD pattern including one, two, three, four, five or six representative peaks described above. As determined by Karl-Fischer titration, H B The water content of the type is 5.1%.

[0070] The crystalline form of the hydrate of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid can be thermally characterized. In one embodiment, the crystalline form of the hydrate of the compound of formula (I) has a differential thermogravimetric curve comprising an endothermic peak starting at about 95° C. (corresponding to dehydration) and an endothermic peak starting at about 198.5° C. (corresponding to melting during decomposition).

[0071] In another embodiment, the crystalline form of the hydrate of the compound of formula (I) has substantially Figure 5 DSC thermogram shown. It will be appreciated that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on instrument parameters and therefore the same material may have thermograms that appear substantially different from one another when data is generated on two different instruments.

[0072] In another embodiment, the crystalline form of the hydrate of the compound of formula (I) has Figure 6 Essentially the same thermogravimetric analysis (TGA) graphs are shown. At 150°C, the weight loss by TGA is about 4.46%.

[0073] In still another embodiment, the above-mentioned crystal form H B It is in the monohydrate form.

[0074] In still another embodiment, Form H B They are basically pure.

[0075] In still another embodiment, the present invention is directed to a crystalline form H for preparing the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. B The method comprises the following steps:

[0076] a) dissolving (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride in water or a solvent mixture THF / water to form a solution,

[0077] b) adjusting the pH of the solution to a pH value between 3.3 and 7.5 with an aqueous NaHCO3 solution or an aqueous NaOH solution under stirring, thereby obtaining a suspension;

[0078] c) Collecting Form H from the suspension B .

[0079] In a specific aspect of the above embodiment, the present invention relates to a method for preparing the crystalline form H B A method wherein in step a), (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride is dissolved in water and the dilution factor is at least 30 volumes per weight. (i.e. 30 volumes of water per weight of compound, e.g. 30 L of water per 1 kg of compound)

[0080] In another aspect of the above embodiment, the present invention relates to a method for preparing the crystalline form H B The method of claim 1, wherein the solvent mixture in step a) is THF / water, and the dilution factor is at least 15 volumes per weight (i.e., at least 15 volumes of mixture THF / water per weight of compound; for example, 15 L of mixture THF / water per 1 kg of compound). In a specific aspect of the embodiment, the THF / water ratio is about 10:90 (w / w: weight ratio).

[0081] In another aspect of the above embodiment, the present invention relates to a method for preparing the crystalline form H B A process according to claim 1, wherein step a) is carried out at room temperature or, if necessary, at a temperature up to 35° C. until a clear solution is obtained.

[0082] In still another embodiment, the present invention relates to preparing Form H B The method of claim 1, wherein in step b), the pH is adjusted to a pH value between 3.3 and 7.5 using an aqueous NaHCO3 solution (preferably a 5-10% w / w NaHCO3 aqueous solution). Preferably, the pH is brought to about 4 or about 5.

[0083] In still another embodiment, the present invention relates to preparing Form H B The method of claim 1, wherein in step b), the pH is adjusted to a pH value between 3.3 and 7.5 using an aqueous NaOH solution (preferably a 32% w / w NaOH aqueous solution). Preferably, the pH is brought to about 4 or about 5.

[0084] In still another embodiment, the present invention relates to preparing Form H B The method of claim 1 , wherein in step b), the pH is adjusted to a pH value between 3.3 and 7.5 under stirring and stirring is continued for up to 20 h.

[0085] In still another embodiment, the present invention relates to preparing Form H B A method wherein in step c), collecting H from the suspension is carried out by filtration B type.

[0086] In still another embodiment, the present invention is directed to a crystalline form H for preparing the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. B The method comprises the following steps:

[0087] a) (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride is dissolved in water or a solvent mixture THF / water to form a solution,

[0088] b) adjusting the pH of the solution to a pH value between 3.3 and 7.5 with an aqueous NaHCO3 solution or an aqueous NaOH solution under stirring, thereby obtaining a suspension;

[0089] c) Collection of suspension crystal form H B ;

[0090] and further comprising steps d) to i) for preparing (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride;

[0091] d) adding toluene to (S)-3-((tert-butoxycarbonyl)amino)-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;

[0092] e) adding an aqueous HCl solution to form a reaction mixture;

[0093] f) heating and stirring the reaction mixture, optionally under pressure, to a temperature between about 50° C. and about 65° C.;

[0094] g) cooling the reaction mixture to about 35° C.,

[0095] h) separating the aqueous layer and cooling the resulting organic layer to a temperature between 18° C. and 25° C., thereby obtaining a suspension,

[0096] i) The suspension was collected with (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride.

[0097] In one embodiment, the present invention relates to preparing H as described above B A method of the present invention further comprising adding toluene in an amount such that the (S)-3-((tert-butoxycarbonyl)amino)-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid / toluene ratio is from 1 to 5 to 1 to 10 (weight to weight).

[0098] In another embodiment, the present invention relates to preparing H as described above B A method of the invention wherein in step e), the aqueous HCl solution is 30%-40% (preferably about 30%) aqueous HCl, and wherein the amount of HCl is about 15 equivalents of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride.

[0099] In another embodiment, the present invention relates to preparing H as described above B The method of the present invention is characterized in that step f) is heating the reaction mixture at a temperature between about 60° C. and about 65° C. and stirring for 10-15 h.

[0100] In still another embodiment, the present invention relates to preparing H as described above B The method of the present invention is characterized in that step f) is carried out under pressure, i.e. the release pressure of the reactor is set so as to minimize the amount of HCl escaping from the reaction mixture. Preferably, the release pressure is set at about 2000 mbar.

[0101] In still another embodiment, the present invention relates to preparing Form H B The method of claim 1, wherein in step i), collecting (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride from the suspension is performed by filtration or by centrifugation.

[0102] In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form (B or H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. B Form B or a combination thereof), and at least one pharmaceutically acceptable carrier, diluent or excipient. In a specific embodiment, the present invention relates to a pharmaceutical composition comprising Form B, and one or more pharmaceutically acceptable carriers, diluents or excipients. In still another aspect, the present invention relates to a pharmaceutical composition comprising Form B substantially pure. In still another embodiment, the present invention relates to a pharmaceutical formulation comprising Form B and further comprising at least one other solid state form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid. In one aspect of this embodiment, another solid state form is Form H B In still another embodiment, another solid state form is an amorphous form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0103] In a specific embodiment, the present invention relates to a pharmaceutical composition comprising crystalline form H B , and one or more pharmaceutically acceptable carriers, diluents or excipients. In still another aspect, the present invention relates to a pharmaceutical composition comprising crystalline Form H in substantially phase-pure form. B In still another embodiment, the present invention relates to a pharmaceutical composition comprising crystalline form H B And further comprises at least one other solid state form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. In one aspect of this embodiment, the other solid state form is Form B. In still another embodiment, the other solid state form is an amorphous form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0104] In other embodiments, the present invention relates to a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid in crystalline form (Form B, Form H B type or a combination thereof), and one or more therapeutic agents.

[0105] In a specific embodiment, the present invention relates to a pharmaceutical combination comprising Form B, and one or more therapeutic agents. In still another aspect, the present invention relates to a pharmaceutical combination comprising Form B in substantially phase-pure form and one or more therapeutic agents. In still another embodiment, the present invention relates to a pharmaceutical combination comprising Form B and further comprising at least one other solid state form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid. In one aspect of this embodiment, another solid state form is Form H B In still another embodiment, another solid state form is an amorphous form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0106] In a specific embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form H B , and one or more therapeutic agents. In still another aspect, the present invention relates to a pharmaceutical combination comprising crystalline Form H in substantially phase-pure form B and one or more therapeutic agents. In still another embodiment, the present invention relates to a pharmaceutical combination comprising Form H B And further comprises at least one other solid state form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. In one aspect of this embodiment, the other solid state form is Form B. In still another embodiment, the other solid state form is an amorphous form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0107] In another embodiment, the present invention provides a pharmaceutical combination as described above, wherein the therapeutic agents are independently selected from the group consisting of immunosuppressants or immunomodulators or other anti-inflammatory agents. More specifically, the therapeutic agent is selected from the group consisting of: COX inhibitors, cysteinyl-leukotriene receptor antagonists (including montelukast, pranlukast, zafirlukast), leukotriene C4 synthase (LTC4S) inhibitors, statins, sulfasalazine, mesalazine, calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, belimumab-7 or belimumab-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salts; mycophenolate mofetil; IL-1β inhibitors.

[0108] In one embodiment, the present invention relates to a method of treating a disease or condition typically improved by inhibiting LTA4H in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a crystalline form (Form B, Form H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. B type or a combination thereof), administered alone or in combination with one or more therapeutic agents.

[0109] In another embodiment, the invention relates to a method of treating a disease or condition typically ameliorated by inhibition of LTA4H in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as described above, alone or in combination with one or more therapeutic agents.

[0110] In another embodiment, the invention relates to a method of treating a disease or condition typically ameliorated by inhibition of LTA4H in a subject in need thereof, the method comprising administering to the subject a pharmaceutical combination as described above.

[0111] In one embodiment, the present invention is directed to a crystalline form (Form B, Form H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid administered alone or in combination with one or more therapeutic agents. B or a combination thereof) for treating a disease or condition typically improved by inhibiting LTA4H.

[0112] In still another embodiment, the present invention relates to a crystalline form (Type B, Type H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. B or a combination thereof) for treating a disease or condition typically ameliorated by inhibition of LTA4H.

[0113] In another embodiment, the present invention relates to a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid (Form B, Form HB or a combination thereof) in combination with one or more therapeutic agents for the treatment of a disease or condition typically improved by inhibiting LTA4H.

[0114] In one embodiment, the present invention relates to a method of treatment, a use, a compound for use, or a combination for use as described above, wherein the disease or condition typically improved by inhibiting LTA4H is selected from inflammation and autoimmune disorders and inflammation of the lungs and airways. More specifically, the disease or condition typically improved by inhibiting LTA4H is selected from acute or chronic inflammation, allergic reactions, allergic reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury and chronic obstructive pulmonary disease, inflammatory bowel disease (including ulcerative colitis, Crohn's disease and postoperative trauma), gastrointestinal ulcers, neutrophilic skin diseases (including but not limited to pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), acne and neutrophilic urticaria), immune complex-mediated glomerulonephritis, autoimmune diseases (including insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus), vasculitis (including but not limited to cutaneous vasculitis, Behcet's disease and Henoch-Schönlein purpura), cardiovascular disorders (including but not limited to hypertension, atherosclerosis, aneurysm, critical lower limb ischemia, peripheral arterial occlusive disease, pulmonary hypertension and Raynaud's syndrome), sepsis, inflammatory and neuropathic pain (including arthritis pain), periodontal disease (including gingivitis), ear infections, migraine, benign prostatic hyperplasia, Sjögren's syndrome and cancer (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumors and colorectal cancer). In a preferred embodiment, the disease or condition typically improved by inhibiting LTA4H is selected from inflammatory bowel disease (including ulcerative colitis, Crohn's disease and post-operative trauma) and neutrophilic skin diseases (including but not limited to pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), acne and neutrophilic urticaria).

[0115] In one embodiment, the invention relates to the method, use or combination for use according to the above embodiments, wherein the therapeutic agents are administered together in a single composition, or separately in the form of two or more different compositions.

[0116] In one embodiment, the invention relates to a method, a use or a combination for use as described above, wherein the therapeutic agent is administered simultaneously with, before, or after the crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

[0117] Characteristics of the crystal form of the present invention

[0118] The crystalline forms described herein have been found to have advantageous properties. The selection criteria were toxicological grounds, crystallinity, melting point, hygroscopicity, bulk stability, compatibility with excipients, pH of aqueous solution, solubility in water and aqueous media, morphology, handling and polymorphic behavior. Free Form B and Hydrate Form H B Demonstrated superior behavior, especially over the HCl salt previously known and described in WO 2015 / 092740. The HCl salt was found to be corrosive, with strong corrosion to steel coupon #1.2767 and moderate corrosion to steel coupon #1.2803, and was therefore shown to be unsuitable for further development.

[0119] Form B is an anhydrous form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid that is highly crystalline exhibiting a columnar habit. It is slightly hygroscopic with a maximum water absorption by DVS at 90% RH at 25°C of less than 0.7%.

[0120] Crystal form H B It is a hydrated form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazolyl-2-yl)butanoic acid. TGA and DVS data show that it is a monohydrate. Form H B It is not hygroscopic between 10%-90% RH, but loses its water below 10% RH. It gradually rehydrates to H B Occurs at 10% RH and above 60% RH.

[0121] Stability in solvents:

[0122] Equilibration with solvent to study H B The relative stability of the type in the solvent. BThe precipitate was equilibrated with 1 mL of solvent in a water bath at 25°C for 24 h (or 7 days, or 28 days) or at 50°C for 7 days. The solution was filtered and dried in air for 10 minutes. The resulting solid was analyzed by XRPD.

[0123] Various solvents were studied: acetone, acetonitrile, dichloromethane, dioxane, ethanol, heptane, methanol, THF, acetone / water mixtures from 10 / 90 to 90 / 10, acetonitrile / water mixtures from 10 / 90 to 90 / 10, dioxane / water mixtures from 10 / 90 to 90 / 10 and ethanol / water mixtures from 10 / 90 to 90 / 10, tetrahydrofuran / water (50 / 50) and 1-propanol / water (70 / 30).

[0124] At 25 °C for 7 days or 28 days, polymorph H B It showed no change in various solvents, but turned into an amorphous substance or a gel-like substance in acetone, dioxane, ethanol, methanol and THF. However, at 50 °C for 7 days, H B The type becomes amorphous in many solvents. In methanol, H B Type is converted to type B. B The conversion of type A to type B usually occurs at low water content. (Table 3)

[0125] Table 3: H B Stability of the type in various solvents at 50°C

[0126]

[0127]

[0128] Competitive slurry experiments were conducted at different water activities at 25°C and 50°C. B Competitive slurry of a (1:1) physical mixture of A and B.

[0129] Table 4A: Competitive slurry experiments at different water activities at 25 degrees Celsius

[0130]

[0131]

[0132] At 25°C, the mixture transforms to pure Form B at a water activity aw ≤ 0.5. Above this water activity, the mixture remains unchanged. A similar trend can be seen at 50°C, however, the maximum water activity for transformation to Form B rises to aw ≤ 0.7.

[0133] Table 4B Competitive slurry experiments at different water activities at 50 degrees

[0134]

[0135] Variant H was found B The conversion to anhydrous modification B can be carried out by slurry in hot or boiling methanol (i.e., a temperature of about 50°C to about 65°C). Modification B can be further obtained by high temperature slurry in an aqueous solvent mixture at 80°C and can also be obtained from modification H. B Variant B does not convert to other forms and therefore shows better stability.

[0136] Solid state stability in bulk and with excipient mixtures

[0137] The B and H B To investigate the chemical and physical stability of the crystalline forms, each form was exposed to high humidity at temperatures ranging from 25°C to 80°C. Both crystalline forms were subjected to different test conditions as described below:

[0138] Test Condition 1: Placed in a sealed container at 80°C, 50°C, 80°C / 75% relative humidity (RH), or 50°C / 75% RH for 1 week.

[0139] Test condition 2: Placed in an open container at 80°C for 1 week.

[0140] Test condition 3: Place in a sealed container at 50°C for 1 week.

[0141] Test condition 4: Place in an open container at 50°C / 75%RH for 1 week.

[0142] Test Condition 5: Place in an open container at room temperature / 92% RH for 1 week.

[0143] Degradation products were analyzed by HPLC and samples were analyzed by XPRD to detect any changes in the solid state.

[0144] HPLC Method:

[0145]

[0146] Under the above test conditions, form B shows good stability and does not transform at all. Except at 80°C in the absence of humidity, variant H B Stable under all conditions.

[0147] Additionally, Form B was found to be stable after 1 week at 40°C / 90% RH and no hydrate formation was detected. Thus, Form B was identified as the preferred form because it does not hydrate when exposed to high relative humidity (RH).

[0148] Physical stability

[0149] Behavior under compression: Form H was also evaluated B Physical stability. Using a hydraulic press (tablet diameter 13mm), 300mf of crystalline form H was pressed under 10 tons. B The compression was carried out for 5 minutes. The samples were then characterized by XRPD to detect any changes in the solid state.

[0150] By XRPD, for Form H B No change in crystal form was observed. B Proven to have good physical stability properties.

[0151] Behavior under grinding : Form H was also evaluated B Physical stability. 50 mg of Form B or H B Grind manually in a mortar for 3 minutes. Form H B The grinding did not result in any changes in the XRPD.

[0152] Behavior under pelleting simulation experiment : In the granulation simulation experiment, the crystal form H was also evaluated. B In these experiments, the granulation solvent was added dropwise to the crystalline form H. B The mixture was then vortexed between each addition at 25°C. The mixture was then dried under vacuum. The crystallinity of the material (after grinding) was re-evaluated by XRPD and / or DSC. The granulation solvent was water or ethanol. After granulation using ethanol or water as the granulation solvent, polymorph H B XRPD showed no crystalline change.

[0153] Solubility

[0154] Form B has a solubility of 0.05 mg / mL at pH 4 to 7.

[0155] Form B showed solubility in aqueous buffer in biorelevant media of 0.07 mg / mL in FaSSIF-V2 (pH=6.6) and 0.18 mg / mL in FeSSIF-V2 (pH=5.9).

[0156] H B The solubility of type 2 in aqueous buffer in biologically relevant media is 0.75 mg / mL in simulated gastric fluid (SGF at pH = 2); 0.09 mg / mL in FaSSIF (pH = 6.5), and 0.009 mg / mL in FeSSIF (pH = 5.8).

[0157] In summary, Form B has demonstrated chemical and physical stability in both solution and solid state conditions. BIt is stable over a wide humidity range and is highly crystalline, but converts to Form B at high temperatures in methanol or aqueous solvents.

[0158] Pharmaceutical compositions, combinations, dosages and administration

[0159] In some embodiments, the crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid described herein may be used alone or they may be formulated into a pharmaceutical composition that also contains at least one pharmaceutically acceptable excipient, and typically contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the purpose and scope of the present application.

[0160] In some embodiments, the present invention utilizes pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0161] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, additives, bulking agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes and the like, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It should be understood that unless the conventional excipient is incompatible with the active ingredient, the present application contemplates the use of any conventional excipient in any therapeutic or pharmaceutical composition.

[0162] The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present invention can be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations (such as sterilization) and / or can contain conventional inert diluents, lubricants, carriers or buffers and adjuvants (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers and swelling agents, etc.).

[0163] Typically, pharmaceutical compositions are tablets or capsules comprising the active ingredient together with at least one excipient, such as:

[0164] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0165] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0166] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired;

[0167] d) Carriers, such as aqueous vehicles containing cosolvation materials, such as captisol, PEG, glycerol, cyclodextrin, etc.;

[0168] e) disintegrating agents, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0169] f) Adsorbents, colorants, flavoring agents and sweeteners.

[0170] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0171] Preferably, the compound or composition is prepared for oral administration, such as tablets or capsules, and optionally packaged in a multidose form suitable for storing and / or dispensing unit doses of a pharmaceutical product. Suitable examples of packaging include, but are not limited to, hermetically sealed foil, unit dose containers (e.g., vials), blister packs, and strip packs.

[0172] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

[0173] These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets are uncoated or coated by known techniques to delay decomposition and absorption in the gastrointestinal tract and thereby provide a long-lasting effect. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0174] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.

[0175] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-water content ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Therefore, it is preferred to use materials known to prevent exposure to water to package the anhydrous compositions so that they can be included in suitable preparation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0176] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compounds of the present invention as active ingredients decompose. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers, etc.

[0177] For a subject of about 50-70kg, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 1-1000mg one or more active ingredients, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 10-50mg of active ingredients. The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof depends on the individual symptom, illness or disease or its severity in the species, body weight, age and treatment of the subject. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for preventing, treating or inhibiting a condition or disease progression.

[0178] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and preparations. The compounds of the present invention can be administered in vitro in the form of a solution (e.g., preferably an aqueous solution), and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. In vitro doses can be administered in about 10 -3 Molar concentration and 10 -9 Depending on the route of administration, the in vivo therapeutically effective amount may be in the range of about 0.1-500 mg / kg, or about 1-100 mg / kg.

[0179] In other embodiments, a pharmaceutical composition is provided, comprising at least one compound according to the above embodiments and at least one carrier.

[0180] The crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid as described herein can also be used as active pharmaceutical ingredients (API) and materials for preparing formulations that are combined with one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects.

[0181] Therefore, in one embodiment of the present disclosure, the crystalline form (B or H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid is B The crystalline form (Form B or Form H) of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in substantially phase pure form is provided. B In some embodiments, the crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid may not maintain its crystallinity in the pharmaceutical composition. For example, in some embodiments, the crystalline form B or H B can be used, for example, in a process involving spray drying or wet granulation to prepare a pharmaceutical composition; thus, little to no crystalline form B or H may be detected in the resulting pharmaceutical composition. B .

[0182] Treatment kit

[0183] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a crystalline form (Form B or Form H) of a compound of Formula (I). B In one embodiment, the kit comprises a device (such as a container, a divided bottle, or a divided foil package) for separately retaining the compositions. An example of such a kit is a blister pack, such as is typically used for packaging of tablets, capsules, and the like.

[0184] The kits of the invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to each other. To aid compliance, the kits of the invention typically include instructions for administration.

[0185] In the combination therapy of the present invention, the crystalline form (i.e., Form B or Form H) of the compound of Formula (I) may be manufactured and / or formulated by the same or different manufacturers. BHowever, the crystalline form of the compound of formula (I) and the other therapeutic agent may be administered together to form a combination therapy: (i) before the combination product is released to the physician (e.g., in the case of a kit comprising the crystalline form of the compound of formula (I) and the other therapeutic agent); (ii) by the physician himself (or under the guidance of the physician) shortly before administration; (iii) in the patient himself, for example, during the sequential administration of the crystalline form of the compound of formula (I) and the other therapeutic agent.

[0186] Therefore, the present invention provides a crystalline form (i.e., Form B or Form H) as described herein. B The present invention also provides a method for treating a disease that is improved by inhibiting LTA4H (e.g., inflammation, autoimmunity, and respiratory diseases), wherein the drug is prepared for administration with another therapeutic agent. The present invention also provides a method for treating a disease that is improved by inhibiting LTA4H (e.g., inflammation, autoimmunity, and respiratory diseases), wherein the drug is administered together with a crystalline form of a compound of formula (I).

[0187] The present invention also provides a crystalline form (i.e., Type B or Type H) of a compound of formula (I). B The present invention also provides another immunotherapeutic agent for use in a method for treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein a crystalline form of the compound of formula (I) is prepared for administration with another therapeutic agent. The present invention also provides another immunotherapeutic agent for use in a method for treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein other therapeutic agents are prepared for administration with a crystalline form of the compound of formula (I). The present invention also provides a crystalline form of the compound of formula (I) for use in a method for treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein the crystalline form of the compound of formula (I) is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method for treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein the other therapeutic agent is administered with a crystalline form of the compound of formula (I).

[0188] The present invention also provides a crystalline form of a compound of formula (I) for use in treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease (e.g., inflammation, autoimmunity, and respiratory disease) that is improved by inhibiting LTA4H, wherein the patient has previously (e.g., within 24 hours) been treated with a crystalline form of a compound of formula (I).

[0189] combination:

[0190] Additional therapeutic agents used in combination with the crystalline forms of the present invention include, but are not limited to, anti-inflammatory agents, immunomodulators, immunosuppressants, or chemotherapeutic agents.

[0191] For example, the compounds of the invention can be used in combination with: COX inhibitors, cysteinyl-leukotriene receptor antagonists (including montelukast, pranlukast, zafirlukast), leukotriene C4 synthase (LTC4S) inhibitors, statins, sulfasalazine, mesalazine, calcineurin inhibitors, such as cyclosporine A or FK 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, belimus-7 or belimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salts; mycophenolate mofetil; IL-1β inhibitors.

[0192] Preparation of a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid:

[0193] Crystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state conversion from another phase, crystallization from a supercritical fluid, and jet spray. Techniques for crystallizing or recrystallizing a crystal form from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding the crystal with a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an antisolvent (counter solvent) to the solvent mixture. Exemplary methods for preparing the crystal forms described herein are listed in detail below.

[0194] Crystals of drugs (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, SR Byrn, RRP Feiffer, and JG Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0195] For crystallization techniques using solvents, the selection of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used, for example, the compound can be dissolved in a first solvent to provide a solution, and then an antisolvent is added to reduce the solubility of the compound in the solution and provide for the formation of crystals. An antisolvent is a solvent in which the compound has a low solubility.

[0196] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and the solvent at a given temperature. This may also be referred to as a suspension.

[0197] Seedlings can be added to any crystallization mixture to promote crystallization. Inoculation can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystallized product. Therefore, the calculation of the required amount of seed depends on the size of the available seed and the desired size of the average product particles, as described in "Programmed Cooling of Batch Crystallizers", JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are needed to effectively control the growth of crystals in a batch. Small-sized seeds can be produced by screening, grinding or micronizing large crystals, or by micronizing a solution. It should be noted that grinding or micronizing of crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., becoming amorphous or another polymorph).

[0198] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as a cold recrystallization solvent), and the separated solid can be dried under a nitrogen purge to provide the desired crystal form. The separated solid can be analyzed by a suitable spectrum or analytical technique, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, etc., to ensure the formation of a preferred crystal form of the product. The resulting crystal form is typically produced in an amount greater than about 70% by weight of the isolated yield, preferably greater than 90% by weight of the isolated yield based on the weight of the compound initially used in the crystallization procedure. If desired, the product can be co-ground or passed through a mesh screen to debulk the product.

[0199] Alternatively, the crystalline form can be prepared directly from the reaction medium of the final process for preparing (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid. This can be achieved, for example, by employing a solvent or a mixture of solvents in the final process step from which (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid can be crystallized. Furthermore, the crystalline form can be obtained by distillation or solvent addition techniques.

[0200] In addition to the methods briefly discussed below, it will be appreciated that a variety of analytical methods can be used to characterize any of the materials described herein.

[0201] The following non-limiting examples illustrate the present disclosure.

[0202] Examples

[0203] abbreviation:

[0204] IT: Internal temperature

[0205] Tj: Reactor jacket temperature

[0206] Tr: reaction temperature

[0207] THF: Tetrahydrofuran

[0208] Rpm: Revolutions per minute

[0209] Example 1: Crystal Form H B Preparation

[0210]

[0211] Int-1 (55 kg) and toluene (810 kg) were added to a 2500 L glass-lined reactor, and the mixture was stirred (55 rpm, anchored). 31% HCl (232 kg) was added. The release pressure of the reactor was set to 2000 mbar. The internal temperature was adjusted to 65°C and stirred (60 rpm) at an internal temperature (IT) between 65°C and 66°C for 11 h 29 min. The internal temperature was then adjusted to 35°C. The mixture was then separated by a Dean-Stark separator-like device (IT max =44 ° C) under reduced pressure to separate 82 kg of aqueous solution, and the internal temperature was adjusted to about 20. The system was stirred at 19 ° C to 24 ° C for 80 min. The solid was collected by centrifugation. The wet cake was washed with toluene (50 kg, 20 mL of antistatic agent was added) and dichloromethane (50 kg). The solid was dried in a titanium tray dryer at 195 mbar with sodium bisulfite solution of JT Baker set at 60 ° C for 8h 26min.

[0212] The hydrochloride salt (Int-2) was obtained.

[0213] 5 kg of Int-2 was added to a 50 L glass-lined reactor, and 59 kg of a solvent mixture of THF / water (w / w=7.2 / 64) was also added to the reactor. The mixture was stirred at 32° C. to 34° C. for 2 h (some insoluble particles were observed). The solution was continuously filtered through a bag filter and a 0.2 μm particle filter.

[0214] The filtrate was transferred to a separate container through another 0.2 μm particle filter. A solution of NaHCO (0.989 kg) in water (15 kg) was added to a separate container. A white solid precipitated during the addition. After the addition was complete, the solid was stably suspended in the liquid and did not settle significantly when stirring stopped. After stirring at 300 rpm for 67 min, the system was sampled and tested with pH paper, and the result was 4. After stirring at 300 rpm for 20 hours, the system was filtered. The solid in the filter was washed with 50 kg of purified water to produce pH 7. B type.

[0215] Alternatively, Example 29 (28 g, 35 mmol) as described in WO 2015 / 092740 and a solvent mixture containing 360 g of water and 40 g of THF were mixed together and stirred for 20 minutes. The mixture was filtered and the filtrate was adjusted to pH = 5 with an aqueous solution of NaHCO. Stirring was continued for 18 h, and then the mixture was filtered to obtain 25.6 g of polymorph H in a wet cake. B , which was used without further purification to prepare polymorph Form B (see Example 2).

[0216] Alternatively, Example 29 (15.0 g, 65 mmol, HCl salt) as described in WO 2015 / 092740 was added to 450 mL of water and stirred for 1 hour. The solution was adjusted to pH about 4 with an aqueous solution of NaHCO. The mixture was stirred at room temperature for 17 h and then filtered. The filter cake was washed with water and dried under vacuum to give 14.7 g of H B The morphology was characterized by XRPD, DSC and TGA (respectively Figure 4-6 )

[0217] Example 2: Preparation of Hydrate Form B

[0218]

[0219] The first method: 505 mg H B The slurry was heated to 50 ° C and stirred for 4 days using a magnetic stirrer. The suspension was cooled to room temperature and filtered. The recovered solid was dried under vacuum at 40 ° C for 2.5 h. The white solid (respectively Figure 1-3 ).

[0220] The second method: stirring H in water / MeOH (2:8, 1:9, 1:2 v / v) at a temperature above 60 °C B type will also result in type B. For example, 20.7g H BForm B (dry weight) was added to a premixed solvent mixture containing 810 mL MeOH and 90 mL H2O. The resulting mixture was heated to 68 ° C for 36 h and then cooled to 25 ° C. The mixture was stirred for another 2 h and filtered. The filter cake was dried under vacuum to obtain Form B (15.8 g, 76% yield) as a white powder.

[0221] M / z=393.1[M+H] + , Rt=2.47min (UPLC-MS conditions), Rt=14.85min (HPLC conditions), 1 HNMR(400MHz,MeOD-d4)δ=8.24(d,2H),7.98(d,1H),7.91(dd,1H),7.36(d,2H),5.17(d,2H),4.25-4.34(m,1H),2.96(dd,1H),2.80(dd,1H)ppm, 19 F NMR(376MHz,MeOD-d4)δ=-135.7(d,1F)ppm

[0222] To characterize Form B, the following UPLC-MS and HPLC conditions were used: UPLC-MS conditions :Machine: Waters AcquityUPLC; Column: Waters Aquity BEH C18 (50 mm, inner diameter 2.1 mm, particle size: 1.7 μm); Column temperature: 30°C, Mobile phase (gradient): 0.1% formic acid in water and 0.1% formic acid in acetonitrile (V / V=90 / 10 to 15 / 85). Flow rate 0.5 mL / min. Detection wavelength: 210 nm; HPLC conditions : Machine: Agilent 1200HPLC column: Waters Xbridge C18 (150 mm, inner diameter 3.0 mm, particle size 3.5 μm), column temperature 30°C; mobile phase (gradient): 0.1% phosphoric acid in water and acetonitrile (V / V=90 / 10 to 15 / 85). Flow rate 0.7 mL / min. Detection wavelength: 210 nm.

[0223] In the third method, the starting material H BThe type (1wt) liquid is charged into the reactor 1 as a suspension in 1-propanol / water of 70 / 30% (41.3wt) by weight. The suspension is heated to a jacket temperature (Tj) = 90°C ((reaction temperature (Tr)> 80°C) to completely dissolve. The solution is filtered through a preheated filtration device (filter jacket at 85°C-90°C) at a pressure of 500mbar and transferred to the reactor 2. Clear filtration is performed by using a Millipore hydrophilic 0.45um and cellulose SeitzK250P filter. Both filters are pre-wetted with a 1-propanol / water 70 / 30 mixture. The transfer line and filter are washed by 1-propanol / water 70 / 30% (4.5wt) by weight and recombined with the raw material suspension / solution into the reactor 2 (spontaneous solid formation may be observed in the collection reactor due to temperature drop).

[0224] Distillation

[0225] The suspension (entering reactor 2) is heated again to about Tj=85°C (Tr>80°C) for complete dissolution. Once complete dissolution is achieved, the reactor temperature is controlled at 70°C-75°C and seeds (type B) are added, the size-reduced seeds (0.01 wt) suspended in 1-propanol (0.1 wt). The jacket temperature is heated to start distillation (at about 80°C-85°C) and the vacuum is set at 500 mbar. The distillation process begins: the internal reactor temperature is controlled between 70°C-75°C and the vacuum is set at 450-500 mbar. During the distillation process, new 1-propanol solvent (70 wt) is added to replace the distilled 1-propanol solvent (distilled at constant volume).

[0226] At the end of the distillation process, the vacuum was released and the reactor contents were cooled to 20°. The suspension was sampled for IPC control (water residual below 2% wt).

[0227] Filtration and washing

[0228] The solid was filtered and washed with 1-propanol (2 x 10 wt). The solid was characterized by long needle-like particles.

[0229] The solid was dried at 45-50° C. under vacuum (10-20 mbar residual pressure) with stirring for 24 hours.

[0230] Powder X-ray diffraction

[0231] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Discovery D8 in reflection geometry. Powders were analyzed using a zero-background Si wafer sample holder. Radiation was Cu Kα The pattern was measured between 2° and 40° 2θ.

[0232] Table 1: X-ray powder diffraction data of hydrate form B

[0233]

[0234]

[0235] Table 2: Crystalline Form H B X-ray powder diffraction data of

[0236]

[0237] DSC:

[0238] Differential scanning calorimetry was performed for each crystalline form using TA instruments (DSC 2500). For each analysis, 2-4 mg of sample was placed in an aluminum T-zero crucible closed with a pinhole cover. The heating rate was 10 ° C per minute in the temperature range between 30 ° C and 300 ° C. Temperatures were reported in degrees Celsius (° C.) and enthalpy was reported in joules / gram (J / g). The figure shows the endothermic peak as follows. The extrapolated onset temperature of the endothermic melting peak (melting point) was evaluated. The accuracy of the sample temperature measured in this way is within about ± 1 ° C, and the heat of fusion can be measured within a relative error of about ± 5%.

[0239] Using Form B and H B Illustrative DSC traces produced are shown in Figure 2 and 4 middle.

[0240] Type B: Melting endotherm: T 起始 =197.4℃(melting temperature during decomposition)

[0241] H B Type: Melting Endothermic: T 起始 =95℃(dehydration) and T 起始 =198.5℃(melting point during decomposition)

[0242] Thermogravimetric analysis (TGA):

[0243] TGA curves were obtained using a TA Instruments Q5000. 5-15 mg of sample was placed in an aluminum crucible and sealed. The sealed crucible was pierced with a robotic autosampler immediately prior to analysis. TGA curves were measured at 10 °C / min between 30 °C-300 °C. The LoD (loss on drying) was calculated to be between 40 °C and 150 °C. Weight loss was plotted for the sample temperature measured. Temperatures were reported in degrees Celsius (°C) and weight loss was reported in %.

[0244] Using Form B and H B Illustrative TGA traces generated are shown in Figure 3 and 6 middle.

Claims

1. A crystalline form of the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, characterized in that Including at 25℃±5% and The invention discloses an X-ray powder diffraction pattern having peaks at the following 2θ values: 11.3±0.2°2θ, 12.8±0.2°2θ, 19.7±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ and 28.5±0.2°2θ, measured at an X-ray wavelength λ of 1.587 nm.

2. The crystal form according to claim 1, characterized in that Including at 25℃±5% and The invention discloses an X-ray powder diffraction pattern having peaks at the following 2θ values: 11.3±0.2°2θ, 12.8±0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ and 30.0±0.2°2θ, measured at an X-ray wavelength λ of 1.587 nm.

3. The crystal form according to claim 1, characterized in that Including at 25℃±5% and The x-ray powder diffraction pattern measured at an x-ray wavelength λ of 10.9 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 15.2 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.0 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.5 ± 0.2° 2θ, °2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3 ±0.2°2θ, 28.5±0.2°2θ, 29.3±0.2°2θ, 30.0±0.2°2θ, 36.4±0.2°2θ, and 39.1±0.2°2θ.

4. The crystal form according to claim 1, characterized in that Including at 25℃±5% and The x-ray powder diffraction pattern measured at an x-ray wavelength λ has the peaks shown in the following table:

5. The crystalline form according to claim 1, which has an x-ray diffraction spectrum substantially the same as the x-ray powder diffraction spectrum shown in FIG1.

6. The crystalline form according to any one of claims 1 to 5, which has a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2.

7. The crystalline form according to any one of claims 1 to 5, which has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 3.

8. The crystalline form according to any one of claims 1 to 5, wherein the crystalline form is in substantially phase pure form.

9. A crystalline form of the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazolyl-2-yl)butanoic acid in the form of its hydrate, characterized in that Including at 25℃±5% and The invention discloses an X-ray powder diffraction pattern having peaks at the following 2θ values: 13.4±0.2°2θ, 20.8±0.2°2θ, 22.1±0.2°2θ, 23.5±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ and 33.8±0.2°2θ, measured at an X-ray wavelength λ of 500 nm.

10. The crystal form according to claim 9, characterized in that Including at 25℃±5% and The invention discloses an X-ray powder diffraction pattern having peaks at the following 2θ values: 13.4±0.2°2θ, 20.8±0.2°2θ, 22.1±0.2°2θ, 23.5±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ and 38.7±0.2°2θ, measured at an X-ray wavelength λ of 1.587°.

11. The crystal form according to claim 9, characterized in that Including at 25℃±5% and The invention further comprises an X-ray powder diffraction pattern measured at an X-ray wavelength λ of 400 nm and having peaks at the following 2θ values: 9.5±0.2°2θ, 13.4±0.2°2θ, 15.6±0.2°2θ, 17.4±0.2°2θ, 20.8±0.2°2θ, 22.1±0.2°2θ, 23.5±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ, 35.7±0.2°2θ, 37.2±0.2°2θ and 38.7±0.2°2θ.

12. The crystal form according to claim 9, characterized in that Including at 25℃±5% and The x-ray powder diffraction pattern measured at an x-ray wavelength λ has the peaks shown in the following table:

13. The crystalline form according to claim 9, which has an X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG4.

14. The crystalline form according to any one of claims 9 to 13, which has a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 5.

15. The crystalline form according to any one of claims 9 to 13, which has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 6.

16. The crystalline form according to any one of claims 9 to 13, wherein the hydrate is a monohydrate.

17. The crystalline form according to any one of claims 9 to 13, wherein the crystalline form is in substantially phase pure form.

18. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 5, and one or more pharmaceutically acceptable excipients.

19. A pharmaceutical composition comprising the crystalline form according to any one of claims 9 to 13, and one or more pharmaceutically acceptable excipients.

20. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 5, in combination with one or more therapeutic agents, wherein the therapeutic agents are independently selected from the group consisting of: COX inhibitors, cysteinyl-leukotriene receptor antagonists, leukotriene C4 synthetase (LTC4S) inhibitors, statins, sulfasalazine, mesalamine, calcineurin inhibitors; mTOR inhibitors; ascomycins with immunosuppressive properties; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salts; mycophenolate mofetil; IL-1β inhibitors.

21. A pharmaceutical composition comprising the crystalline form according to any one of claims 9 to 13, in combination with one or more therapeutic agents, wherein the therapeutic agents are independently selected from the group consisting of: COX inhibitors, cysteinyl-leukotriene receptor antagonists, leukotriene C4 synthetase (LTC4S) inhibitors, statins, sulfasalazine, mesalamine, calcineurin inhibitors; mTOR inhibitors; ascomycins with immunosuppressive properties; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salts; mycophenolate mofetil; IL-1β inhibitors.

22. Use of a crystalline form according to claim 1 or claim 9 in the preparation of a medicament for treating a disease or condition typically ameliorated by inhibition of LTA4H in a subject in need thereof, comprising administering to a mammal a therapeutically effective amount of the respective crystalline form.

23. A method for preparing a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid as defined in any one of claims 1 to 5, the method comprising the following steps: a) suspending a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid as defined in any one of claims 9 to 13 in methanol or a water / alcohol mixture to form a suspension mixture; b) heating and stirring the suspension mixture to a temperature above 50° C.; c) cooling the solution to room temperature to form a suspension mixture; and d) collecting the crystalline form as defined in any one of claims 1 to 5 from the suspension.

24. A method for preparing a crystalline form of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid as defined in any one of claims 9 to 13, the method comprising the following steps: a) dissolving (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride in water or a solvent mixture THF / water to form a solution, b) adjusting the pH of the solution to a pH value between 3.3 and 7.5 with an aqueous NaHCO3 solution or an aqueous NaOH solution under stirring to obtain a suspension; and c) collecting the crystalline form as defined in any one of claims 9 to 13 from the suspension.

25. The method of claim 24, further comprising steps d) to i) for preparing (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride; wherein d) adding toluene to (S)-3-((tert-butoxycarbonyl)amino)-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; e) adding an aqueous HCl solution to form a reaction mixture; f) heating and stirring the reaction mixture to a temperature between 50°C ± 5% and 65°C ± 5%; g) cooling the reaction mixture to 35°C ± 5%, h) separating the aqueous layer and cooling the resulting organic layer to a temperature between 18° C. and 25° C., thereby obtaining a suspension, and i) collecting the (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid hydrochloride from the suspension.

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