Novel polymorphism of piperidinose dihydrothienopyrimidine sulfoxide
Novel crystalline forms of PDE4B inhibitors with unique X-ray diffraction patterns and thermal properties address stability issues, enhancing therapeutic efficacy in respiratory and neurodegenerative diseases.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2024-03-12
- Publication Date
- 2026-03-25
AI Technical Summary
Existing PDE4B inhibitors lack alternative crystalline forms that offer improved stability and distinct X-ray diffraction patterns, limiting their therapeutic potential in various diseases.
Development of novel crystalline forms IV, V, VI, and VII of the PDE4B inhibitor, characterized by specific X-ray diffraction peaks and production methods such as dynamic vapor adsorption and controlled humidity cycles, providing distinct polymorphic structures.
The new crystalline forms exhibit unique X-ray diffraction patterns and thermal properties, enhancing stability and potentially improving therapeutic efficacy in diseases like COPD, asthma, and neurodegenerative disorders.
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Abstract
Description
Technical Field
[0001] 1. Background of the present invention The present invention relates to novel polymorphic / crystalline forms of a PDE4B inhibitor of formula I
[0002]
Chem.
Background Art
[0003] PDE4B inhibitors such as the compounds of formula I have broad potential in different therapeutic fields. Examples include respiratory diseases (chronic obstructive bronchitis (COPD), cough, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, progressive fibrotic interstitial lung disease (PF-ILD) and idiopathic pulmonary fibrosis (IPF)), or gastrointestinal diseases or disorders (Crohn's disease, ulcerative colitis, etc.), inflammatory diseases of joints, skin or eyes (rheumatoid arthritis, systemic sclerosis, etc., cancer, and diseases of the peripheral or central nervous system (Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, depression, and brain damage due to stroke, hypoxia or head trauma, etc.).
[0004] The PDE4 inhibitor of formula I is disclosed in WO2013 / 026797. Furthermore, WO2013 / 026797 discloses the following crystalline forms / polymorphs of the PDE4 inhibitor of formula I and methods for their production: · Form A (alias Form I), which is an anhydrous crystalline form / polymorph of the PDE4 inhibitor of formula I and represents the most kinetically stable form of the PDE4 inhibitor of formula I • Form B (also known as 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 (also known as Form III) is a dihydrate crystalline form / polymorph of the PDE4 inhibitor of formula I. [Overview of the Initiative]
[0005] The object of the present invention was to provide alternative polymorphs for the PDE4B inhibitor of formula I, starting with the disclosure of WO2013 / 026797 as the closest prior art. Surprisingly, in addition to crystalline forms A, B, and C described in WO2013 / 026797, further crystalline forms / polymorphs of the PDE4 inhibitor of formula I were found.
[0006] [ka] I
[0007] In one embodiment, the present invention relates to a crystalline / polymorphic form IV (also known as form D) of a compound of formula I, which is in a "dehydrated monohydrate form" and can be produced from a dried dihydrate form III (= dihydrate form C) that has been subjected to dynamic vapor adsorption (DVS) overnight at 0% relative humidity (%RH) and 25°C. In another aspect, the present invention relates to a crystalline / polymorphic form V (also known as form E) of the compound of formula I, which is an anhydrous "high-temperature" form that can be produced from anhydrous form II (= anhydrous form B) heated to 225°C at 10°C / min. Form V has never been isolated in its pure form at room temperature (RT). In a further embodiment, the present invention relates to a crystalline / polymorphic form VI (also known as form F) of the compound of formula I, which is a "monohydrate form" that can be produced from dihydrate form III (= dihydrate form C) subjected to dynamic vapor adsorption (DVS) in a stepwise relative humidity cycle (90%-0%-90%) at 25°C, with a step size of 10% relative humidity and a step duration of 2 hours. In another aspect, the present invention relates to a crystalline form / polymorph VII (also known as form G) of the compound of formula I, which is a "dihydrate form" that can be produced from 0.5 g of form A (= form I) and 5 ml of water, by stirring the mixture overnight at room temperature and filtering and drying the resulting slurry at 40°C under humidified, sealed vacuum. [Modes for carrying out the invention]
[0008] 2. Description of the present invention In a first embodiment, the present invention relates to a crystalline form of a PDE4 inhibitor of formula I.
[0009] [ka] I
[0010] In a preferred embodiment, the present invention relates to a crystalline form of a PDE4 inhibitor of formula I, which is in monohydrate form.
[0011] In a more preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form IV, exhibiting a reflectance peak in an X-ray powder diffraction diagram containing the following 2-theta values: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2, and 23.8 ±0.2 when measured in degrees using CuKα rays.
[0012] The crystalline monohydrate form IV of the PDE4B inhibitor of formula I is, • 2-theta value of 13.9 ±0.2 (Anhydrous form I only has a reflectance peak including a 2-theta value of 13.44) • 2-theta value of 19.6 ±0.2 (Anhydrous form I only has a reflectance peak including a 2-theta value of 19.18) In the XRPD diagram having the above characteristics, the reflection peak differs from that of anhydrous form I (=anhydrous form A) disclosed in WO2013 / 026797.
[0013] The crystalline monohydrate form IV of the PDE4B inhibitor of formula I is ·characterized by reflection peaks in the XRPD diagram having a 2-theta value of 13.9 ± 0.2 (the anhydrous form II only has a reflection peak with a 2-theta value of 14.56) ·characterized by reflection peaks in the XRPD diagram having a 2-theta value of 19.6 ± 0.2 (the anhydrous form II only has a reflection peak with a 2-theta value of 19.18) and is different from the anhydrous form II (= anhydrous form B) disclosed in WO2013 / 026797 in the reflection peaks in the XRPD diagram.
[0014] The crystalline monohydrate form IV of the PDE4B inhibitor of formula I is ·characterized by reflection peaks in the XRPD diagram having a 2-theta value of 4.60 ± 0.2 (the dihydrate form III only has a reflection peak with a 2-theta value of 8.60) and is different from the dihydrate form III (= dihydrate form C) disclosed in WO2013 / 026797 in the reflection peaks in the XRPD diagram.
[0015] In another more preferred embodiment, the present invention relates to the crystalline monohydrate form of the PDE4 inhibitor of formula I as described above, which is form IV showing reflection peaks in the X-ray powder diffraction diagram including the following d values: 19.2 Å, 6.3 Å, 4.5 Å and 3.7 Å.
[0016] In a particularly preferred embodiment, the present invention relates to the crystalline monohydrate form of the PDE4 inhibitor of formula I as described above, which is form IV showing reflection peaks in the X-ray powder diffraction diagram including 2-theta values of 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 when measured in degrees using CuKα radiation.
[0017] In a particularly preferred embodiment, the present invention relates to the crystalline monohydrate form of the PDE4 inhibitor of formula I as described above, which is form IV showing reflection peaks in the X-ray powder diffraction diagram including d values of 19.2 Å, 12.8 Å, 6.3 Å, 4.7 Å, 4.5 Å, 4.1 Å and 3.
[0018] In another particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of Formula I, which is Form IV showing reflection peaks in an X-ray powder diffraction diagram including the following 2-theta values: 4.6 ± 0.2, 13.9 ± 0.2, 19.6 ± 0.2 and 23.8 ± 0.2 when measured in degrees using CuKα radiation, and which can be produced from the dry dihydrate Form C of the compound of Formula I that is subjected to the dynamic vapor sorption method (DVS) at 0% relative humidity (%RH) and 25°C overnight.
[0019] In another particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of Formula I, which is Form IV showing reflection peaks in an X-ray powder diffraction diagram including the following 2-theta values: 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 when measured in degrees using CuKα radiation, and which can be produced from the dry dihydrate Form C of the compound of Formula I that is subjected to the dynamic vapor sorption method (DVS) at 0% relative humidity (%RH) and 25°C overnight.
[0020] In another more preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of Formula I, which is Form VI showing reflection peaks in an X-ray powder diffraction diagram including the 2-theta values of 4.6 ± 0.2, 18.7 ± 0.2, 19.6 ± 0.2, 21.7 ± 0.2 and 26.4 ± 0.2. <0000• 26.4 ±0.2 2-theta value (Anhydrous form I only has a reflectance peak including a 2-theta value of 26.61) The reflection peak in the XRPD diagram, including the one shown, differs from that of anhydrous form I (=anhydrous form A) disclosed in WO2013 / 026797.
[0022] The crystalline monohydrate form VI of the PDE4B inhibitor of formula I is • 2-theta value of 18.7 ±0.2 (Anhydrous form II only has a reflectance peak including a 2-theta value of 19.18) • 26.4 ±0.2 2-theta value (Anhydrous form II only has a reflectance peak including a 2-theta value of 26.64) The reflection peak in the XRPD diagram, including the one shown, differs from that of anhydrous form II (= anhydrous form B) disclosed in WO2013 / 026797.
[0023] The crystalline monohydrate form VI of the PDE4B inhibitor of formula I is • 4.60 ±0.2 2-theta value (Dihydrate form III only has a reflectance peak including a 2-theta value of 8.60) The reflection peak in the XRPD diagram, including the above, differs from dihydrate form III (= dihydrate form C) disclosed in WO2013 / 026797.
[0024] In another, more preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting reflectance peaks in an X-ray powder diffraction diagram including d values of 19.1 Å, 4.7 Å, 4.5 Å, 4.1 Å, and 3.4 Å.
[0025] In a particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting a reflectance peak in an X-ray powder diffraction diagram including 2-theta values of 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 when measured in degrees using CuKα rays.
[0026] In a particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting reflection peaks in an X-ray powder diffraction diagram including d values of 19.1 Å, 12.7 Å, 5.3 Å, 5.2 Å, 4.7 Å, 4.5 Å, 4.1 Å, 4.0 Å, 3.7 Å, and 3.4 Å.
[0027] In another particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 when measured in degrees using CuKα rays, and which can be produced from dihydrate form C subjected to dynamic vapor adsorption (DVS) in a stepwise 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.
[0028] In a particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 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 when measured in degrees using CuKα rays, and which can be produced from dihydrate form C subjected to dynamic vapor adsorption (DVS) in a stepwise 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.
[0029] In a particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting reflectance peaks in an X-ray powder diffraction diagram including two theta values of 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 when measured in degrees using CuKα rays, and which exhibits endothermic fusion at about 105°C in DSC analysis (preferably endothermic fusion at about 105°C and endothermic fusion at about 209°C in DSC analysis).
[0030] In a particularly preferred embodiment, the present invention relates to a crystalline monohydrate form of the PDE4 inhibitor of formula I described above, which is form VI, exhibiting a reflectance peak in an X-ray powder diffraction diagram containing two theta values of 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 when measured in degrees using CuKα rays, and which is form VI, exhibiting endothermic melting at about 105°C in DSC analysis (preferably exhibiting endothermic melting at about 105°C and endothermic melting at about 209°C in DSC analysis).
[0031] In another preferred embodiment, the present invention relates to a crystalline form of a PDE4 inhibitor of formula I, which is an anhydrous form.
[0032] In a more preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high temperature" form V that exhibits reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 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 when measured in degrees using CuKα rays.
[0033] The crystalline anhydrous "high temperature" form V of the PDE4B inhibitor of formula I is, • 2-theta value of 4.8 ±0.2 (Anhydrous form I only has a reflectance peak including a 2-theta value of 4.48) • 2-theta value of 9.8 ±0.2 (Anhydrous form I only has a reflectance peak including a 2-theta value of 9.54) • 2-theta value of 19.6 ±0.2 (Anhydrous form I only has a reflectance peak including a 2-theta value of 19.18) • 21.2 ±0.2 2-theta value (Anhydrous form I only has a reflectance peak including a 2-theta value of 21.48) • 26.2 ±0.2 2-theta value (Anhydrous form I only has a reflectance peak including a 2-theta value of 26.61) The reflection peak in the XRPD diagram, including the one shown, differs from that of anhydrous form I (=anhydrous form A) disclosed in WO2013 / 026797.
[0034] The crystalline anhydrous "high temperature" form V of the PDE4B inhibitor of formula I is, • 26.2 ±0.2 2-theta value (Anhydrous form II only has a reflectance peak including a 2-theta value of 26.64) The reflection peak in the XRPD diagram, including the one shown, differs from that of anhydrous form II (= anhydrous form B) disclosed in WO2013 / 026797.
[0035] The crystalline anhydrous "high temperature" form V of the PDE4B inhibitor of formula I is, • 4.8 ±0.2 2-theta value (Dihydrate form III only has a reflectance peak including a 2-theta value of 8.60) • 21.2 ±0.2 2-theta value (Dihydrate form III only has a reflectance peak including a 2-theta value of 21.54) • 26.2 ±0.2 2-theta value (Dihydrate form III only has a reflectance peak including a 2-theta value of 26.50) The reflection peak in the XRPD diagram, including the above, differs from dihydrate form III (= dihydrate form C) disclosed in WO2013 / 026797.
[0036] In a more preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high temperature" form V exhibiting reflection peaks in an X-ray powder diffraction diagram including d values of 18.4 Å, 9.0 Å, 4.5 Å, 5.2 Å, 4.2 Å, and 3.4 Å.
[0037] In a particularly preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high temperature" form V that exhibits a reflectance peak in an X-ray powder diffraction diagram including 2-theta values of 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, 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2 when measured in degrees using CuKα rays.
[0038] In a particularly preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high temperature" form V exhibiting reflection peaks in an X-ray powder diffraction diagram including d values of 18.4 Å, 9.0 Å, 5.2 Å, 5.1 Å, 4.7 Å, 4.6 Å, 4.5 Å, 4.3 Å, 4.2 Å, 4.1 Å, 3.7 Å, and 3.4 Å.
[0039] In another particularly preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high-temperature" form V that exhibits reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 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 when measured in degrees using CuKα rays, and which is an anhydrous "high-temperature" form V that can be produced from anhydrous form B heated to 225°C at 10°C / min.
[0040] In another particularly preferred embodiment, the present invention relates to an anhydrous crystalline form of the PDE4 inhibitor of formula I described above, which is an anhydrous "high temperature" form V that exhibits reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 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, 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2 when measured in degrees using CuKα rays, and which is an anhydrous "high temperature" form V that can be produced from anhydrous form B heated to 225°C at 10°C / min.
[0041] In another preferred embodiment, the present invention relates to dihydrate form VII (= dihydrate form G) of the PDE4 inhibitor of formula I described above, which exhibits reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2, and 19.11 ±0.2 when measured in degrees using CuKα rays.
[0042] In another particularly preferred embodiment, the present invention relates to dihydrate form VII (= dihydrate form G) of the PDE4 inhibitor of formula I described above, which exhibits reflectance peaks in an X-ray powder diffraction diagram including 2-theta values of 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 25.03 ±0.2 when measured in degrees using CuKα rays.
[0043] 3. Method for preparing different polymorphs of PDE4B inhibitors of formula I PDE4B inhibitors of formula I can be manufactured as described in detail in WO2013 / 026797.
[0044] [ka] I
[0045] Preparation route for Form I (identical to "Form A" disclosed in WO2013 / 026797): Preparation of seed crystals (anhydrous form I or anhydrous form A) A small amount of crude compound of formula I (1-2 mg) was 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 heating / cooling cycles, analysis by X-ray powder diffraction revealed that the sample yielded a suspension of crystalline anhydrous form I.
[0046] a. Crystallization from acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone: Approximately 1 g of the 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 above 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. An anhydrous form I (=form A) crystal of the compound of formula I is added as a seed crystal to the solution, and the solution is cooled to 20°C. To increase the yield, an additional amount of antisolvent (5-10 ml) is added. The resulting slurry is filtered within 1 hour of cooling, and the wet cake is dried under vacuum at 60°C. Anhydrous form I (=anhydrous form A) is obtained as a white solid, as confirmed by X-ray powder diffraction (XRPD) of the recorded anhydrous form A standard.
[0047] 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 above 60°C. The solution is cooled to 40-50°C, a seed crystal of anhydrous form I (= anhydrous form A) of the compound of formula I is added, and the mixture is further cooled to 20°C in less than 1 hour. Approximately 5-10 ml of an antisolvent (organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is filtered within 1 hour after the addition of the antisolvent, and the wet cake is dried under vacuum at 60°C. Anhydrous form I (= anhydrous form A) is obtained as a white solid, as confirmed by X-ray powder diffraction (XRPD) of the recorded anhydrous form I standard.
[0048] c. Drying from dihydrate form III (=dihydrate form C): Approximately 1 g of the compound of formula I in dihydrate form III (= dihydrate form C) is washed on a Buchner funnel with approximately 5 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, or acetone. The wet cake is then dried under vacuum at 60°C. Anhydrous form I (= anhydrous form A) is obtained as a white solid, as confirmed by X-ray powder diffraction (XRPD) of the recorded anhydrous form I standard.
[0049] Preparation route for Form II (identical to "Form B" disclosed in WO2013 / 026797): Preparation of seed crystals in anhydrous form B A small amount of crude compound of formula I (1-2 mg) was suspended in approximately 0.1 ml of a mixture of 2-propanol and water (one mixture containing 3.3% water, and the other containing 6.6% water). After heating / cooling cycles, X-ray powder diffraction analysis revealed that the sample produced a suspension of crystalline anhydrous form II (= anhydrous form B). X-ray powder diffraction analysis also revealed that the sample in anhydrous 2-propanol, exposed to the same conditions, produced a mixture of form I and form II. The mixture of form I and form II was slurryed at 20°C for 4 days with water and a mixture of the following solvents: methanol, ethanol, 2-propanol, 1-propanol, and acetone (each containing approximately 9% water). X-ray powder diffraction analysis revealed that form II (= anhydrous form B) was produced.
[0050] a. Crystallization from n-propanol / water Dissolve 10 g of the crude compound of formula I in 160 ml of n-propanol / water mixture (9:1, v / v) at a temperature above 65°C. Cool the solution to 60°C, add seed crystals of anhydrous form II (anhydrous form B) of compound I, and age for 0.5 hours. Cool the slurry to 30°C over at least 5 hours. Optionally, to maximize yield, distill the slurry under reduced pressure at 30°C to reduce its volume to approximately 80-100 ml. Cool the slurry further to 0°C and age the slurry for at least 8 hours or until anhydrous form I (=anhydrous form A) is no longer detectable. Filter the slurry and dry the wet cake under vacuum at 60°C. Anhydrous form II (=anhydrous form B) of compound I is obtained as a white solid in 90% yield. Powder X-ray diffraction (XRPD) matches the recorded anhydrous form II (=anhydrous form B) standard.
[0051] 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 above 60°C. The solution is cooled to 40-50°C, a seed crystal of anhydrous form II (anhydrous form B) of the compound of formula I is added, and the mixture is further cooled to 20°C over 2 hours. Approximately 10 ml of an antisolvent (organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is aged for at least 8 hours or until anhydrous form I (=anhydrous form A) is no longer detectable. The slurry is filtered, and the wet cake is dried under vacuum at 60°C. Anhydrous form II (=anhydrous form B) of the compound of formula I is obtained as a white solid. Powder X-ray diffraction (XRPD) matches the recorded anhydrous form II (=anhydrous form B) standard.
[0052] c. Transformation from dihydrate form III (= dihydrate form C): Approximately 1 g of the compound of formula I in dihydrate form III is suspended in 5-10 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. Anhydrous form II crystals (= anhydrous form B crystals) of the compound of formula I are added as a seed crystal to the suspension, and the mixture is stirred at 20-40°C for at least 4 hours or until the conversion to anhydrous form II (= anhydrous form B) is complete, as confirmed by X-ray powder diffraction (XRPD) analysis.
[0053] d. Transformation from anhydrous form I (=anhydrous form A): Approximately 1 g of the compound of formula I in anhydrous form I (= anhydrous form A) is suspended in 5-10 ml of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. Anhydrous form II crystals of the compound of formula I (= anhydrous form B crystals) are added as seed crystals to the suspension, and the mixture is stirred at 20-40°C for at least 4 hours or until the conversion to anhydrous form II (= anhydrous form B) is complete, as confirmed by X-ray powder diffraction (XRPD) analysis.
[0054] Preparation route for Form III (identical to "Form C" disclosed in WO2013 / 026797): Preparation of seed crystals of dihydrate form III (=dihydrate form C) When a mixture of anhydrous form I crystals (= anhydrous form A) and anhydrous form II crystals (= anhydrous form B) of the compound of formula I is slurryed in 2-butanone / water (containing 9% water) at 20°C for 4 days, dihydrate form III crystals (= dihydrate form C crystals) are formed, as confirmed by X-ray powder diffraction analysis.
[0055] a. Crystallization from n-propanol / water: Dissolve 10 g of the crude compound of formula I in 120 ml of n-propanol / water mixture (8:2, v / v) at a temperature above 65°C. Cool the solution to 50°C, add seed crystals of the compound of formula I in dihydrate form III (= dihydrate form C crystals), and age for 0.5 hours. Add water (approximately 60-100 ml) to the slurry. Cool the slurry to 20°C over at least 5 hours, and then age for at least 8 hours. Filter the slurry, wash the wet cake with water, and then air dry.
[0056] b. THF / crystallization in 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 above 60°C. The solution is cooled to 30-50°C, a seed crystal of dihydrate form III (= dihydrate form C) of the compound of formula I is added, and the mixture is further cooled to 20°C over 2 hours. Approximately 10 ml of water is added to the slurry. The resulting slurry is aged for at least 8 hours. The slurry is filtered, the wet cake is washed with water, and then air-dried. X-ray powder diffraction (XRPD) of the product shows a pattern of dihydrate form III (= form C).
[0057] c. Conversion from anhydrous form I (=anhydrous form A) or anhydrous form II (=anhydrous form B): Approximately 1 g of compound I of formula I, in anhydrous form I (=anhydrous form A)Alternatively, the anhydrous form II (= anhydrous form B) 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. A seed crystal of the compound of formula I in dihydrate form III (= dihydrate form C crystal) is added to the suspension, and the mixture is stirred at 20°C for at least 4 hours or until conversion to dihydrate form III (= dihydrate form C) is complete, as confirmed by X-ray powder diffraction (XRPD) analysis. The slurry is filtered, and the wet cake is washed with water and then air-dried.
[0058] Preparation route for dehydrated monohydrate form IV (also known as "form D"): The dried dihydrate form III (= dihydrate form C, WO2013 / 026797 or prepared as described above) of the PDE4B inhibitor of formula I is subjected to dynamic vapor adsorption (DVS) overnight at 0% relative humidity (RH) and 25°C to obtain the dehydrated monohydrate form IV of the compound of formula I.
[0059] Preparation route for anhydrous "high temperature" form V (also known as "form E"): The anhydrous form II (= anhydrous form B, WO2013 / 026797 or prepared 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.
[0060] Preparation route for monohydrate form VI (also known as "form F"): 10 mg of dihydrate form III (= dihydrate form C, WO2013 / 026797 or prepared as described above) of the compound of formula I was placed in a sample dish of a dynamic vapor adsorption apparatus (DVS), and subjected to a step-wise relative humidity cycle (RH cycle) (90%-0%-90%) at 25°C with a step size of 10% relative humidity and a step duration of 2 hours (dynamic vapor adsorption via a moisture adsorption / desorption cycle) to obtain monohydrate form VI (= monohydrate form F) of the compound of formula I.
[0061] Preparation route for dihydrate form VII (also known as "form G") Method a) Dissolve 10 g of form B (=form II) in 55 ml of n-propanol in 22% water. Stir the mixture at 15°C, then add seed crystals of dihydrate crystalline form G. Then reduce the temperature to 0°C and allow to stand for at least 48 hours for aging. Filter the product, wash with n-propanol, and then dry in an oven under nitrogen without heating.
[0062] Method b) Mix 0.5 g of Form A (=Form I) and 5 ml of water at room temperature overnight. Filter the slurry and dry it at 40°C under humidified, sealed vacuum.
[0063] Method c) Forms A (=Form I), B (=Form II), and G (=Form VII) (25-50 mg) were each slurried in 13% water-n-propanol at 5°C and 15°C for 1 day. Then, Form VII was recovered by filtration.
[0064] 4. X-ray powder diffraction (XRPD) diagram analysis of different polymorphisms of PDE4B inhibitors of formula I The polymorphic / crystalline forms of the compound of formula I were characterized by X-ray powder diffraction (XRPD), as shown in Figures 1 to 6, which show the X-ray powder diffraction diagrams for each of the different polymorphic / crystalline forms of the PDE4B inhibitor of formula I, and as shown in the following table, which includes all observable reflectance peaks for each of the different polymorphic / crystalline forms of the PDE4B inhibitor of formula I.
[0065] For X-ray powder diffraction analysis, a Rigaku Miniflex II instrument was used with a Type Power 450W X-ray generator (30 kV-15 mA) (optics: variable divergence slit). The goniometer range was 3.0–35.0° 2θ, and the scan speed was 0.02° 2θ / min with an accuracy of more than 0.01°. A foil filter / graphite was used for the monochromator, and a 23.0 mm diameter NaL scintillation counter was used as the detector. Samples were analyzed on a low-background Si(510) sample holder. [Brief explanation of the drawing]
[0066] [Figure 1] X-ray powder diffraction diagram (XRPD) of the anhydrous form I (=anhydrous form A) of the compound of formula I. [Figure 2] X-ray powder diffraction diagram (XRPD) of the anhydrous form II (= anhydrous form B) of the compound of formula I. [Figure 3] X-ray powder diffraction diagram (XRPD) of the compound of formula I in dihydrate form III (= dihydrate form C). [Figure 4] X-ray powder diffraction diagram (XRPD) of dehydrated monohydrate form IV (= dehydrated monohydrate form D) of compound I. [Figure 5] X-ray powder diffraction diagram (XRPD) of the anhydrous "high temperature" form V (= anhydrous "high temperature" form E) of the compound of formula I. [Figure 6] X-ray powder diffraction diagram (XRPD) of monohydrate form VI (= monohydrate form F) of compound I. [Figure 7] Thermogravimetric analysis (TGA) of monohydrate form VI (= monohydrate form F) of compound I. [Figure 8] Differential scanning calorimetry (DSC) of monohydrate form VI (= monohydrate form F) of compound I (DSC shows endothermic fusion at approximately 105°C and endothermic fusion at approximately 209°C). [Figure 9] X-ray powder diffraction diagram (XRPD) of dihydrate form VII (= dihydrate form G) of compound I. [Figure 10]Thermogravimetric analysis (TGA) of dihydrate form VII (=dihydrate form G) of the compound of formula I [Figure 11] Differential scanning calorimetry (DSC) of dihydrate form VII (=dihydrate form G)
[0067] 4.1 XRPD analysis of the anhydrous form I (=anhydrous form A) of the compound of formula I Figure 1 shows the X-ray powder diffraction diagram of the compound of formula I in anhydrous form I (= anhydrous form A). In this XRPD diagram in Figure 1, the following 2-theta values (2θ values) and d values can be observed (see Table 1).
[0068] Table 1: All observable peaks of the anhydrous form I (=anhydrous form A disclosed in WO2013 / 026797) of the compound of formula I (see Figure 1): TIFF2026509733000006.tif172151
[0069] Table 2 shows the main peaks in the XRPD diagram of the anhydrous form I (=anhydrous form A) of the compound of formula I (see Figure 1):
[0070] Table 2: Main peaks of anhydrous form I (=anhydrous form A): TIFF2026509733000007.tif57129
[0071] Table 3 shows the most prominent peaks in the XRPD diagram of the anhydrous form I (=anhydrous form A) of the compound of formula I (see Figure 1).
[0072] Table 3: Prominent peaks in anhydrous form I (=anhydrous form A): TIFF2026509733000008.tif31139
[0073] 4.2 XRPD analysis of the anhydrous form II (=anhydrous form B) of the compound of formula I Figure 2 shows the X-ray powder diffraction diagram of the compound of formula I in anhydrous form II (= anhydrous form B). In this XRPD diagram of the compound of formula I in anhydrous form II (= anhydrous form B), the following 2-theta values (= 2θ values) and d values can be observed (Table 4).
[0074] Table 4: All observable peaks of the anhydrous form II (=anhydrous form B disclosed in WO2013 / 026797) of the compound of formula I (see Figure 2): TIFF2026509733000009.tif156141
[0075] Table 5 shows the main peaks in the XRPD diagram of the anhydrous form II (=anhydrous form B) of the compound of formula I.
[0076] Table 5: Main peaks in anhydrous form II (=anhydrous form B): TIFF2026509733000010.tif8255
[0077] Table 6 shows the most prominent peaks in the XRPD diagram of the anhydrous form II (=anhydrous form B) of the compound of formula I.
[0078] Table 6: Prominent peaks in anhydrous form II (= anhydrous form B) TIFF2026509733000011.tif47140
[0079] 4.3 XRPD analysis of dihydrate form III (= dihydrate form C) of compound I Figure 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 (= 2θ values) and d values can be observed (Table 7).
[0080] Table 7: All observable peaks of dihydrate form III (= dihydrate form C disclosed in WO2013 / 026797) of the compound of formula I (see Figure 3): TIFF2026509733000012.tif177141
[0081] Table 8 shows the main peaks in the XRPD diagram of the dihydrate form III (= dihydrate form C) of the compound of formula I.
[0082] Table 8: Main peaks of dihydrate form III (=dihydrate form C): TIFF2026509733000013.tif67131
[0083] Table 9 shows the most prominent peaks in the XRPD diagram of the dihydrate form III (= dihydrate form C) of the compound of formula I.
[0084] Table 9: Prominent peaks of dihydrate form III (= dihydrate form C): TIFF2026509733000014.tif41140
[0085] 4.4 XRPD analysis of dehydrated monohydrate form IV (= dehydrated monohydrate form D) of compound 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 in Figure 4, the following 2-theta values (2θ values) and d values can be observed (see Table 10).
[0086] Table 10: All observable peaks of dehydrated monohydrate form IV (= dehydrated monohydrate form D): TIFF2026509733000015.tif218142
[0087] Table 11 shows the main peaks in the XRPD diagram of the dehydrated monohydrate form IV (= dehydrated monohydrate form D) of the compound of formula I (see Figure 4).
[0088] Table 11: Main peaks of dehydrated monohydrate form IV (= dehydrated monohydrate form D) TIFF2026509733000016.tif47124
[0089] Table 12 shows the most prominent peaks in the XRPD diagram of the dehydrated monohydrate form IV (= dehydrated monohydrate form D) of the compound of formula I (see Figure 4).
[0090] Table 12: Prominent peaks of dehydrated monohydrate form IV (= dehydrated monohydrate form D): TIFF2026509733000017.tif36138
[0091] 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 compound of formula I in its anhydrous "high temperature" form V (= anhydrous "high temperature" form E). In this XRPD diagram in Figure 5, the following 2-theta values (2θ values) and d values can be observed (see Table 13).
[0092] Table 13: All observable peaks of the anhydrous "high temperature" form V (= anhydrous "high temperature" form E): TIFF2026509733000018.tif177143
[0093] Table 14 shows the main peaks in the XRPD diagram of the anhydrous "high temperature" form V (= anhydrous "high temperature" form E) of the compound of formula I (see Figure 5).
[0094] Table 14: Main peaks of the anhydrous "high temperature" form V (= anhydrous "high temperature" form E): TIFF2026509733000019.tif73129
[0095] Table 15 shows the most prominent peaks in the XRPD diagram of the anhydrous "high temperature" form V (= anhydrous "high temperature" form E) of the compound of formula I (see Figure 5).
[0096] Table 15: Prominent peaks in the anhydrous "high temperature" form V (= anhydrous "high temperature" form E): TIFF2026509733000020.tif47138
[0097] 4.6 XRPD analysis of monohydrate form VI (= monohydrate form F) of compound I Figure 6 shows the X-ray powder diffraction diagram of monohydrate form VI (= monohydrate form F) of the compound of formula I. In this XRPD diagram in Figure 6, the following 2-theta values (2θ values) and d values can be observed (see Table 16).
[0098] Table 16: All observable peaks of monohydrate form VI (= monohydrate form F): TIFF2026509733000021.tif208142 TIFF2026509733000022.tif47138
[0099] Table 17 shows the main peaks in the XRPD diagram of monohydrate form VI (= monohydrate form F) of the compound of formula I (see Figure 6).
[0100] Table 17: Main peaks of monohydrate form VI (= monohydrate form F): TIFF2026509733000023.tif67138
[0101] Table 18 shows the most prominent peaks in the XRPD diagram of monohydrate form VI (= monohydrate form F) of the compound of formula I (see Figure 6).
[0102] Table 18: Prominent peaks in monohydrate form VI (= monohydrate form F): TIFF2026509733000024.tif41138
[0103] 4.7 XRPD analysis of dihydrate form VII (= dihydrate form G) of compound I Figure 9 shows the X-ray powder diffraction diagram of dihydrate form VII (= dihydrate form G) of the compound of formula I. In this XRPD diagram in Figure 9, the following 2-theta values (2θ values) and d values can be observed (see Table 19).
[0104] Table 19: All observable peaks of dihydrate form VII (= dihydrate form G): TIFF2026509733000025.tif218142 TIFF2026509733000026.tif57126
[0105] Table 20 shows the main peaks in the XRPD diagram of dihydrate form VII (= dihydrate form G) of the compound of formula I (see Figure 9).
[0106] Table 20: Main peaks of dihydrate form VII (=dihydrate form G):
[0107] TIFF2026509733000027.tif99146
[0108] Table 21 shows the most prominent peaks in the XRPD diagram of dihydrate form VII (= dihydrate form G) of the compound of formula I (see Figure 9).
[0109] Table 21: Prominent peaks in dihydrate form VII (= dihydrate form G): TIFF2026509733000028.tif52135
[0110] 5. Thermogravimetric analysis (TGA) of different polymorphs of PDE4B inhibitors of formula I As shown in Figure 7 (monohydrate form VI) and Figure 10 (dihydrate form VII), the monohydrate form VI (=monohydrate form F) and dihydrate form VII (=dihydrate form G) of the compound of formula I were further characterized by thermogravimetric analysis (TGA) using TA Instruments' TGA Q500. The sample was analyzed in an open platinum sample dish under a nitrogen atmosphere. The rate of ascent used for the measurement was 10°C / min from 20°C to 300°C.
[0111] 6. Differential scanning calorimetry (DSC) analysis of different polymorphisms of PDE4B inhibitors of formula I As shown in Figure 8 (monohydrate form VI) and Figure 11 (dihydrate form VII), the monohydrate form VI (=monohydrate form F) and dihydrate form VII (=dihydrate form G) of the compound of formula I were further characterized by differential scanning calorimetry (DSC) using TA Instruments' DSC Q1000. The samples were analyzed in an unsealed aluminum dish under a nitrogen stream. The rate of ascent used for the measurements was 10°C / min from 20°C to 300°C.
[0112] DSC analysis of monohydrate form VI (= monohydrate form F) of compound I shows endothermic effects at approximately 105°C and approximately 209°C. DSC analysis of dihydrate form VII (= dihydrate form G) of the compound of formula I shows endothermic activity at approximately 235°C.
Claims
1. Crystalline form of the PDE4 inhibitor of formula I. I
2. A crystalline form of the PDE4 inhibitor of formula I according to claim 1, characterized in that it is in monohydrate form.
3. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2, characterized in that it is form IV, which shows a reflectance peak in an X-ray powder diffraction diagram containing the following two-theta values: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2, and 23.8 ±0.2 when measured using CuKα radiation.
4. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2, characterized in that it is form IV, which shows reflection peaks in an X-ray powder diffraction diagram including the following d values of 19.2 Å, 6.3 Å, 4.5 Å, and 3.7 Å.
5. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2 or 3, characterized in that it is form IV, which shows reflection peaks in an X-ray powder diffraction diagram including two-theta values of 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 when measured using CuKα radiation.
6. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2 or 4, characterized in that it is form IV, which shows reflection peaks in an X-ray powder diffraction diagram including d values of 19.2 Å, 12.8 Å, 6.3 Å, 4.7 Å, 4.5 Å, 4.1 Å, and 3.7 Å.
7. The crystalline monohydrate form IV of the PDE4 inhibitor of formula I according to claim 3, characterized in that it exhibits a reflectance peak in an X-ray powder diffraction diagram including the following two-theta values: 4.6 ±0.2, 13.9 ±0.2, 19.6 ±0.2, and 23.8 ±0.2 when measured using CuKα radiation, and can be produced from a dried dihydrate form C of the compound of formula I, which is subjected to dynamic vapor adsorption (DVS) overnight at 0% relative humidity (%RH) and 25°C.
8. The crystalline monohydrate form IV of the PDE4 inhibitor of formula I according to claim 5, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including the following two-theta values when measured using CuKα 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 can be produced from a dried dihydrate form C of the compound of formula I, which is subjected to dynamic vapor adsorption (DVS) overnight at 0% relative humidity (%RH) and 25°C.
9. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2, characterized in that it is form VI, which shows reflection peaks in an X-ray powder diffraction diagram including two-theta values of 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 when measured using CuKα radiation.
10. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2, characterized in that it is form VI, which shows reflection peaks in an X-ray powder diffraction diagram including d values of 19.1 Å, 4.7 Å, 4.5 Å, 4.1 Å, and 3.4 Å.
11. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2 or 9, characterized in that it is form VI, which shows a reflectance peak in an X-ray powder diffraction diagram containing two theta values of 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 when measured using CuKα rays.
12. The crystalline monohydrate form of the PDE4 inhibitor of formula I according to claim 2 or 10, characterized in that it is form VI, which shows reflection peaks in an X-ray powder diffraction diagram including d values of 19.1 Å, 12.7 Å, 5.3 Å, 5.2 Å, 4.7 Å, 4.5 Å, 4.1 Å, 4.0 Å, 3.7 Å, and 3.4 Å.
13. Crystalline monohydrate form VI of the PDE4 inhibitor of formula I according to claim 9, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including two-theta values of 4.6 ±0.2, 18.7 ±0.2, 19.6 ±0.2, 21.7 ±0.2 and 26.4 ±0.2 when measured using CuKα radiation, and can be produced from dihydrate form C subjected to dynamic vapor adsorption (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. Crystalline monohydrate form VI of the PDE4 inhibitor of formula I according to claim 11, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including two-theta values of 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 when measured using CuKα radiation, and can be produced from dihydrate form C subjected to dynamic vapor adsorption (DVS) with a step size of 10% relative humidity and a step duration of 2 hours in a stepwise relative humidity (RH) cycle (90%-0%-90%) at 25°C.
15. A crystalline form of the PDE4 inhibitor of formula I according to claim 1, characterized in that it is in an anhydrous form.
16. An anhydrous crystalline form of the PDE4 inhibitor of formula I according to claim 15, characterized in that it is an anhydrous "high-temperature form" V that exhibits reflection peaks in an X-ray powder diffraction diagram including two-theta values of 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 when measured using CuKα rays.
17. The anhydrous crystalline form of the PDE4 inhibitor of formula I according to claim 15, characterized in that it is an anhydrous "high temperature" form V that exhibits reflection peaks in an X-ray powder diffraction diagram including d values of 18.4 Å, 9.0 Å, 4.5 Å, 5.2 Å, 4.2 Å, and 3.4 Å.
18. The anhydrous crystalline form of the PDE4 inhibitor of formula I according to claim 15 or 16, characterized in that it is an anhydrous "high temperature" form V that exhibits a reflectance peak in an X-ray powder diffraction diagram including two theta values of 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, 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2, and 26.4 ±0.2 when measured using CuKα rays, in an anhydrous "high temperature" form V.
19. The anhydrous crystalline form of the PDE4 inhibitor of formula I according to claim 15 or 17, characterized in that it is an anhydrous "high temperature" form V that shows reflection peaks in an X-ray powder diffraction diagram including d values of 18.4 Å, 9.0 Å, 5.2 Å, 5.1 Å, 4.7 Å, 4.6 Å, 4.5 Å, 4.3 Å, 4.2 Å, 4.1 Å, 3.7 Å and 3.4 Å.
20. Crystalline anhydrous "high-temperature" form V of the PDE4 inhibitor of formula I according to claim 16, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including two-theta values of 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 when measured using CuKα radiation, and can be produced from anhydrous form B heated to 225°C at 10°C / min.
21. Crystalline anhydrous "high-temperature" form V of the PDE4 inhibitor of formula I according to claim 18, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including two-theta values of 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, 21.2 ±0.2, 21.6 ±0.2, 23.7 ±0.2 and 26.4 ±0.2 when measured using CuKα rays, and can be produced from anhydrous form B heated to 225°C at 10°C / min.
22. A crystalline form of the PDE4 inhibitor of formula I according to claim 1, characterized in that it is in a dihydrate form.
23. The crystalline dihydrate form VII of the PDE4 inhibitor of formula I according to claim 22, characterized in that it exhibits reflectance peaks in an X-ray powder diffraction diagram including two theta values of 4.31 ±0.2, 8.64 ±0.2, 12.99 ±0.2, and 19.11 ±0.2 when measured in degrees using CuKα rays.
24. The crystalline dihydrate form VII of the PDE4 inhibitor of formula I according to claim 22, characterized by exhibiting reflectance peaks in an X-ray powder diffraction diagram including two-theta values of 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 25.03 ±0.2 when measured in degrees using CuKα rays.