EP4683922A1 - New polymorphs for a piperidino-dihydrothienopyrimidine sulfoxide - Google Patents

New polymorphs for a piperidino-dihydrothienopyrimidine sulfoxide

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Publication number
EP4683922A1
EP4683922A1 EP24709772.8A EP24709772A EP4683922A1 EP 4683922 A1 EP4683922 A1 EP 4683922A1 EP 24709772 A EP24709772 A EP 24709772A EP 4683922 A1 EP4683922 A1 EP 4683922A1
Authority
EP
European Patent Office
Prior art keywords
formula
anhydrous
inhibitor
ray powder
powder diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24709772.8A
Other languages
German (de)
French (fr)
Inventor
Dabing CHEN
Ruoshi LI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP4683922A1 publication Critical patent/EP4683922A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention concerns new polymorphs/crystalline forms for the PDE4B -inhibitor of formula I in particular
  • PDE4B-inhibitors such as the compound of formula I have a broad potential in different therapeutic fields. Examples include respiratory diseases (such as chronic obstructive bronchitis (COPD), coughing, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, progressive fibrosing interstitious lung diseases (PF-ILD) and idiopathic pulmonary fibrosis (IPF)) or gastrointestinal diseases or complaints (such as Crohn’s disease, ulcerative colitis etc.), inflammatory diseases of the joints, skin or eyes (such as rheumatoid arthritis, systemic sclerosis etc, cancers, and also diseases of the peripheral or central nervous system (such as Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis, depression and brain injuries caused by stroke, hypoxia or craniocerebral trauma).
  • the PDE4-inhibitor of formula I has been disclosed in WO2013/026797.
  • WO2013/026797 discloses the following crystalline forms/polymorphs of the PDE4- inhibitor of formula I and methods to manufacture them:
  • Form A (alternatively called Form I) which is an anhydrous crystalline form /polymorph of the PDE4-inhibitor of formula I and represents the kinetically most stable form of the PDE4-inhibitor of formula I,
  • Form B (alternatively called Form II) which is another anhydrous crystalline form /polymorph of the PDE4-inhibitor of formula I and represents the thermodynamically most stable form of the PDE4-inhibitor of formula I, and
  • Form C (alternatively called Form III) which is a dihydrate crystalline form/ polymorph of the PDE4-inhibitor of formula I.
  • Form D crystalline form/polymorph form IV
  • D Dynamic vapor sorption
  • Form V has never been isolated as pure form at room temperature (RT).
  • Form G crystalline form/polymorph form VII
  • the invention concerns a crystalline form of the PDE4-inhibitor of formula I
  • the invention relates to a crystalline form of the PDE4-inhibitor of formula I that it is a monohydrated form.
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 13.9 ⁇ 0.2, 19.6 ⁇ 0.2 and 23.8 ⁇ 0.2.
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following d-values of 19.2 A, 6.3 A, 4.5 A and 3.7 A.
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 6.9 ⁇ 0.2, 13.9 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, 21.6 ⁇ 0.2 and 23.8 ⁇ 0.2.
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.2 A, 12.8 A, 6.3 A, 4.7 A, 4.5 A, 4.1 A and 3.7 A.
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 13.9 ⁇ 0.2, 19.6 ⁇ 0.2 and 23.8 ⁇ 0.2 and which can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25°C overnight.
  • DVS Dynamic vapor sorption
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: : 4.6 ⁇ 0.2, 6.9 ⁇ 0.2, 13.9 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, 21.6 ⁇ 0.2 and 23.8 ⁇ 0.2 and which can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25°C overnight.
  • DVDS Dynamic vapor sorption
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2 and 26.4 ⁇ 0.2.
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 4.7 A, 4.5 A, 4.1 A and 3.4 A.
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 6.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2, 22.2 ⁇ 0.2, 23.8 ⁇ 0.2 and 26.4 ⁇ 0.2.
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 12.7 A, 5.3 A, 5.2 A, 4.7 A, 4.5 A, 4.1 A, 4.0 A, 3.7 A and 3.4 A.
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2 and 26.4 ⁇ 0.2 and which can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours.
  • DVS Dynamic vapor sorption
  • the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 6.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2, 22.2 ⁇ 0.2, 23.8 ⁇ 0.2 and 26.4 ⁇ 0.2 and which can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours.
  • DVS Dynamic vapor sorption
  • RH step-wise relative humidity
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2 and 26.4 ⁇ 0.2 and which shows in a DSC analysis a melt endotherm at about 105 °C (preferably shows in a DSC analysis a melt endotherm at about 105°C and additionally an endotherm at about 209°C).
  • the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ⁇ 0.2, 6.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 18.7 ⁇ 0.2, 19.6 ⁇ 0.2, 21.7 ⁇ 0.2, 22.2 ⁇ 0.2, 23.8 ⁇ 0.2 and 26.4 ⁇ 0.2 and which shows in a DSC analysis a melt endotherm at about 105 °C (preferably shows in a DSC analysis a melt endotherm at about 105°C and additionally an endotherm at about 209°C).
  • the invention relates to a crystalline form of the PDE4- inhibitor of formula I that is an anhydrous form.
  • the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ⁇ 0.2, 9.8 ⁇ 0.2, 19.6 ⁇ 0.2, 17.0 ⁇ 0.2, 21.2 ⁇ 0.2 and 26.2 ⁇ 0.2.
  • the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 4.5 A, 5.2 A, 4.2 A and 3.4 A.
  • the invention relates to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ⁇ 0.2, 9.8 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 18.9 ⁇ 0.2, 19.3 ⁇ 0.2, 19.6 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.2 ⁇ 0.2, 21.6 ⁇ 0.2, 23.7 ⁇ 0.2 and 26.4 ⁇ 0.2.
  • the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that it is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 5.2 A, 5.1 A, 4.7 A, 4.6 A, 4.5 A, 4.3 A, 4.2 A, 4.1 A, 3.7 A and 3.4 A.
  • the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ⁇ 0.2, 9.8 ⁇ 0.2, 19.6 ⁇ 0.2, 17.0 ⁇ 0.2, 21.2 ⁇ 0.2 and 26.2 ⁇ 0.2 and which can be manufactured from Anhydrous Form B that is heated to 225 °C at 10°C/min.
  • the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ⁇ 0.2, 9.8 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 18.9 ⁇ 0.2, 19.3 ⁇ 0.2, 19.6 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.2 ⁇ 0.2, 21.6 ⁇ 0.2, 23.7 ⁇ 0.2 and 26.4 ⁇ 0.2 and which can be manufactured from Anhydrous Form B that is heated to 225°C at 10°C/min.
  • the PDE4B -inhibitor of formula I can be manufactured as described in detail in WO2013/026797.
  • a polar organic solvent such as acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone
  • An additional amount of antisolvent (5-10 ml) is added to increase the yield.
  • the resulting slurry is filtered within 1 hr of cooling and the wet cake is dried at 60 °C under vacuum.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Dihydrate Form III Dihydrate Form C
  • an anhydrous solvent such as ethanol, methanol, isopropanol, or acetone
  • the wet cake is then dried at 60 °C under vacuum.
  • XRPD X-ray powder diffraction
  • Dihydrate Form III of the compound of formula I is suspended in 5-10 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • DVD Dynamic vapor sorption
  • RH relative humidity
  • the anhydrous “high temperature” Form V has never been isolated in its pure form at room temperature.
  • Dihydrate Form III Dihydrate Form C, manufactured as described in WO2013/026797 or as described above
  • DVS Dynamic Vapor Sorption
  • RH cycle step- wise relative humidity cycle
  • step size 10% RH
  • step duration 2 hours (dynamic vapor sorption through water sorption/desorption cycles)
  • 5 mL of water stirred overnight at room temperature.
  • the slurry is filtered dried at 40 °C under humidification and closed vacuum.
  • a Rigaku Miniflex II instrument was used with an X-ray generator of the type Power 450 W (30 kV-15 mA) (Optics: variable divergence slit).
  • the Goniometer range was 3.0 - 35.0 ° 2 0 and the scan speed was 0.02° 2 0/min with an accuracy of more than 0.01°.
  • a monochromator a foil filter/graphite was used and as a detector the scintillation counter Nal 23.0 mm diameter was used.
  • the sample was analysed on a low background Si (510) sample holder.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Fig. 4 X-ray powder diffraction diagram (XRPD) of Dehydrated Monohydrate Form IV
  • Monohydrate Form F) of the compound of formula I (DSC indicates a melt endotherm at about 105 °C and an endotherm at about 209 °C)
  • This XRPD diagram of Figure 1 the following 2- Theta- values (20-values) and d- values could be observed (see Table 1).
  • this XRPD diagram of Figure 4 the following 2-Theta-values (20-values) and d- values could be observed (see Table 10).
  • this XRPD diagram of Figure 5 the following 2-Theta- values (20-values) and d- values could be observed (see Table 13).
  • this XRPD diagram of Figure 9 the following 2- Theta-values (20-values) and d-values could be observed (see Table 19).
  • TGA thermogravimetric analysis
  • the samples were analyzed in an open platinum sample pan under N2 flow. The ramp that was used for the measurement was 10°C/min from 20°C to 300°C.
  • DSC differential scanning calorimetry
  • the sample was analyzed in an unsealed Aluminium pan under an N2 flow.
  • the ramp that was used for the measurement was 10°C/min from 20°C to 300°C.

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Abstract

The invention concerns new crystalline forms of the PDE4B-inhibitor of formula (I) in particular the Dehydrated Monohydrate Form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta-values measured using CuKα radiation: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2 and 23.8 ±0.2, the Anhydrous "high temperature" Form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKα radiation: 4.8 ±0.2, 9.8 ±0.2, 19.6 ±0.2, 17.0 ±0.2, 21.2 ±0.2 and 26.2 ±0.2, the Monohydrate Form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKα radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2, and the Dihydrate Form VII which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKα radiation: 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2 and 19.11 ±0.2.

Description

New Polymorphs for a Piperidino-Dihydrothienopyrimidine sulfoxide
1 BACKGROUND OF THE INVENTION
The invention concerns new polymorphs/crystalline forms for the PDE4B -inhibitor of formula I in particular
• Form IV which is a dehydrated monohydrate form
• Form V which is an anhydrous high-temperature form and
• Form VI which is another monohydrate form.
PDE4B-inhibitors such as the compound of formula I have a broad potential in different therapeutic fields. Examples include respiratory diseases (such as chronic obstructive bronchitis (COPD), coughing, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, progressive fibrosing interstitious lung diseases (PF-ILD) and idiopathic pulmonary fibrosis (IPF)) or gastrointestinal diseases or complaints (such as Crohn’s disease, ulcerative colitis etc.), inflammatory diseases of the joints, skin or eyes (such as rheumatoid arthritis, systemic sclerosis etc, cancers, and also diseases of the peripheral or central nervous system (such as Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis, depression and brain injuries caused by stroke, hypoxia or craniocerebral trauma). The PDE4-inhibitor of formula I has been disclosed in WO2013/026797.
Further WO2013/026797 discloses the following crystalline forms/polymorphs of the PDE4- inhibitor of formula I and methods to manufacture them:
• Form A (alternatively called Form I) which is an anhydrous crystalline form /polymorph of the PDE4-inhibitor of formula I and represents the kinetically most stable form of the PDE4-inhibitor of formula I,
• Form B (alternatively called Form II) which is another anhydrous crystalline form /polymorph of the PDE4-inhibitor of formula I and represents the thermodynamically most stable form of the PDE4-inhibitor of formula I, and
• Form C (alternatively called Form III) which is a dihydrate crystalline form/ polymorph of the PDE4-inhibitor of formula I.
Starting from the disclosure of WO2013/026797 as closest piece of prior art, it was the aim of the instant invention to provide alternative polymorphs of the PDE4B-inhibitor of formula I.
Surprisingly it has been found that - additionally to crystalline forms A, B and C as described in WO20 13/026797 - further crystalline forms/ polymorphs of the PDE4-inhibitor of formula I In one aspect, the invention concerns crystalline form/polymorph form IV (alternatively called Form D) of the compound of formula I which is a “dehydrated monohydrate form” and which can be manufactured from dried Dihydrate Form III (=Dihydrate Form C) that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25°C overnight.
In another aspect, the invention concerns crystalline form/polymorph form V (alternatively called Form E) of the compound of formula I which is an anhydrous “high-temperature” form that can be manufactured from Anhydrous Form II (= Anhydrate Form B) that is heated to 225 °C at 10°C/min. Form V has never been isolated as pure form at room temperature (RT).
In a further aspect, the invention concerns crystalline form/polymorph form VI (alternatively called Form F) of the compound of formula I which is a “monohydrate form” that can be manufactured from Dihydrate Form III (= Dihydrate Form C) that is subjected in Dynamic vapor sorption (DVS) in a step-wise RH cycle (90%-0%-90%) at 25°C, with a step size of 10% RH and a step duration of 2 hours.
In another aspect, the invention relates to crystalline form/polymorph form VII (alternatively called Form G) of the compound of formula I which is a “dihydrate form” that can be manufactured from 0,5 g of Form A (= Form I) and 5 ml of water which are stirred at room temperature overnight and whereby the resulting slurry is then filtered dried at 40°C under humidification and closed vacuum.
2 DESCRIPTION OF THE INVENTION
In a first aspect, the invention concerns a crystalline form of the PDE4-inhibitor of formula I
In a preferred embodiment, the invention relates to a crystalline form of the PDE4-inhibitor of formula I that it is a monohydrated form.
In a more preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2 and 23.8 ±0.2.
The crystalline monohydrate form IV of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form I (=anhydrous Form A) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 13.9 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 13.44)
• the 2Theta-value of 19.6 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 19.18).
The crystalline monohydrate form IV of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form II (=anhydrous Form B) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 13.9 ±0.2 (anhydrous Form II only has a reflex peak with a 2Theta- value of 14.56)
• the 2Theta-value of 19.6 ±0.2 (anhydrous Form II only has a reflex peak with a 2Theta- value of 19.18). The crystalline monohydrate form IV of the PDE4B-inhibitor of formula I hereby differentiates from the Dihydrate Form III (=Dihydrate Form C) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 4.60±0.2 (Dihydrate Form III only has a reflex peak with a 2Theta- value of 8.60).
In another more preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following d-values of 19.2 A, 6.3 A, 4.5 A and 3.7 A.
In a particularly preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 6.9±0.2, 13.9 ±0.2, 18.6 ±0.2, 19.6 ±0.2, 21.6 ±0.2 and 23.8 ±0.2.
In a particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.2 A, 12.8 A, 6.3 A, 4.7 A, 4.5 A, 4.1 A and 3.7 A.
In another particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2 and 23.8 ±0.2 and which can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25°C overnight. In another particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta- values measured in degrees using CuKa radiation: : 4.6 ±0.2, 6.9±0.2, 13.9 ±0.2, 18.6 ±0.2, 19.6 ±0.2, 21.6 ±0.2 and 23.8 ±0.2 and which can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25°C overnight.
In another more preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2.
The crystalline monohydrate form VI of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form I (=anhydrous Form A) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 19.6 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 19.18)
• the 2Theta-value of 21.7 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 21.48)
• the 2Theta-value of 26.4 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 26.61).
The crystalline monohydrate form VI of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form II (=anhydrous Form B) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 18.7 ±0.2 (anhydrous Form II only has a reflex peak with a 2Theta- value of 19.18)
• the 2Theta-value of 26.4 ±0.2 (anhydrous Form II only has a reflex peak with a 2Theta- value of 26.64). The crystalline monohydrate form VI of the PDE4B-inhibitor of formula I hereby differentiates from the Dihydrate Form III (=Dihydrate Form C) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 4.60±0.2 (Dihydrate Form III only has a reflex peak with a 2Theta- value of 8.60).
In another more preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 4.7 A, 4.5 A, 4.1 A and 3.4 A.
In a further particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 6.9 ±0.2, 16.7 ±0.2, 17.1 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2, 22.2 ±0.2, 23.8 ±0.2 and 26.4 ±0.2.
In a further particularly preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 12.7 A, 5.3 A, 5.2 A, 4.7 A, 4.5 A, 4.1 A, 4.0 A, 3.7 A and 3.4 A.
In another particularly preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 and which can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours. In a further particularly preferred embodiment, the invention refers to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 6.9 ±0.2, 16.7 ±0.2, 17.1 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2, 22.2 ±0.2, 23.8 ±0.2 and 26.4 ±0.2 and which can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours.
In a further particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 and which shows in a DSC analysis a melt endotherm at about 105 °C (preferably shows in a DSC analysis a melt endotherm at about 105°C and additionally an endotherm at about 209°C).
In a further particularly preferred embodiment, the invention relates to the above-mentioned crystalline monohydrate form of the PDE4-inhibitor of formula I that is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.6 ±0.2, 6.9 ±0.2, 16.7 ±0.2, 17.1 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2, 22.2 ±0.2, 23.8 ±0.2 and 26.4 ±0.2 and which shows in a DSC analysis a melt endotherm at about 105 °C (preferably shows in a DSC analysis a melt endotherm at about 105°C and additionally an endotherm at about 209°C).
In another preferred embodiment, the invention relates to a crystalline form of the PDE4- inhibitor of formula I that is an anhydrous form.
In a more preferred embodiment, the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 19.6 ±0.2, 17.0 ±0.2, 21.2 ±0.2 and 26.2 ±0.2.
The crystalline Anhydrous “high temperature” Form V of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form I (=anhydrous Form A) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 4.8 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 4.48)
• the 2Theta-value of 9.8 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 9.54)
• the 2Theta-value of 19.6 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 19.18).
• the 2Theta-value of 21.2 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 21.48).
• the 2Theta-value of 26.2 ±0.2 (anhydrous Form I only has a reflex peak with a 2Theta- value of 26.61).
The crystalline Anhydrous “high temperature” Form V of the PDE4B-inhibitor of formula I hereby differentiates from the anhydrous Form II (=anhydrous Form B) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 26.2 ±0.2 (anhydrous Form II only has a reflex peak with a 2Theta- value of 26.64).
The crystalline Anhydrous “high temperature” Form V of the PDE4B-inhibitor of formula I hereby differentiates from the Dihydrate Form III (=Dihydrate Form C) as disclosed in WO2013/026797 in a reflex peak in the XRPD diagram with
• the 2Theta-value of 4.80±0.2 (Dihydrate Form III only has a reflex peak with a 2Theta- value of 8.60)
• the 2Theta-value of 21 ,2±0.2 (Dihydrate Form III only has a reflex peak with a 2Theta- value of 21.54). • the 2Theta-value of 26.2±0.2 (Dihydrate Form III only has a reflex peak with a 2Theta- value of 26.50).
In a more preferred embodiment, the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 4.5 A, 5.2 A, 4.2 A and 3.4 A.
In a further particularly preferred embodiment, the invention relates to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 17.0 ±0.2, 17.5 ±0.2, 18.9 ±0.2, 19.3 ±0.2, 19.6 ±0.2, 20.5 ±0.2 and 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2.
In a further particularly preferred embodiment, the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that it is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 5.2 A, 5.1 A, 4.7 A, 4.6 A, 4.5 A, 4.3 A, 4.2 A, 4.1 A, 3.7 A and 3.4 A.
In another particularly preferred embodiment, the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 19.6 ±0.2, 17.0 ±0.2, 21.2 ±0.2 and 26.2 ±0.2 and which can be manufactured from Anhydrous Form B that is heated to 225 °C at 10°C/min.
In another particularly preferred embodiment, the invention refers to the above-mentioned anhydrous crystalline form of the PDE4-inhibitor of formula I that is the anhydrous “high- temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 17.0 ±0.2, 17.5 ±0.2, 18.9 ±0.2, 19.3 ±0.2, 19.6 ±0.2, 20.5 ±0.2 and 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2 and which can be manufactured from Anhydrous Form B that is heated to 225°C at 10°C/min.
In another preferred embodiment, the invention relates to the above-mentioned Dihydrate Form VII (= Dihydrate Form G) of the PDE4-inhibitor of formula I which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2 and 19.11 ±0.2.
In another particularly preferred embodiment, the invention relates to the above-mentioned Dihydrate Form VII (= Dihydrate Form G) of the PDE4-inhibitor of formula I which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2, 17.34 ±0.2, 19.11 ±0.2, 19.57 ±0.2, 21.56 ±0.2 and 25.0 3±0.2.
3 Methods of Preparation of the different polymorphs of the PDE4B-inhibitor of formula I
The PDE4B -inhibitor of formula I can be manufactured as described in detail in WO2013/026797.
Preparation route for Form I (identical to “Form A” as disclosed in WO2013/026797):
Preparation of seed crystals (anhydrous Form I or anhydrous Form A)
Small amounts of the crude compound of formula 1 (1-2 mg) were suspended in approximately 0.1 ml of the following solvents: ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1 -propanol, 2-butanol, and acetonitrile. After a heating/cooling cycle, the samples resulted in suspensions of crystalline anhydrous Form I as analysed by X-ray powder diffraction. a. Crystallization from acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone: Approximately 1 g of crude compound of formula I is dissolved in 10 ml of a polar organic solvent such as acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone at a temperature of^60°C. The solution is cooled to 30-40°C and an antisolvent (approximately 5-10 ml) such as isopropyl alcohol, ethyl alcohol, or acetone is added. The solution is seeded with anhydrous Form I (= Form A) crystals of the compound of formula I and cooled to 20°C. An additional amount of antisolvent (5-10 ml) is added to increase the yield. The resulting slurry is filtered within 1 hr of cooling and the wet cake is dried at 60 °C under vacuum. Anhydrous Form I (=anhydrous Form A) is obtained as a white solid as confirmed by X-ray powder diffraction (XRPD) of the anhydrous Form A standard on file. b. Crystallization from tetrahydrofuran/water:
Approximately 1 g of crude compound of formula I is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60°C. The solution is cooled to 40- 50°C, seeded with anhydrous Form I (= anhydrous Form A) crystals of the compound of formula I, and further cooled to 20°C in less than 1 hr. Approximately 5-10 ml of antisolvent (an organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is filtered within 1 hr after the antisolvent addition and the wet cake is dried at 60 °C under vacuum. Anhydrous Form I (= anhydrous Form A) is obtained as a white solid as confirmed by X-ray powder diffraction (XRPD) of the anhydrous Form I standard on file. c. Drying from Dihydrate Form III (= Dihydrate Form C):
Approximately 1 g of the Dihydrate form III(= Dihydrate Form C) of the compound of formula I is washed with approximately 5 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, or acetone on a buchner funnel. The wet cake is then dried at 60 °C under vacuum. Anhydrous Form I (= anhydrous Form A) is obtained as a white solid as confirmed by X-ray powder diffraction (XRPD) of the anhydrous Form I standard on file.
Preparation route for Form II (identical to “Form B” as disclosed in WO2013/026797):
Preparation of seed crystals of anhydrous Form B
Small amounts of the crude compound of formula 1 (1-2 mg) were suspended in approximately 0.1 ml of 2-propanol and water mixtures (one with 3.3% of water and another with 6.6% water). After a heating/cooling cycle, the samples resulted in suspensions of crystalline anhydrous Form II (= anhydrous Form B) by X-ray powder diffraction analysis. The samples in anhydrous 2- pr opanol subjected to the same conditions resulted in the mixture of Form I and Form II as analysed by X-ray powder diffraction. The mixture of Form I and Form II, slurried at 20°C for 4 days in mixtures of water and the following solvents: methanol, ethanol, 2-propanol, 1 -propanol, and acetone (all with approximately 9% water), resulted in Form II (= anhydrous Form B) as analysed by X-ray powder diffraction. a. Crystallization from n-propanol/water:
10 g of the crude compound of formula I is dissolved in 160 ml of n-propanol/water mixture (9:1, v/v) at a temperature of >65°C. The solution is cooled to 60°C, seeded with anhydrous Form II crystals (= anhydrous Form B) of the compound of formula I, and aged for 0.5 hr. The slurry is cooled to 30°C over at least 5 hrs. Optionally the slurry is distilled at 30°C under reduced pressure to reduce the volume to approximately 80-100 ml in order to maximize the yield. The slurry is further cooled to 0° C and the slurry is aged for at least 8 hrs or until anhydrous Form I (= anhydrous Form A) is no longer detected. The slurry is filtered and the wet cake is dried at 60 °C under vacuum. Anhydrous Form II (= anhydrous Form B) of the compound of formula I is obtained as a white solid in a 90% yield. X-ray powder diffraction (XRPD) conforms to the anhydrous Form II (= anhydrous Form B) standard on file. b. Crystallization from tetrahydrofuran/water:
Approximately 1 g of the crude compound of formula I is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60°C. The solution is cooled to 40- 50°C, seeded with anhydrous Form II crystals (= anhydrous Form B) of the compound of formula I, and is further cooled to 20°C over 2 hrs. Approximately 10 ml of antisolvent (an organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is aged for at least 8 hrs or until anhydrous Form I (= anhydrous Form A) is no longer detected. The slurry is then filtered and the wet cake is dried at 60 °C under vacuum.
Anhydrous Form II (= anhydrous Form B) of the compound of formula I is obtained as a white solid. X-ray powder diffraction (XRPD) conforms to the anhydrous Form II (= anhydrous Form B) standard on file. c. Conversion from Dihydrate Form III (= Dihydrate Form C):
Approximately 1 g of Dihydrate Form III of the compound of formula I is suspended in 5-10 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form II crystals (= anhydrous Form B crystals) of the compound of formula I and stirred at 20-40 °C for at least 4 hours or until the conversion to anhydrous Form II (= anhydrous Form B) is complete as checked by X-ray powder diffraction (XRPD) analysis. d. Conversion from anhydrous Form I (=anhydrous Form A):
Approximately 1 g of anhydrous Form I (= anhydrous Form A) of the compound of formula I is suspended in 5-10 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form II crystals (= anhydrous Form B crystals) of the compound of formula I and stirred at 20-40 °C for at least 4 hours or until the conversion to anhydrous Form II (= anhydrous Form B) is complete as checked by X-ray powder diffraction (XRPD) analysis.
Preparation route for Form HI (identical to “Form C” as disclosed in WO2013/026797):
Preparation of seed crystals of the Dihydrate Form III (= Dihydrate Form C)
The mixture of anhydrous Form I crystals (= anhydrous Form A) and anhydrous Form II crystals (= anhydrous Form B) of the compound of formula I slurried at 20°C for 4 days in 2- butanone/water (with 9% water), resulted in the Dihydrate Form III crystals (= Dihydrate Form C crystals) as confirmed by X-ray powder diffraction analysis. a. Crystallization from n-propanol/water:
10 g of the crude compound of formula I is dissolved in 120 ml of n-propanol/water mixture (8:2, v/v) at a temperature of >65°C. The solution is cooled to 50°C, seeded with Dihydrate Form III crystals (= Dihydrate Form C crystals) of the compound of formula I, and aged for 0.5 hr. Water (approximately 60-100 ml) is added to the slurry. The slurry is cooled to 20°C over at least 5 hrs and then aged for at least 8 hrs. The slurry is filtered, and the wet cake is washed with water and then air-dried. b. Crystallization in THF/water:
Approximately 1 g of the crude compound of formula I is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60°C. The solution is cooled to 30- 50°C, seeded with Dihydrate Form III crystals (= Dihydrate Form C crystals) of the compound of formula I, and further cooled to 20°C over 2 hrs. Approximately 10 ml of water is added to the slurry. The resulting slurry is aged for at least 8 hrs. The slurry is filtered, and the wet cake is washed with water and then air-dried. X-ray powder diffraction (XRPD) of the product shows the Dihydrate pattern of Form III (= Form C). c. Conversion from anhydrous Form I (= anhydrous Form A) or from anhydrous Form II (= anhydrous Form B):
Approximately 1 g of anhydrous Form I (= anhydrous Form A) or of anhydrous Form II (= anhydrous Form B) of the compound of formula I is suspended in approximately 5-10 ml of a mixture of at least 30% water and an organic solvent such as ethanol, methanol, isopropanol, acetone, or tetrahydrofuran. The suspension is seeded with Dihydrate Form III crystals (= Dihydrate Form C crystals) of the compound of formula I, and stirred at 20°C for at least 4 hrs or until the conversion to the Dihydrate Form III (= Dihydrate Form C) is complete as checked by X-ray powder diffraction (XRPD) analysis. The slurry is filtered, and the wet cake is washed with water and then air-dried.
Preparation route for the dehydrated monohydrate Form TV (alternatively named “Form D”):
Dried Dihydrate Form III (= Dihydrate Form C, manufactured as described in WO2013/026797 or as described above) of the PDE4B-inhibitor of formula I is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (RH) at 25 °C overnight to obtain the dehydrated monohydrate Form IV of the compound of formula I.
Preparation route for the anhydrous “high temperature” Form V (alternatively named “Form E”): Anhydrous Form II (= anhydrous Form B, manufactured as described in WO2013/026797 or as described above) of the PDE4B-inhibitor of formula I is heated to 225 °C at 10 °C / min to obtain the anhydrous “high temperature” Form V (= anhydrous “high temperature” Form E) of the compound of formula I. The anhydrous “high temperature” Form V has never been isolated in its pure form at room temperature.
Preparation route for the Monohydrate Form VI (alternatively named “Form F”):
10 mg of Dihydrate Form III (= Dihydrate Form C, manufactured as described in WO2013/026797 or as described above) of the compound of formula I was placed in a Dynamic Vapor Sorption (DVS) sample pan and subjected to a step- wise relative humidity cycle (RH cycle) of (90%-0%-90%) at 25 °C, with a step size of 10% RH and a step duration of 2 hours (dynamic vapor sorption through water sorption/desorption cycles) to obtain the Monohydrate Form VI (= Monohydrate Form F) of the compound of formula I.
Preparation route for the Dihydrate Form VII (alternatively named “Form G”)
Method a)
10 g of Form B (= Form II) is dissolved in 55 mL 22% water in n-propanol. The mixture is stirred at 15 °C and then seeded with dihydrate crystal Form G. The temperature is then lowered to 0 °C and left for aging for at least 48 h. The product is filtered and washed with n-propanol, then dried in the oven without heat under nitrogen.
Method b)
0.5 g of Form A (= Form I) and 5 mL of water stirred overnight at room temperature. The slurry is filtered dried at 40 °C under humidification and closed vacuum.
Method c)
Form A (= Form I), Form B (= Form II) and Form G (=Form VII) (25-50 mg) each were slurried in 13% water in n-propanol for 1 day at 5 °C and 15 °C. Form VII was then collected by filtration.
Y1 4 X-ray powder diffraction diagram (XRPD) analysis of the different polymorphs of the PDE4B-inhibitor of formula I
The polymorphs/crystalline forms of the compound of formula I were characterized by X-ray powder diffraction (XRPD) as shown in Figures 1 to 6 showing the X-ray powder diffraction diagrams for each of the different polymorphs/crystalline forms of the PDE4B-inhibitor of formula I and as shown the following tables with all observable reflex peaks for each of the different polymorphs/crystalline forms of the PDE4B-inhibitor of formula I.
For the performance of the X-ray powder diffraction analysis a Rigaku Miniflex II instrument was used with an X-ray generator of the type Power 450 W (30 kV-15 mA) (Optics: variable divergence slit). The Goniometer range was 3.0 - 35.0 ° 2 0 and the scan speed was 0.02° 2 0/min with an accuracy of more than 0.01°. As a monochromator a foil filter/graphite was used and as a detector the scintillation counter Nal 23.0 mm diameter was used. The sample was analysed on a low background Si (510) sample holder.
FIGURES:
Fig. 1 : X-ray powder diffraction diagram (XRPD) of Anhydrous Form I (= Anhydrous
Form A) of the compound of formula I
Fig. 2: X-ray powder diffraction diagram (XRPD) of Anhydrous Form II (= Anhydrous
Form B) of the compound of formula I
Fig. 3: X-ray powder diffraction diagram (XRPD) of Dihydrate Form III (= Dihydrate
Form C) of the compound of formula I
Fig. 4: X-ray powder diffraction diagram (XRPD) of Dehydrated Monohydrate Form IV
(= Dehydrated Monohydrate Form D) of the compound of formula I
Fig. 5: X-ray powder diffraction diagram (XRPD) of Anhydrous “high temperature”
Form V (= Anhydrous “high temperature” Form E) of the compound of formula I
Fig. 6: X-ray powder diffraction diagram (XRPD) of Monohydrate Form VI (=
Monohydrate Form F) of the compound of formula I Fig. 7: Thermogravimetric Analysis (TGA) of Monohydrate Form VI (= Monohydrate
Form F) of the compound of formula I
Fig. 8: Differential Scanning Calorimetry (DSC) of Monohydrate Form VI (=
Monohydrate Form F) of the compound of formula I (DSC indicates a melt endotherm at about 105 °C and an endotherm at about 209 °C)
Fig. 9: X-ray powder diffraction diagram (XRPD) of Dihydrate Form VII (= Dihydrate
Form G) of the compound of formula I
Fig. 10: Thermogravimetric Analysis (TGA) of Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I
Fig. 11: Differential Scanning Calorimetry (DSC) of Dihydrate Form VII (= Dihydrate
Form G)
4.1 XRPD analysis of the Anhydrous Form I (=Anhydrate Form A) of the compound of formula I
Figure 1 shows the X-ray powder diffraction diagram of the Anhydrous Form I (= Anhydrous Form A) of the compound of formula I. In this XRPD diagram of Figure 1 the following 2- Theta- values (20-values) and d- values could be observed (see Table 1).
Table 1: All observable peaks for the Anhydrous Form I ( = Anhydrate Form A as disclosed in WO2013/026797) of the compound of formula I (see Fig. 1):
The major peaks of the XRPD diagram of the anhydrous Form I (= anhydrous Form A) of the compound of formula I are listed in Table 2 (see Fig. 1): Table 2: Major peaks for the Anhydrous Form I (= Anhydrate Form A):
The most prominent peaks of the XRPD diagram of the Anhydrous Form I (= Anhydrate Form A) of the compound of formula I are listed in Table 3 (see Fig. 1).
Table 3: Prominent peaks for the Anhydrous Form I (= Anhydrate Form A):
4.2 XRPD analysis of the Anhydrous Form II (=Anhydrate Form B) of the compound of formula I Fig. 2 shows the X-ray powder diffraction diagram of the Anhydrous Form II (=Anhydrate Form B) of the compound of formula I. In this XRPD diagram of the Anhydrous Form II (=Anhydrate Form B) of the compound of formula I the following 2-Theta- values (=20-values) and d- values could be observed (Table 4).
Table 4: All observable peaks for the Anhydrous Form II (= Anhydrate Form B as disclosed in WO2013/026797) of the compound of formula I (see Fig. 2):
The major peaks of the XRPD diagram of the Anhydrous Form II (= Anhydrate Form B) of the compound of formula I are listed in Table 5.
Table 5: Major peaks for the Anhydrous Form II (=Anhydrate Form B): The most prominent peaks of the XRPD diagram of Anhydrous Form II (=Anhydrate Form B) of the compound of formula I are listed in Table 6.
Table 6: Prominent peaks for the Anhydrous Form II (=Anhydrate Form B)
4.3 XRPD analysis of the Dihydrate Form III (=Dihydrate Form C) of the compound of formula I
Fig. 3 shows the X-ray powder diffraction diagram of the Dihydrate Form III (= Dihydrate Form C) of the compound of formula I. In this XRPD diagram of the Dihydrate Form III (=Dihydrate Form C) of the compound of formula I the following 2-Theta- values (=20-values) and d- values could be observed (Table 7).
Table 7: All observable peaks for the Dihydrate Form III (=Dihydrate Form C as disclosed in WO2013/026797) of the compound of formula I (see Fig. 3): The major peaks of the XRPD diagram of the Dihydrate Form III (= Dihydrate Form C) of the compound of formula I are listed in Table 8.
Table 8: Major peaks for the Dihydrate Form III (= Dihydrate Form C):
The most prominent peaks of the XRPD diagram of Dihydrate Form III (=Dihydrate Form C) of the compound of formula I are listed in Table 9.
Table 9: Prominent peaks for the Dihydrate Form III (= Dihydrate Form C):
4.4 XRPD analysis of the Dehydrated Monohydrate Form IV (=Dehydrated Monohydrate Form D) of the compound of formula I
Figure 4 shows the X-ray powder diffraction diagram of the Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D) of the compound of formula I. In this XRPD diagram of Figure 4 the following 2-Theta-values (20-values) and d- values could be observed (see Table 10).
Table 10: All observable peaks for the Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D):
The major peaks of the XRPD diagram of the Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D) of the compound of formula I are listed in Table 11 (see Fig. 4).
Table 11 : Major peaks for the Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D): The most prominent peaks of the XRPD diagram of Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D) of the compound of formula I are listed in Table 12 (see Fig. 4).
Table 12: Prominent peaks for the Dehydrated Monohydrate Form IV (= Dehydrated Monohydrate Form D):
4.5 XRPD analysis of the Anhydrous “high temperature” Form V (=Anhydrous “high temperature Form E) of the compound of formula I
Figure 5 shows the X-ray powder diffraction diagram of the Anhydrous “high temperature” Form V (= Anhydrous “high temperature” Form E) of the compound of formula I. In this XRPD diagram of Figure 5 the following 2-Theta- values (20-values) and d- values could be observed (see Table 13).
Table 13: All observable peaks for the Anhydrous “high temperature” Form V (= Anhydrous “high temperature” Form E):
The major peaks of the XRPD diagram of the Anhydrous “high temperature” Form V (= Anhydrous “high temperature” Form E) of the compound of formula I are listed in Table 14 (see Fig- 5).
Table 14: Major peaks for the Anhydrous “high temperature” Form V (= Anhydrous “high temperature” Form E):
The most prominent peaks of the XRPD diagram of Anhydrous “high temperature” Form V (= Anhydrous “high temperature Form E) of the compound of formula I are listed in Table 15 (see Fig- 5).
Table 15: Prominent peaks for the Anhydrous “high temperature” Form V (= Anhydrous “high temperature” Form E):
4.6 XRPD analysis of the Monohydrate Form VI (=Monohydrate Form F) of the compound of formula I
Figure 6 shows the X-ray powder diffraction diagram of the Monohydrate Form VI (= Monohydrate Form F) of the compound of formula I. In this XRPD diagram of Figure 6 the following 2-Theta-values (20-values) and d-values could be observed (see Table 16). Table 16: All observable peaks for the Monohydrate Form VI (= Monohydrate Form F):
The major peaks of the XRPD diagram of the Monohydrate Form VI (= Monohydrate Form F) of the compound of formula I are listed in Table 17 (see Fig. 6).
Table 17: Major peaks for the Monohydrate Form VI (= Monohydrate Form F):
The most prominent peaks of the XRPD diagram of Monohydrate Form VI (= Monohydrate Form F) of the compound of formula I are listed in Table 18 (see Fig. 6).
Table 18: Prominent peaks for the Monohydrate Form VI (= Monohydrate Form F):
4.7 XRPD analysis of the Dihydrate Form VII (=Dihydrate Form G) of the compound of formula I
Figure 9 shows the X-ray powder diffraction diagram of the Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I. In this XRPD diagram of Figure 9 the following 2- Theta-values (20-values) and d-values could be observed (see Table 19).
Table 19: All observable peaks for the Dihydrate Form VII (= Dihydrate Form G):
The major peaks of the XRPD diagram of the Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I are listed in Table 20 (see Fig. 9).
Table 20: Major peaks for the Dihydrate Form VII (= Dihydrate Form G):
The most prominent peaks of the XRPD diagram of Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I are listed in Table 21 (see Fig. 9).
Table 21 : Prominent peaks for the Dihydrate Form VII (= Dihydrate Form G): 5. Thermoqravimetric Analysis (TGA) of the different polymorphs of the PDE4B- inhibitor of formula I
The Monohydrate Form VI (= Monohydrate Form F) and the Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I were further characterized by thermogravimetric analysis (TGA) with a TA Instruments TGA Q500 as shown in Fig. 7 (for Monohydrate Form VI) and in Fig. 10 (for Dihydrate Form VII). The samples were analyzed in an open platinum sample pan under N2 flow. The ramp that was used for the measurement was 10°C/min from 20°C to 300°C.
6. Differential Scanning Calorimetry (DSC) analysis of the different polymorphs of the PDE4B-inhibitor of formula I
The Monohydrate Form VI (= Monohydrate Form F) and the Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I were further characterized by differential scanning calorimetry (DSC) with a TA Instruments DSC QI 000 as shown in Fig. 8 (for Monohydrate Form VI) and in Fig. 11 (for Dihydrate Form VII). The sample was analyzed in an unsealed Aluminium pan under an N2 flow. The ramp that was used for the measurement was 10°C/min from 20°C to 300°C.
DSC analysis of the Monohydrate Form VI (= Monohydrate Form F) of the compound of formula I indicates an endotherm at about 105 °C and an endotherm at about 209 °C.
DSC analysis of the Dihydrate Form VII (= Dihydrate Form G) of the compound of formula I indicates an endotherm at about 235 °C.

Claims

Patent Claims
1. Crystalline form of the PDE4-inhibitor of formula I
2. The crystalline form of the PDE4-inhibitor of formula I according to claim 1 , characterized therein that it is a monohydrate form.
3. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2, characterized therein that it is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2 and 23.8 ±0.2.
4. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2, characterized therein that it is form IV which shows reflex peaks in the X-ray powder diffraction diagram with the following d- values of 19.2 A, 6.3 A, 4.5 A and 3.7 A.
5. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2 and 3, characterized therein that it is form IV which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 6.9±0.2, 13.9 ±0.2, 18.6 ±0.2, 19.6 ±0.2, 21.6 ±0.2 and 23.8 ±0.2.
6. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2 and 4, characterized therein that it is form IV which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.2 A, 12.8 A, 6.3 A, 4.7 A, 4.5 A, 4.1 A and 3.7 A.
7. The crystalline monohydrate form IV of the PDE4-inhibitor of formula I according to claim 3 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with the following 2 Theta- values measured using CuKa radiation: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2 and 23.8 ±0.2 and therein that it can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25 °C overnight.
8. The crystalline monohydrate form IV of the PDE4-inhibitor of formula I according to claim 5 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with the following 2 Theta- values measured using CuKa radiation: 4.6 ±0.2, 6.9±0.2, 13.9 ±0.2, 18.6 ±0.2, 19.6 ±0.2, 21.6 ±0.2 and 23.8 ±0.2 and therein that it can be manufactured from dried Dihydrate Form C of the compound of formula I that is subjected to Dynamic vapor sorption (DVS) at 0% relative humidity (% RH) at 25 °C overnight.
9. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2, characterized therein that it is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2.
10. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2, characterized therein that it is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 4.7 A, 4.5 A, 4.1 A and 3.4 A.
11. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2 and 9, characterized therein that it is form VI which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 6.9 ±0.2, 16.7 ±0.2, 17.1 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2, 22.2 ±0.2, 23.8 ±0.2 and 26.4 ±0.2.
12. The crystalline monohydrate form of the PDE4-inhibitor of formula I according to claim 2 and 10, characterized therein that it is form VI which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 19.1 A, 12.7 A, 5.3 A, 5.2 A, 4.7 A, 4.5 A, 4.1 A, 4.0 A, 3.7 A and 3.4 A.
13. The crystalline monohydrate form VI of the PDE4-inhibitor of formula I according to claim 9 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 and therein that it can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours.
14. The crystalline monohydrate form VI of the PDE4-inhibitor of formula I according to claim 11 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.6 ±0.2, 6.9 ±0.2, 16.7 ±0.2, 17.1 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2, 22.2 ±0.2, 23.8 ±0.2 and 26.4 ±0.2 and therein that it can be manufactured from Dihydrate Form C that is subjected in Dynamic vapor sorption (DVS) in a step-wise relative humidity (RH) cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours.
15. The crystalline form of the PDE4-inhibitor of formula I according to claim 1, characterized therein that it is an anhydrous form.
16. The anhydrous crystalline form of the PDE4-inhibitor of formula I according to claim 15, characterized therein that it is the anhydrous “high-temperature form” V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 19.6 ±0.2, 17.0 ±0.2, 21.2 ±0.2 and 26.2 ±0.2.
17. The anhydrous crystalline form of the PDE4-inhibitor of formula I according to claim 15, characterized therein that it is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 4.5 A, 5.2 A, 4.2 A and 3.4 A.
18. The anhydrous crystalline form of the PDE4-inhibitor of formula I according to claims 15 and 16, characterized therein that it is the anhydrous “high-temperature” form V which shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 17.0 ±0.2, 17.5 ±0.2, 18.9 ±0.2, 19.3 ±0.2, 19.6 ±0.2, 20.5 ±0.2 and 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2.
19. The anhydrous crystalline form of the PDE4-inhibitor of formula I according to claims 15 and 17, characterized therein that it is the anhydrous “high-temperature“ form V which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 18.4 A, 9.0 A, 5.2 A, 5.1 A, 4.7 A, 4.6 A, 4.5 A, 4.3 A, 4.2 A, 4.1 A, 3.7 A and 3.4 A.
20. The crystalline anhydrous “high temperature” Form V of the PDE4-inhibitor of formula I according to claim 16 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 19.6 ±0.2, 17.0 ±0.2, 21.2 ±0.2 and 26.2 ±0.2 and therein that it can be manufactured from Anhydrous Form B that is heated to 225°C at 10°C/min.
21. The crystalline anhydrous “high temperature” Form V of the PDE4-inhibitor of formula I according to claim 18 characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured using CuKa radiation: 4.8 ±0.2, 9.8 ±0.2, 17.0 ±0.2, 17.5 ±0.2, 18.9 ±0.2, 19.3 ±0.2, 19.6 ±0.2, 20.5 ±0.2 and 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2 and therein that it can be manufactured from Anhydrous Form B that is heated to 225°C at 10°C/min.
22. The crystalline form of the PDE4-inhibitor of formula I according to claim 1 , characterized therein that it is a dihydrate form.
23. The crystalline dihydrate Form VII of the PDE4-inhibitor of formula I according to claim 22, characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2 and 19.11 ±0.2.
24. The crystalline dihydrate Form VII of the PDE4-inhibitor of formula I according to claim 22, characterized therein that it shows reflex peaks in the X-ray powder diffraction diagram with 2Theta-values measured in degrees using CuKa radiation: 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2, 17.34 ±0.2, 19.11 ±0.2, 19.57 ±0.2, 21.56 ±0.2 and 25.0 3±0.2.
EP24709772.8A 2023-03-20 2024-03-12 New polymorphs for a piperidino-dihydrothienopyrimidine sulfoxide Pending EP4683922A1 (en)

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PCT/EP2024/056476 WO2024194075A1 (en) 2023-03-20 2024-03-12 New polymorphs for a piperidino-dihydrothienopyrimidine sulfoxide

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US9802954B2 (en) * 2011-08-24 2017-10-31 Boehringer Ingelheim International Gmbh Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma
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