(19)
(11)EP 3 339 306 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
06.05.2020 Bulletin 2020/19

(21)Application number: 16834669.0

(22)Date of filing:  11.08.2016
(51)Int. Cl.: 
C07D 405/12  (2006.01)
A61P 11/00  (2006.01)
A61K 31/443  (2006.01)
(86)International application number:
PCT/CN2016/094589
(87)International publication number:
WO 2017/025045 (16.02.2017 Gazette  2017/07)

(54)

CRYSTAL FORM OF 3-(6-(1-(2,2-DIFLUOROBENZO[D][1,3]DIOXOLE-5-YL)CYCLOPROPANE FORMAMIDO)-3-METHYLPYRIDINE-2-YL)BENZOIC ACID AND PREPARATION METHOD THEREOF

KRISTALLFORM VON 3-(6-(1-(2,2-DIFLUORBENZO[D][1,3]DIOXOL-5-YL)CYCLOPROPAN-FORMAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOESÄURE UND HERSTELLUNGSVERFAHREN DAFÜR

FORME CRISTALLINE DE L'ACIDE 3-(6-(1-(2,2-DIFLUOROBENZO[D][1,3]DIOXOLE-5-YL)CYCLOPROPANE FORMAMIDO)-3-MÉTHYLPYRIDINE-2-YL)BENZOÏQUE ET SON PROCÉDÉ DE PRÉPARATION


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 11.08.2015 CN 201510489485

(43)Date of publication of application:
27.06.2018 Bulletin 2018/26

(73)Proprietor: Crystal Pharmatech Co., Ltd.
Suzhou, Jiangsu 215123 (CN)

(72)Inventors:
  • CHEN, Minhua
    Suzhou Jiangsu 215123 (CN)
  • ZHANG, Yanfeng
    Suzhou Jiangsu 215123 (CN)
  • LIU, Kai
    Suzhou Jiangsu 215123 (CN)
  • ZOU, Po
    Suzhou Jiangsu 215123 (CN)
  • ZHANG, Xiaoyu
    Suzhou Jiangsu 215123 (CN)

(74)Representative: Grünecker Patent- und Rechtsanwälte PartG mbB 
Leopoldstraße 4
80802 München
80802 München (DE)


(56)References cited: : 
WO-A2-2010/037066
CN-A- 101 910 156
CN-A- 104 168 890
WO-A2-2010/138484
CN-A- 102 164 587
US-A1- 2013 186 801
  
     
    Remarks:
    The file contains technical information submitted after the application was filed and not included in this specification
     
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    TECHNICAL FIELD



    [0001] The present disclosure relates to the field of pharmaceutical chemistry, particularly relates to crystalline form of 3-(6-(1-(2, 2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and process of preparation thereof.

    BACKGROUND



    [0002] Lumacaftor is developed by Vertex and combined with Ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR). Combination of Lumacaftor/Ivacaftor was approved in the United States on July 2, 2015 under the brand name Orkambi. The chemical name of Lumacaftor is 3-(6-(1-(2, 2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid, and the structure is shown as formula (I):

    CN101910156A disclosed crystalline Form I of Lumacaftor and Form I has an X-ray powder diffraction pattern comprising the following 2theta values measured using CuKα radiation: 15.2-15.6°, 16.1-16.5°, 14.6-15.0°, 17.6-18.0° and 14.3-14.7°. Form I can be obtained by suspending the hydrochloride of compound of formula (I) in water. Additionally, the patent disclosed another method to obtain Form I through intermediate of compound of formula (I). The preparation method of the new crystalline form in present disclosure is directly obtained from compound of formula (I) free form, which is different from that of Form I in CN101910156A.

    [0003] US 2013/0186801 disclosed form I and solvates of form II of Lumacaftor.

    [0004] As is known to the skilled in the art, the presence of new solid polymorphic forms of a known chemical substance is unpredictable. The existence of the polymorphic compound or the number of the polymorphic forms is also unpredictable. In addition, it is also unpredictable under what conditions to obtain a specific form, and how are the characteristics of the polymorphic form. Since the properties (e.g., solubility, stability) of each polymorph of the compound cause the different performance on drug's application and storage, it is necessary to study all solid forms, including all polymorphic forms to provide drugs with improved stability or solubility.

    [0005] CN101910156A disclosed crystalline Form I but there is no description on the characteristics such as stability and solubility. The inventor of the present disclosure found a new crystalline form of Lumacaftor with better characteristics. The crystalline form in present disclosure has good stability and higher solubility than prior art. It has unexpected technical effect and great value for further development of the drug.

    SUMMARY



    [0006] To solve the problems of prior art, the objectives of present disclosure are to provide a novel crystalline form of compound of formula (I) that has good stability and higher solubility, and the novel crystalline form is designated as crystalline Form A, which can be obtained directly by compound of formula (I) free form.

    [0007] The crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern (CuKα radiation) at 25°C shows characteristic peaks at 2theta values of 8.8°±0.2°, 21.3°±0.2°, 22.2°±0.2°.

    [0008] Furthermore, the crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern shows one or more characteristic peaks at 2theta values of 9.9°+0.2°, 18.1°±0.2°, 23.5°±0.2°. Preferably, the crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 9.9°+0.2°, 18.1°±0.2°, 23.5°±0.2°.

    [0009] Furthermore, the crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern shows one or more characteristic peaks at 2theta values of 10.6°±0.2°, 16.2°±0.2°, 20.0°±0.2°; Preferably, the crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 10.6°±0.2°, 16.2°±0.2°, 20.0°±0.2°.

    [0010] The crystalline Form A of the present disclosure, wherein the X-ray powder diffraction pattern (CuKα radiation) at 25°C shows one or more characteristic peaks at 2theta values of 8.8°±0.2°, 21.3°+0.2°, 22.2°±0.2°, 10.6°±0.2°, 18.1°±0.2°, 23.5°±0.2°, 9.8°±0.2°, 16.2°±0.2°, 20.0°±0.2°.

    [0011] In a specific and preferred embodiment, the X-ray powder diffraction pattern of Form A is substantially as depicted in Fig. 1. Furthermore, the X-ray powder diffraction pattern shows 28 diffraction peaks and the position and intensity of peaks are listed in table 1.

    [0012] In another specific and preferred embodiment, the X-ray powder diffraction pattern of Form A shows 23 diffraction peaks and the position and intensity of peaks are listed in table 2.

    [0013] In a specific and preferred embodiment, the X-ray powder diffraction pattern of Form A shows 26 diffraction peaks and the position and intensity of peaks are listed in table 3.

    [0014] Preferably, the crystalline Form A of the present disclosure, wherein the differential scanning calorimetry (DSC) thermogram shows an endothermic peaks when heated to around 195 °C (onset temperature), and the DSC thermogram is substantially as depicted in Fig. 2. The melting point (initial melting) of Form A is 193°C∼197°C.

    [0015] The IR spectrum of crystalline Form A of present disclosure is shown in Fig.4, comprising one or more peaks at 428.02cm-1, 440.02 cm-1, 552.63cm-1, 633.98cm-1, 653.98cm-1, 672.13cm-1, 703.67cm-1, 719.88cm-1, 747.06cm-1, 758.22cm-1, 773.98cm-1, 819.54cm-1, 827.73cm-1, 863.16cm-1, 907.65cm-1, 941.69cm-1, 964.44cm-1, 999.06cm-1, 1034.29cm-1, 1070.98cm-1, 1083.97cm-1, 1111.81cm-1, 1165.13cm-1, 1235.34cm-1, 1303.65cm-1, 1374.39cm-1, 1409.47cm-1, 1421.75cm-1, 1446.91cm-1, 1468.87cm-1, 1505.25cm-1, 1589.40cm-1, 1607.45cm-1, 1673.39cm-1, 1693.20cm-1, 1920.00cm-1, 2546.90cm-1, 2657.45cm-1, 3011.44cm-1 (±2cm-1).

    [0016] Another objective of the present disclosure is to provide a process of preparing crystalline Form A of compound of formula (I). The method comprises dissolving compound of formula (I) in ketones or the mixture of ketones and ethers, and white solid is obtained by evaporation at the temperature of 20-80 °C.

    [0017] Preferably, said temperature is 30 °C-70 °C, more preferably, said temperature is 40 °C-60 °C.

    [0018] Preferably, volume ratio of mixture of ketones and ethers is 1:1 to 1:4.

    [0019] According to the present disclosure, preferably, said ketones are acetone or methyl isobutyl ketone (MIBK), said ether is methyl tertiary butyl ether (MTBE).

    [0020] According to a specific and preferred embodiment, Form A is obtained by dissolving the compound of formula (1) into MIBK or the mixture of acetone and MTBE. Form A is obtained after evaporation at 50 °C. Preferably, the volume ratio of mixture of acetone or MIBK with MTBE is 1:1 to 1:4.

    [0021] Furthermore, the content of compound of formula (I) in said solvent (mg/mL) is 1-20; preferably, the content of compound of formula (I) in said solvent is 5-15; more preferably, the content of compound of formula (I) in said solvent is 10.

    [0022] Said compound of formula (I) can be a solid, semisolid, waxy or oil form.



    [0023] Another objective of the disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A of compound of formula (I) and pharmaceutically acceptable excipient. Generally, a therapeutically effective amount of crystalline Form A of compound of formula (I) is mixed or contacted with one or more pharmaceutical acceptable excipients to make pharmaceutical composition or formulation, and the pharmaceutical composition or formulation are prepared by well-known method in the pharmaceutical field.

    [0024] Another objective of the disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A of compound of formula (I), Ivacaftor and pharmaceutically acceptable excipient. Generally, a therapeutically effective amount of crystalline Form A of compound of formula (I) and Ivacaftor are mixed or contacted with one or more pharmaceutical excipients to make pharmaceutical composition or formulation, and the pharmaceutical composition or formulation are prepared by well-known method in the pharmaceutical field.

    [0025] The pharmaceutical composition above can be developed into a certain dosage form, and is administrated by a suitable route. Dosage form such as: solid oral dosage forms, including but not limited to powders, granules, pills, tablets and capsules; Liquid oral dosage forms, including but not limited to sirups, suspensions, dispersants and emulsions; and injections, including but not limited to solutions, dispersants and lyophilized formulations. Dosage forms may be instant-release, delayed-release or time controlled-release and instant-release may be common, dispersal, chewable, orally disintegrating or instant. Time controlled-release may be a skeleton or repository system that consists of hydrophilic, hydrophobic material or a combination of hydrophilic and hydrophobic material to control the release rate. The formulation process is possible to use the method such as direct compression, dry granulation, wet granulation and extrusion-spheronization. The possible presentation of the dosage form includes un-coating, film coating, sugar coating, powder coating, enteric coating or sustained-release coating. The administration route such as oral administration and parenteral administration (including subcutaneous, muscle, vein or skin), rectal, transdermal, nasal and vagina, and so on. The dosage form suitable for oral administration comprises tablets, capsules, granules, powders and pills, a powder, an ingot, a solution, a syrup or a suspension according to needs, and can be used for rapid release, delayed release or regulation release of active pharmaceutical ingredients. The dosage form suitable for parenteral administration comprises an aqueous or non-aqueous sterile injection solution, an emulsion or a suspension. The dosage form suitable for rectal administration comprises a suppository or an enema. The dosage form suitable for transdermal administration comprises an ointment, a cream and a patch. The dosage form suitable for nasal administration comprises an aerosol, a spray and a nose drop. The dosage form suitable for vaginal administration comprises a suppository, a plugging agent and a gel, a paste or a spray.

    [0026] Furthermore, crystalline Form A of compound of formula (I) or the pharmaceutical composition thereof can be used for preparing drugs for treating cystic fibrosis.

    [0027] Furthermore, crystalline Form A of compound of formula (I) or the pharmaceutical composition thereof can be used in combination with one or more drugs for preparing drugs for treating cystic fibrosis.

    [0028] Furthermore, crystalline Form A of compound of formula (I) or the pharmaceutical composition thereof can be used in combination with Ivacaftor for preparing drugs for treating cystic fibrosis.

    [0029] The present disclosure relates to methods of treating patients with CFTR mediated disease and the method comprising administrating an effective amount of crystalline Form A of compound of formula (I) or the pharmaceutical composition thereof. Preferably, the present disclosure relates to methods of treating patients with cystic fibrosis and the method comprising administrating an effective amount of crystalline Form A of compound of formula (I) or the pharmaceutical composition thereof.

    [0030] The present disclosure relates to methods of treating patients with CFTR mediated disease and the methods comprising administrating an effective amount of combination of crystalline Form A of compound of formula (I) and Ivacaftor. Preferably, the present disclosure also relates to methods of treating patients with cystic fibrosis and the method comprising administrating an effective amount of combination of crystalline Form A of compound of formula (I) and Ivacaftor.

    [0031] The said CFTR mediated disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as 1-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hyperparathyroidism, melanoma, glycan CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal of DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington, Spinocerebellar ataxia type 1, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, Parkinson's disease.

    [0032] The terms in the present disclosure have common sense to those skilled in the art if there is no definition.

    [0033] The term "effective treatment amount" or "therapeutically effective amount" as used herein means that amount of an active compound that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

    [0034] As used herein, the term "treatment" refers to one or more of the following: (1) Preventing disease, for example, preventing the disease, illness or disorder in an individual who may be suffering from a disease, illness or disorder but not suffering from or displaying a lesion or symptom of the disease, (2) Inhibiting the disease, for example, inhibiting the disease, illness or disorder in an individual who is suffering from or displaying a lesion or symptom of the disease, illness or disorder, and (3) Improving the disease, for example, improving the disease, illness or disorder in an individual who is suffering from or displaying a lesion or symptom of the disease, illness or disorder (that is to reverse the lesion and/or symptoms), for example, reducing the severity of the disease.

    [0035] As used herein, the term "polymorphic form" refers to different crystalline forms of the same compound and includes, but is not limited to other solid forms including hydrates and solvates of the same compound. The phenomenon that the same drug molecule forms a variety of crystalline forms is called drug polymorphism, drug polymorphism is a phenomenon commonly found in solid drugs. It is known that pharmaceutical compounds having such polymorphs have an influence on pharmacological activity, solubility, bioavailability and stability due to their different physical and chemical properties. Therefore, in the case where a compound useful as a drug has polymorphic forms, it is desirable to produce a crystalline compound that is more useful from these polymorphs.

    [0036] The term "X-ray powder diffraction pattern" as used herein refers to a diffraction pattern observed by an experiment or a parameter derived therefrom. The X-ray powder diffraction pattern is characterized by the peak position and the peak intensity.

    [0037] The present disclosure has the following advantages:
    The novel crystalline form of compound of formula (I) in present disclosure has higher solubility than Form I in prior art, it is of great value in improving drug efficacy and reducing drug-loading.

    [0038] In addition, the crystalline Form A has good stability and it is easy to be prepared directly from the free form of compound, which is suitable for the development of the drug.

    BRIEF DESCRIPTION OF DRAWINGS



    [0039] 

    Fig. 1 shows an XRPD pattern of crystalline Form A.

    Fig. 2 shows a DSC thermogram of crystalline Form A.

    Fig. 3 shows a 1H NMR spectrum of crystalline Form A.

    Fig. 4 shows an 1R spectrum of crystalline Form A.

    Fig. 5 shows a DVS plot of crystalline Form A.

    Fig.6 shows an XRPD comparison pattern of crystalline Form A before and after DVS (the pattern above is before DVS and the below one is after DVS).

    Fig.7 shows an XRPD overlay pattern of crystalline Form A after storing at 25 °C/60%RH and 40°C/75%RH for 90 days (the top, middle and bottom patterns are initial crystalline Form A, crystalline Form A after storing at 25 °C/60%RH and 40°C/75%RH for 90 days, respectively).

    Fig.8 shows a PLM image of crystalline Form I.

    Fig.9 shows a PLM image of crystalline Form A.


    DETAILED DESCRIPTION OF THE DISCLOSURE



    [0040] The present disclosure will be further explained by the specific embodiments, but are not intended to limit the scope of the present disclosure. In the following examples, general conditions or conditions recommended by the manufacturer are used in tests methods; the said compound of Lumacaftor was obtained commercially.

    [0041] The experimental conditions not specified are general conditions.

    [0042] The abbreviations used in the disclosure are explained as follows:

    XRPD: X-ray Powder Diffraction

    DSC: Differential Scanning Calorimetry 1H NMR: 1H Nuclear Magnetic Resonance

    DVS: Dynamic Vapor Sorption

    PLM: Polarized Light Microscopy

    IR: Infrared Radiation



    [0043] X-ray powder diffraction pattern in the present disclosure was acquired by a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure were as follows:

    X-ray Reflection: Cu, Kα

    Kα1 (Å): 1.540598; Kα2 (Å): 1.544426

    Kα2 / Kα1 intensity ratio: 0.50

    Voltage: 45 (kV)

    Current: 40 (mA)

    Scan range: from 3.0 degree to 40.0 degree



    [0044] Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the differential scanning calorimetry (DSC) method of the present disclosure were as follows:

    Heating rate: 10°C/min

    Purge gas: nitrogen



    [0045] Dynamic vapor sorption (DVS) data in the present disclosure was acquired by a SMS (Surface Measurement Systems Ltd.) DVS Intrinsic. About 10 mg of crystalline Form A of present disclosure was used for DVS test. The parameters of the dynamic vapor sorption (DVS) method of the present disclosure were as follows:

    Temperature: 25 °C

    Gas and flow rate: N2, 200mL/min

    dm/dt: 0.002%/min

    RH range: 0%RH to 95%RH

    Stable duration: 10 min

    Maximum equilibrate time: 180 min

    Humidity gradient: 10% (0%RH-90%RH), 5% (90%RH-95%RH).



    [0046] Polarized light microscope (PLM) image in the present disclosure were acquired by a ZEISS Axio Lab.A1 upright microscope.

    [0047] Infrared radiation (IR) spectrum in the present disclosure was acquired by a Nicolet 6700 Fourier Transform Infrared Spectrometer (Thermo Fisher Scientific). The parameters of the Fourier Transform Infrared Spectrometer method of the present disclosure were as follows:

    Light: infrared light

    Detector: DTGS

    Beam splitter: KBr

    Number of scans: 32

    Resolution: 4.000


    Example 1



    [0048] Process for preparing crystalline Form A of the compound of formula (I):
    5.3 mg of the compound of formula (I) was dissolved into 0.5 mL methyl isobutyl ketone. Then the solution was evaporated at 50 °C for three days. The obtained white solid was identified as crystalline Form A.

    [0049] The XRPD data of crystalline Form A prepared in this example are including but not limited to the data listed in Table 1. The XRPD pattern is displayed in Fig. 1.
    Table 1 The XRPD data of crystalline Form A
    2thetad spacingIntensity %
    8.77 10.08 52.78
    9.58 9.24 13.30
    9.85 8.98 24.45
    10.56 8.38 35.38
    11.14 7.94 11.76
    12.60 7.02 11.70
    13.35 6.63 10.08
    14.13 6.27 20.29
    15.54 5.70 19.57
    16.23 5.46 28.07
    17.38 5.10 20.11
    17.65 5.03 14.66
    18.10 4.90 40.65
    18.92 4.69 16.40
    20.04 4.43 32.37
    21.25 4.18 83.17
    22.21 4.00 100.00
    23.00 3.87 18.04
    23.46 3.79 43.79
    24.03 3.70 8.68
    24.50 3.63 7.46
    25.42 3.50 4.38
    26.39 3.38 9.83
    27.45 3.25 10.73
    28.05 3.18 14.01
    28.95 3.08 1.96
    30.02 2.98 3.95
    34.98 2.57 2.12


    [0050] The DSC thermogram of crystalline Form A shows an endothermic peak when heated to around 195 °C (onset temperature), which is substantially depicted in Fig. 2.

    [0051] The 1H NMR spectrum of crystalline Form A is displayed in Fig. 3. The 1H NMR data are as follows :
    1H NMR (400 MHz, DMSO) δ 13.08 (s, 1H), 9.01 (s, 1H), 8.00 - 7.87 (m, 3H), 7.77 - 7.68 (m, 2H), 7.60 - 7.51 (m, 2H), 7.35 (dt, J = 8.3, 5.0 Hz, 2H), 2.23 (s, 3H), 1.51 (q, J = 4.1 Hz, 2H), 1.16 (dd, J = 7.0, 4.2 Hz, 2H)

    Example 2



    [0052] Process for preparing crystalline Form A of the compound of formula (1):
    5.4 mg of the compound of formula (I) was dissolved into 0.5 mL mixture of acetone and methyl tertiary butyl ether (The volume ratio of acetone and methyl tertiary butyl ether is 1:2.). Then the solution was evaporated at 50 °C for three days. The obtained white solid was identified as crystalline Form A.

    [0053] The XRPD data of crystalline Form A prepared in this example are including but not limited to the data listed in Table 2.
    Table 2 The XRPD data of crystalline Form A
    2thetad spacingIntensity %
    8.77 10.08 55.12
    9.86 8.97 17.80
    10.56 8.38 35.17
    11.13 7.95 4.50
    12.61 7.02 6.16
    14.14 6.27 29.04
    15.54 5.70 13.39
    16.24 5.46 26.21
    17.38 5.10 10.27
    17.66 5.02 9.46
    18.10 4.90 35.72
    18.91 4.69 10.83
    20.05 4.43 24.97
    21.26 4.18 100.00
    22.21 4.00 90.23
    22.99 3.87 17.07
    23.46 3.79 31.12
    24.05 3.70 6.80
    24.49 3.63 9.87
    25.30 3.52 2.62
    26.39 3.38 8.06
    27.43 3.25 7.17
    28.07 3.18 11.73

    Example 3



    [0054] Process for preparing crystalline Form A of the compound of formula (I):
    10.1 mg of the compound of formula (I) was dissolved into 1.0 mL of methyl isobutyl ketone. Then the solution was evaporated at 50 °C for three days. The obtained white solid was identified as crystalline Form A.

    [0055] The XRPD data of crystalline Form A prepared in this example are including but not limited to the data listed in Table 3.
    Table 3 The XRPD data of crystalline Form A
    2thetad spacingIntensity %
    8.77 10.08 70.87
    9.85 8.98 11.77
    10.56 8.38 50.38
    11.15 7.94 5.84
    12.62 7.02 6.50
    13.36 6.63 15.57
    14.14 6.27 24.94
    15.54 5.70 14.46
    16.24 5.46 47.68
    16.76 5.29 3.05
    17.38 5.10 6.13
    17.65 5.02 11.64
    18.10 4.90 27.67
    18.91 4.69 11.92
    20.05 4.43 41.72
    21.26 4.18 100.00
    22.21 4.00 79.65
    23.01 3.87 23.02
    23.47 3.79 37.10
    24.03 3.70 6.64
    24.49 3.63 7.32
    25.30 3.52 2.01
    26.42 3.37 4.81
    27.46 3.25 13.07
    28.06 3.18 24.23
    34.94 2.57 1.39

    Example 4



    [0056] Hygroscopicity assessment of crystalline Form A of compound of formula (I):
    About 12.2 mg of crystalline Form A of the present disclosure was used for hygroscopicity testing using dynamic vapor sorption (DVS), crystalline Form A underwent a 0-95%-0 cycle of the relative humidity (RH) change. The result is listed in Table. 4. The DVS isotherm plot of crystalline Form A is shown in Fig. 5. The XRPD patterns of crystalline Form A before and after hygroscopicity assessment are depicted in Fig. 6. The pattern above is before DVS and the below one is after DVS. This result shown that crystalline Form A didn't change after DVS test.
    Table 4
    Solid FormWeight Gain under 80% Relative Humidity
    Crystalline Form A of the compound of formula (I) 0.10%


    [0057] About hygroscopicity characterization description and definition of hygroscopicity (Chinese Pharmacopoeia 2010 edition appendix XIXJ Drug hygroscopic test guidelines, test at 25 °C+/-1 °C, 80% Relative Humidity)
    • deliquescent: sufficient water is absorbed to form a liquid.
    • very hygroscopic: increase in mass is equal to or greater than 15%.
    • hygroscopic: increase in mass is less than 15% and equal to or greater than 2%.
    • slightly hygroscopic: increase in mass is less than 2% and equal to or greater than 0.2%.
    • no or almost no hygroscopic: increase in mass is less than 0.2%.


    [0058] The result shows that weight gain of crystalline Form A of the compound of formula (I) of the present disclosure is 0.10% at 80%RH. According to the criteria of hygroscopicity, Form A is a non-hygroscopic or almost non-hygroscopic form. This property indicates that the crystalline Form A is not sensitive to moisture and it is convenient for long-term storage. On the other hand, no special drying conditions are required in the preparation process due to its low hygroscopicity, which simplifies the preparation and post-treatment process to some extent, and the process is easy to be industrialized.

    Example 5



    [0059] Stability assessment of crystalline Form A of the compound of formula (I):
    The crystalline Form A of the compound of formula (I) of the present disclosure was stored under 25 °C/60% RH and 40 °C/75% RH for 90 days. XRPD and purity of the samples were collected after storing for 15 days, 30 days and 90 days. The results indicate that crystalline Form A has good physical stability and high chemical purity. The chemical purity data are shown in Table 5. The XRPD results of crystalline Form A before and after storing under 25 °C/60% RH and 40 °C/75% RH for 90 days are depicted in Fig. 7 (Fig. 7: the top, middle and bottom are initial crystalline Form A, crystalline Form A after storing at 25 °C/60%RH and 40°C/75%RH for 90 days respectively).
    Table 5 Stability of crystalline Form A (Purity%)
     25°C/60%RH/%40°C/75%R.H/%
    Initial 99.82 99.82
    15 days 99.94 99.94
    30 days 99.90 99.94
    90 days 99.93 99.94


    [0060] The results show that the crystalline Form A of the compound of formula (I) is stable under long-term stability condition (25°C/60%RH) and accelerated stability condition (40°C/75%R.H), and the chemical purity is almost unchanged. Therefore, the crystalline Form A of the compound of formula (I) of the present disclosure has good physical stability and high chemical purity.

    Example 6



    [0061] Solubility comparison of crystalline Form A of the compound formula (I) and Form I disclosed in CN101910156A:
    Crystalline Form A of the present disclosure and Form I disclosed in CN101910156A are prepared into saturated solution in SGF (Simulated gastric fluids), pH5.0 FeSSIF (Fed state simulated intestinal fluids), pH6.5 FaSSIF (Fasted state simulated intestinal fluids) and water. Concentrations in the saturation solutions were tested after 1 hour, 4 hours and 24 hours by HPLC.

    [0062] The results are listed in Table 6.



    [0063] The comparison results above indicate that the solubility of crystalline Form A of the present disclosure is higher than that of Form I disclosed in CN101910156A in SGF, FaSSIF, FeSSIF and H2O after 1 hour, 2 hours and 24 hours. Therefore, crystalline Form A of the present disclosure can improve drug's bioavailability, and is more suitable for drug development.

    Example 7



    [0064] Method of PLM test: placed about 0.5 mg of the sample on a glass slide and add a small amount of mineral oil to disperse the sample. After covering the coverslip, gently press with fingertips to ensure that there is no bubble between the glass slide and coverslip. Then adjust the eyepiece and objective lenses of the microscope and fine-tune the sample stage to focus on the sample. The PLM results of Form I disclosed in CN101910156A and Form A of the present disclosure are shown in Fig. 8 and Fig. 9, respectively. Form I disclosed in CN101910156A has a needle-like shape, while Form A of the present disclosure has a long rod-like shape. Therefore, Form A of the present disclosure has better fluidity, and is more suitable for process development.

    [0065] It should be noted that the reason why the compound of formula (1) in solid state is used as the starting material in the above examples is that the compound of formula (I) in solid state is easier to obtain, and it does not mean that only solid state form can be used. The said compound of formula (I) can be in solid, semi-solid, waxy or oil forms. According to the inventors' experiments, the final crystalline form is closely related to the preparation conditions and methods, regardless of the physical state of the starting material.

    [0066] The examples described above are only for illustrating the technical concepts and features of the present disclosure, and intended to make those skilled in the art being able to understand the present disclosure and thereby implement it, and should not be concluded to limit the protective scope of this disclosure.


    Claims

    1. A crystalline Form A of compound of formula (I),

    wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 8.8°±0.2°, 21.3°±0.2°, 22.2°±0.2°.
     
    2. The crystalline Form A according to claim 1, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 9.9°±0.2°, 18.1°±0.2°, 23.5°±0.2°.
     
    3. The crystalline Form A according to claim 1 or 2, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 10.6°±0.2°, 16.2°±0.2°. 20.0°±0.2°.
     
    4. A process of preparing crystalline Form A of compound of formula (I) according to any one of claims 1 to 3, comprising dissolving compound of formula (I) in ketones or the mixture of ketones and ethers, and obtaining a white solid by evaporation at the temperature of 20-80 °C.
     
    5. The process according to claim 4, wherein said temperature is 30°C∼70°C.
     
    6. The process according to claim 5, wherein said temperature is 40°C∼60°C.
     
    7. The process according to claim 4, wherein said ketones are acetone or methyl isobutyl ketone and said ether is methyl tertiary butyl ether.
     
    8. The process according to claim 4, wherein the volume ratio of the mixture of ketones and ethers is 1:1 to 1:4.
     
    9. The process according to claim 7 or 8, wherein the volume ratio of acetone or methyl isobutyl ketone with methyl tertiary butyl ether is 1:1 to 1:4.
     
    10. A pharmaceutical composition, wherein the said pharmaceutical composition comprises a therapeutically effective amount of crystalline Form A according to any one of claims 1-3 and pharmaceutically acceptable excipient.
     
    11. The use of crystalline Form A according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 10 for preparing drugs for treating cystic fibrosis.
     
    12. The use of crystalline Form A according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 10 in combination with one or more drugs for preparing drugs for treating cystic fibrosis.
     
    13. The use of crystalline Form A according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 10 in combination with Ivacaftor for preparing drugs for treating cystic fibrosis.
     


    Ansprüche

    1. Kristalline Form A der Verbindung der Formel (I),

    wobei das Röntgenpulverdiffraktogramm charakteristische Peaks bei 2Theta-Werten von 8,8°±0,2°, 21,3°±0,2°, 22,2°±0,2° zeigt.
     
    2. Die kristalline Form A nach Anspruch 1, wobei das Röntgenpulverdiffraktogramm ferner einen oder mehrere der charakteristischen Peaks bei 2Theta-Werten von 9,9°±0,2°, 18,1°±0,2°, 23,5°±0,2° zeigt.
     
    3. Die kristalline Form A nach Anspruch 1 oder 2, wobei das Röntgenpulverdiffraktogramm ferner einen oder mehrere der charakteristischen Peaks bei 2Theta-Werten von 10,6°±0,2°, 16,2°±0,2°, 20,0°±0,2° zeigt.
     
    4. Verfahren zur Herstellung der kristallinen Form A einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 3, umfassend das Auflösen der Verbindung der Formel (I) in Ketonen oder einer Mischung von Ketonen und Ethern, und das Erhalten eines weißen Feststoffs durch Verdampfen bei einer Temperatur von 20-80°C.
     
    5. Das Verfahren nach Anspruch 4, wobei die Temperatur 30°C∼70°C beträgt.
     
    6. Das Verfahren nach Anspruch 5, wobei die Temperatur 40°C∼60°C beträgt.
     
    7. Das Verfahren nach Anspruch 4, wobei die Ketone Aceton oder Methylisobutylketon und der Ether Methyl-tert-butylether sind.
     
    8. Das Verfahren nach Anspruch 4, wobei das Volumenverhältnis der Mischung von Ketonen und Ethern 1:1 bis 1:4 beträgt.
     
    9. Das Verfahren nach Anspruch 7 oder 8, wobei das Volumenverhältnis von Aceton oder Methylisobutylketon mit Methyl-tert-butylether 1:1 bis 1:4 beträgt.
     
    10. Pharmazeutische Zusammensetzung, wobei die pharmazeutische Zusammensetzung eine therapeutisch wirksame Menge der kristallinen Form A nach einem der Ansprüche 1-3 und einen pharmazeutisch annehmbaren Hilfsstoff umfasst.
     
    11. Verwendung der kristallinen Form A nach einem der Ansprüche 1 bis 3 oder der pharmazeutischen Zusammensetzung nach Anspruch 10 zur Herstellung von Arzneimitteln zur Behandlung von Mukoviszidose.
     
    12. Verwendung der kristallinen Form A nach einem der Ansprüche 1 bis 3 oder der pharmazeutischen Zusammensetzung nach Anspruch 10 in Kombination mit einem oder mehreren Arzneimitteln zur Herstellung von Arzneimitteln zur Behandlung von Mukoviszidose.
     
    13. Verwendung der kristallinen Form A nach einem der Ansprüche 1 bis 3 oder der pharmazeutischen Zusammensetzung nach Anspruch 10 in Kombination mit Ivacaftor zur Herstellung von Arzneimitteln zur Behandlung von Mukoviszidose.
     


    Revendications

    1. Forme A cristalline du composé de formule (I),

    le diffractogramme de rayons X sur poudre présentant des pics caractéristiques aux valeurs 2thêta de 8,8° ± 0,2°, 21,3° ± 0,2°, 22,2° ± 0,2°.
     
    2. Forme A cristalline selon la revendication 1, le diffractogramme de rayons X sur poudre présentant en outre un ou plusieurs des pics caractéristiques aux valeurs 2thêta de 9,9° ± 0,2°, 18,1° ± 0,2°, 23,5° ± 0,2°.
     
    3. Forme A cristalline selon la revendication 1 ou 2, le diffractogramme de rayons X sur poudre présentant en outre un ou plusieurs des pics caractéristiques aux valeurs 2thêta de 10,6° ± 0,2°, 16,2° ± 0,2°, 20,0° ± 0,2°.
     
    4. Procédé de préparation de la forme A cristalline du composé de formule (I) selon l'une quelconque des revendications 1 à 3, comprenant la dissolution du composé de formule (I) dans des cétones ou un mélange de cétones et d'éthers, et l'obtention d'un solide blanc par évaporation à la température de 20 à 80 °C.
     
    5. Procédé selon la revendication 4, dans lequel ladite température va de 30 °C à 70 °C.
     
    6. Procédé selon la revendication 5, dans lequel ladite température va de 40 °C à 60 °C.
     
    7. Procédé selon la revendication 4, dans lequel lesdites cétones sont l'acétone ou la méthylisobutylcétone et ledit éther est l'éther de méthyle et de tert-butyle.
     
    8. Procédé selon la revendication 4, dans lequel le rapport volumique du mélange de cétones et d'éthers va de 1/1 à 1/4.
     
    9. Procédé selon la revendication 7 ou 8, dans lequel le rapport volumique d'acétone ou de méthylisobutylcétone à l'éther de méthyle et de tert-butyle va de 1/1 à 1/4.
     
    10. Composition pharmaceutique, ladite composition pharmaceutique comprenant une quantité efficace, sur le plan thérapeutique, de forme A cristalline selon l'une quelconque des revendications 1 à 3 et un excipient pharmaceutiquement acceptable.
     
    11. Utilisation de la forme A cristalline selon l'une quelconque des revendications 1 à 3 ou de la composition pharmaceutique selon la revendication 10 selon la revendication 10 pour préparer des médicaments pour traiter la mucoviscidose.
     
    12. Utilisation de la forme A cristalline selon l'une quelconque des revendications 1 à 3 ou de la composition pharmaceutique selon la revendication 10 en association avec un ou plusieurs médicaments pour préparer des médicaments pour traiter la mucoviscidose.
     
    13. Utilisation de la forme A cristalline selon l'une quelconque des revendications 1 à 3 ou de la composition pharmaceutique selon la revendication 10 en association avec l'Ivacaftor pour préparer des médicaments pour traiter la mucoviscidose.
     




    Drawing


















    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description