WO2017093773A1 - New polymorphic and solvate form of idelalisib - Google Patents
New polymorphic and solvate form of idelalisib Download PDFInfo
- Publication number
- WO2017093773A1 WO2017093773A1 PCT/HU2016/050031 HU2016050031W WO2017093773A1 WO 2017093773 A1 WO2017093773 A1 WO 2017093773A1 HU 2016050031 W HU2016050031 W HU 2016050031W WO 2017093773 A1 WO2017093773 A1 WO 2017093773A1
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- WIPO (PCT)
- Prior art keywords
- idelalisib
- ray powder
- characteristic
- powder diffraction
- diffraction peaks
- Prior art date
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- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 title claims abstract description 63
- 239000012453 solvate Substances 0.000 title claims abstract description 26
- 229960003445 idelalisib Drugs 0.000 title abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 21
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 78
- 238000000034 method Methods 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000002178 crystalline material Substances 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 201000003444 follicular lymphoma Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000000843 powder Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000013543 active substance Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 238000005259 measurement Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 238000007906 compression Methods 0.000 description 7
- 230000006835 compression Effects 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000003825 pressing Methods 0.000 description 6
- 239000007790 solid phase Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108091007960 PI3Ks Proteins 0.000 description 3
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 3
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IFSDAJWBUCMOAH-HNNXBMFYSA-N CC[C@@H](C(N1c2ccccc2)=Nc(cccc2F)c2C1=O)Nc1ncnc2c1nc[nH]2 Chemical compound CC[C@@H](C(N1c2ccccc2)=Nc(cccc2F)c2C1=O)Nc1ncnc2c1nc[nH]2 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 2
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 2
- 102100027340 Slit homolog 2 protein Human genes 0.000 description 2
- 101710133576 Slit homolog 2 protein Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- -1 elixirs Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- IAKOZHOLGAGEJT-UHFFFAOYSA-N 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)-Ethane Chemical compound C1=CC(OC)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(OC)C=C1 IAKOZHOLGAGEJT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012669 compression test Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Definitions
- the subject of our invention relates to a new polymorphic form of the pharmaceutical active substance idelalisib, to a method for its production, to pharmaceutical preparations containing the new form, as well as the therapeutic use of all these.
- Idelalisib is a phosphoinositide-3-kinase (PI3K) enzyme inhibitor.
- the phosphoinositide-3- kinase enzymes participate in the regulation of numerous cell functions (growth regulation, metabolism, translation initiation). Idelalisib has been registered for the treatment of various forms of leukaemia.
- the production of idelalisib was first presented in international patent application number WO 2005113556.
- the solid material obtained following column chromatography purification was dissolved in ethanol, and then the solution was evaporated. On the basis of element analysis the composition of the light yellow solid material obtained in this way is idelalisib ⁇ EtOH ⁇ 0.4 H 2 0.
- the inventors do not present analytical results serving to characterise the crystallography of the solid phase.
- WO 2013134288 presents the seven forms of idelalisib (Form I, II, III, IV, V, VI and VII), their production, their use for the production of pharmaceutical preparations and their medical use.
- the characteristic x-ray powder diffractogram of each form was disclosed (the unit cell parameters of Forms I, II, III, IV, and V were also given), and also the individual crystal forms were also examined using thermal analysis methods (TG, DSC).
- Form I and Form II are solvent-free crystalline forms, and all of the other crystalline forms are solvates of the idelalisib base.
- the Form I polymorph is crystalized from a methanol-water mixture, with the temperature of the mixture being precisely regulated.
- the Form II polymorph is obtained by grinding the Form I polymorph, optionally with related solvent suspension or by the compression of the Form I polymorph.
- the Form I polymorph may be partially transformed into Form II in the course of certain preparation development operations (e.g. tableting) under generally used conditions.
- the joint presence of the two forms in the pharmaceutical preparation presumably in varying proportions with respect to the specific characteristics of the pharmaceutical technology operations performed, in all events represents technological and quality control difficulties.
- the objective of the invention is to overcome the disadvantages of the known methods and elaborate a method for the production of new polymorphs of the idelalisib active substance that may be simply and economically implemented at industrial scales, that maintains its homogenous polymorphic form during pharmaceutical technology operations (grinding, granulations, tableting) and during the stability tests required when developing pharmaceutical preparations.
- the idelalisib base Form E according to the invention has numerous preferable properties as compared to earlier idelalisib forms. Prominent among these is that during pressing it maintains its crystalline form. Furthermore, it has a preferably low degree of hygroscopicity.
- An especially preferable feature of the idelalisib base Form E according to the invention is that the stability exhibited in the course of pressing and especially low hygroscopicity are both characteristic of it at the same time.
- Preferably low hygroscopicity in a wide range of relative humidity is characteristic of idelalisib base Form E.
- Figure 1 the x-ray powder diffractogram of the idelalisib base Form
- Figure 2 The effect of compression on the crystal structure of the idelalisib base Form E.
- the upper curve shows the x-ray powder diffractogram of a sample of an idelalisib Form E tablet produced by high-pressure compression, while the lower curve depicts the x-ray powder diffractogram of a sample not subjected to compression.
- Figure 3 The effect of compression on the crystal structure of the idelalisib base Form I.
- the upper curve the x-ray powder diffractogram of idelalisib Form II.
- the lower curve the x-ray powder diffractogram of idelalisib Form I.
- the middle curve shows the x-ray powder diffractogram of idelalisib Form I subjected to pressure.
- Figure 4 The 25 °C water sorption isotherms of Form I and Form II of the patent application number WO 2013134288 and of the Form E idelalisib base. The figure depicts the percentage equilibrium moisture content as a function of relative humidity.
- Figure 5 The x-ray powder diffractogram of idelalisib base acetonitrile solvate (Form E-S)
- the subject of the invention relates to the crystalline Form E of the idelalisib base, the characteristic x-ray powder diffraction peaks of which are the following: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 11.56; 12.80; 14.96; 20.85. More specifically it may be characterised by the following x- ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 11.56; 12.80; 14.96; 15.70; 18.24; 19.34; 20.25; 20.85; 22.73; 23.91; 32.42.
- the resistance of the crystal structure of the new idelalisib base form (Form E) according to our invention to mechanical stress was investigated with compression tests.
- the set pressure value (approx. 50 MPa) is comparable to the pressure values usually used when producing tablets.
- the x-ray powder diffractogram of a sample from a tablet of idelalisib base Form E produced using high pressure is presented in figure 2. It can be seen that the diffractogram is the same as that of the initial sample (before compression), in other words the pressing did not result in solid phase transformation in the sample.
- a similar experiment was performed with idelalisib Form I according to patent application number WO 2013134288, the results can be seen in figure 3.
- the diffraction peaks (indicated with arrows in figure 3) characteristic of idelalisib base Form II appeared in the diffractogram of the tablet obtained, in other words the sample partially transformed into a crystal structure that is not homogenous.
- the sample suffered solid phase transformation due to the effect of high-pressure compression.
- the phenomenon experienced in the case of Form I is not preferable, as during preparation formulation (e.g. tableting) the active substance is subjected to pressure of this order, as a result of which the crystal structure of the active substance in the preparation will not be homogenous.
- the water sorption isotherms of the idelalisib base Form E recorded at 25 °C are presented in figure 4. It can be seen that the substance does not display hygroscopicity: in the relative humidity range of 0-85% the maximum water absorption is under 0.15%. According to the measurement results the hygroscopicity of idelalisib base Form E in the examined range is lower than that of Form I and Form II according to patent application number WO 2013134288, and is also preferably lower than that of the two new solvent-free forms (Form IV and Form VIII) presented in patent application number WO 2015014315. The lower hygroscopicity experienced in the case of Form E is also preferable from the points of view of stability and preparation formulation.
- the subject of our invention also relates to the acetonitrile solvate of the crystalline idelalisib base (Form E-S), the significance of which is that the idelalisib Form E crystalline form according to the invention may be produced via this.
- the characteristic x-ray powder diffraction peaks characteristic of the Form E-S acetonitrile solvate are the following: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.81; 7.94; 8.65; 12.47; 20.99. More specifically it can be characterised by the following x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.81;
- the subject of the invention also relates to a method for the production of the Form E-S acetonitrile solvate of 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin- 4(3H)-one (idelalisib) in such a way that 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6- ylamino)propyl]quinazolin-4(3H)-one is dissolved in acetonitrile, the solution is stirred, the crystalline substance precipitated during stirring is the acetonitrile solvate Form E-S of 3- phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one.
- the subject of the invention also relates to a method for the production 3-phenyl-5-fluoro-2- [l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one (idelalisib) Form E, in such a way that the Form E-S acetonitrile solvate form according to the invention is dried. Furthermore, the subject of the invention relates to a pharmaceutical preparation containing idelalisib Form E and pharmaceutically acceptable additives.
- the subject of the invention also relates to a medical preparation containing a therapeutically effective amount of idelalisib base Form E according to the invention and, optionally, one or more excipients used in the production of medical preparations. Furthermore, a method for the production of a medical preparation, characterised by that the idelalisib base Form E according to the invention is mixed with an appropriate amount of medically acceptable carrier and, optionally, other medically suitable excipients, and is then placed in a galenic formulation.
- the medial preparations according to the invention are preferably administered orally.
- Orally administered preparations may include, for example, tablets, capsules, dragees, solutions, elixirs, suspensions and emulsions.
- the medical preparations according to the invention may contain the usual medical carriers and/or excipients.
- Carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting point wax, PEG, cocoa butter, etc.
- Orally administered preparations also include sachets and lozenges. Tablets, powders, capsules, pills, sachets and lozenges are especially suitable solid preparation forms.
- An especially preferable medical preparation is the film-coated tablet containing idelalisib in the tablet core.
- the tablet core contains the following excipients: microcrystalline cellulose, hydroxypropyl cellulose (E463), croscarmellose-sodium, carboxymethyl starch sodium and magnesium stearate.
- the tablets may be produced by mixing the active substance with carrier materials with suitable characteristics in the appropriate ratio, and by pressing the desired shape and size tablets from the mixture.
- Powders are produced by mixing the finely powdered active substance with finely powdered carrier material.
- Liquid preparations include solutions, suspensions and emulsions, from which, optionally, the active substance is released in a delayed way.
- the medical preparations according to the invention are preferably produced in the form of dose units.
- the dose units contain the desired amount of active substance.
- the dose units may be distributed in packaged form, which contains separated amounts of the preparations (e.g. packaged tablets, capsules, powder in vials or ampules).
- the dose unit relates to the capsule, the tablet, sachet, lozenge as well as to the packaging containing a sufficient number of unit doses.
- the subject of the invention also relates to a method for the production of the above medical preparations, in such a way that the idelalisib base Form E according to the invention is mixed with medically suitable solid or liquid diluents and/or excipients, and the mixture is placed into a galenic form.
- the medical preparations according to the invention are produced using the usual methods of pharmaceutical production. If necessary, the medical preparations according to the invention may also contain further medical active substances with the compounds or a mixture of compounds according to the invention.
- the subject of the invention also relates to the use of the compounds according to the present invention as a medical active substance.
- the subject of the present invention relates to the use of the idelalisib base Form E according to the invention for the production of a medical preparation serving for the treatment of cancer diseases.
- the subject of the invention also relates to the use of the idelalisib base Form E according to the invention on its own or in combination with the active substance rituximab for the treatment of cancer diseases.
- the treated cancer disease may include leukaemia, preferably chronic lymphocytic leukaemia or follicular lymphoma.
- the compounds according to the invention are substances with uniform morphology and preferable crystalline forms. Accordingly, these substances have preferable and reproducible characteristics in terms of dissolution rate, bioavailability, chemical stability, hygroscopicity and processability (filtration features, drying, tableting, etc.).
- the active substances according to the invention may be advantageously produced using reproducible processes at industrial scales.
- Diffusion inhibitor slit Fixed slit 1/2 °
- Diffusion inhibitor slit Programmable slit in fixed mode: 1/2
- PrXcel 3D 1 x 1 area detector Mode Scanning line detector (ID) operation mode
- Step gap 0.0131° 2 ⁇
- Step duration 109.650 s
- Example 1 The production of the idelalisib base Form E-S acetonitrile solvate (method "A")
- the evaporation residue is dissolved in 200 ml of dichloromethane (DCM), then washed in 2x 50 ml of water.
- the organic phase is dried with 10 g of magnesium sulphate (stirred for 1 hour), and cleared with 0.6 g of active carbon.
- the drying agent and clearing carbon are filtered out, then washing is performed with 2x20 ml of DCM, the solvent is removed in a vacuum.
- 100 ml of acetonitrile (ACN) is added to the residue resin-type material at room temperature. A homogenous solution is obtained after stirring, and a few minutes after continued stirring the crystallization of the idelalisib Form E- S acetonitrile solvate starts.
- the material obtained is the acetonitrile solvate of idelalisib (Form E-S).
- Example 2 The production of the idelalisib base Form E-S acetonitrile solvate (method "B")
- the material obtained is the acetonitrile solvate of idelalisib (Form E-S).
- Example 3 The production of the idelalisib base (I) Form E polymorph
- the idelalisib Form E-S acetonitrile solvate obtained in either of examples 1 or 2 is dried in a drying cabinet at 100 °C for 15 hours.
- Form E idelalisib polymorph is obtained as an off- white crystalline material.
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Abstract
The subject of our invention relates to a new polymorph and solvate form of idelalisib and to their production methods. The subject of the invention also relates to a pharmaceutical preparation containing the idelalisib polymorph according to the invention, as well as to the therapeutic use of the preparation.
Description
New polymorphic and solvate form of idelalisib
The field of the invention
The subject of our invention relates to a new polymorphic form of the pharmaceutical active substance idelalisib, to a method for its production, to pharmaceutical preparations containing the new form, as well as the therapeutic use of all these.
The state of the art
The structural formula of 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin- 4(3H)-one, with the international non-proprietary name idelalisib is the following:
Idelalisib is a phosphoinositide-3-kinase (PI3K) enzyme inhibitor. The phosphoinositide-3- kinase enzymes participate in the regulation of numerous cell functions (growth regulation, metabolism, translation initiation). Idelalisib has been registered for the treatment of various forms of leukaemia. The production of idelalisib was first presented in international patent application number WO 2005113556. The solid material obtained following column chromatography purification was dissolved in ethanol, and then the solution was evaporated. On the basis of element analysis the composition of the light yellow solid material obtained in this way is idelalisib · EtOH · 0.4 H20. The inventors do not present analytical results serving to characterise the crystallography of the solid phase.
International patent application number WO 2013134288 presents the seven forms of idelalisib (Form I, II, III, IV, V, VI and VII), their production, their use for the production of
pharmaceutical preparations and their medical use. The characteristic x-ray powder diffractogram of each form was disclosed (the unit cell parameters of Forms I, II, III, IV, and V were also given), and also the individual crystal forms were also examined using thermal analysis methods (TG, DSC). Form I and Form II are solvent-free crystalline forms, and all of the other crystalline forms are solvates of the idelalisib base. The Form I polymorph is crystalized from a methanol-water mixture, with the temperature of the mixture being precisely regulated. The Form II polymorph is obtained by grinding the Form I polymorph, optionally with related solvent suspension or by the compression of the Form I polymorph. In other words, the Form I polymorph may be partially transformed into Form II in the course of certain preparation development operations (e.g. tableting) under generally used conditions. The joint presence of the two forms in the pharmaceutical preparation, presumably in varying proportions with respect to the specific characteristics of the pharmaceutical technology operations performed, in all events represents technological and quality control difficulties.
International patent application number WO 2015014315 presents ten forms of idelalisib, of which four are solvent-free crystalline forms, and the others some form of solvate. Among the solvent-free crystalline forms two are the same as the Form I and Form II polymorphs presented in patent application number WO 2013134288. One of the most important advantages of the two other forms (Form IV and Form VIII) is mentioned as being low hygroscopicity: in the case of Form IV the amount of water bound from the environmental moisture content is 0.3% while this amount in the case of Form VIII is 0.84% in the 20-80% relative humidity range.
International patent application number WO 2015092810 presents the amorphous form of idelalisib. In the knowledge of the numerous crystalline forms, it is obvious that the production of the amorphous form is only possible under special, strictly controlled conditions. Another disadvantage of the amorphous form in such cases is that during storage it may become transformed into one of the more thermodynamically stable crystalline forms . According to the examples described in the patent application, the amorphous form was only obtained using spray drying technology, or by evaporation of an idelalisib solution in the presence of a pharmaceutical excipient (polyvinylpyrrolidone, hydroxypropyl methylcellulose).
A brief description of the invention
The characteristics of solid phase pharmaceutical active substances have a fundamental influence on the determinant features of the pharmaceutical preparations made from them, such as release with its effect on bioavailability, stability, and also determine the range of pharmaceutical technology procedures that may be used. Therefore, the production of the solid phase forms of pharmaceutical active substances (polymorphs, salts, solvates, complexes) and the analysis of their characteristics are essential parts of the medicine development process.
The objective of the invention is to overcome the disadvantages of the known methods and elaborate a method for the production of new polymorphs of the idelalisib active substance that may be simply and economically implemented at industrial scales, that maintains its homogenous polymorphic form during pharmaceutical technology operations (grinding, granulations, tableting) and during the stability tests required when developing pharmaceutical preparations.
The idelalisib base Form E according to the invention has numerous preferable properties as compared to earlier idelalisib forms. Prominent among these is that during pressing it maintains its crystalline form. Furthermore, it has a preferably low degree of hygroscopicity. An especially preferable feature of the idelalisib base Form E according to the invention is that the stability exhibited in the course of pressing and especially low hygroscopicity are both characteristic of it at the same time. Preferably low hygroscopicity in a wide range of relative humidity is characteristic of idelalisib base Form E. These characteristics together make the crystalline form of the idelalisib base Form E especially preferable for use as a pharmaceutical active substance as compared to the earlier idelalisib forms.
Figures
Figure 1: the x-ray powder diffractogram of the idelalisib base Form E Figure 2: The effect of compression on the crystal structure of the idelalisib base Form E. The upper curve shows the x-ray powder diffractogram of a sample of an idelalisib Form E tablet produced by high-pressure compression, while the lower curve depicts the x-ray powder diffractogram of a sample not subjected to compression.
Figure 3: The effect of compression on the crystal structure of the idelalisib base Form I. The upper curve: the x-ray powder diffractogram of idelalisib Form II. The lower curve: the x-ray
powder diffractogram of idelalisib Form I. The middle curve shows the x-ray powder diffractogram of idelalisib Form I subjected to pressure.
Figure 4: The 25 °C water sorption isotherms of Form I and Form II of the patent application number WO 2013134288 and of the Form E idelalisib base. The figure depicts the percentage equilibrium moisture content as a function of relative humidity.
Figure 5: The x-ray powder diffractogram of idelalisib base acetonitrile solvate (Form E-S)
A detailed description of the invention
More specifically the subject of the invention relates to the crystalline Form E of the idelalisib base, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 11.56; 12.80; 14.96; 20.85. More specifically it may be characterised by the following x- ray powder diffraction peaks: 2Θ (±0.2° 2Θ): 11.56; 12.80; 14.96; 15.70; 18.24; 19.34; 20.25; 20.85; 22.73; 23.91; 32.42. Even more specifically it may be characterised by the following x- ray powder diffraction peaks: 2Θ (±0.2° 2Θ): 11.56; 11.73; 12.80; 13.71; 14.96; 15.55; 15.70; 17.57; 18.24; 19.34; 20.25; 20.47; 20.85; 22.18; 22.52; 22.73; 23.26; 23.62; 23.91; 24.16; 24.41; 24.86; 25.54; 25.85; 26.35; 27.04; 27.24; 27.40; 30.63; 30.86; 31.44; 31.71; 32.01; 32.42; 32.81; 33.67. The characteristic x-ray powder diffractogram of Form E may be seen in figure 1, and the 1% or greater intensity peaks are summarised in table 1.
Table 1 The x-ray powder diffraction data of idelalisib base Form E
( relative intensities > 1%)
8 17.57 5.04 4
9 18.24 4.86 10
10 19.34 4.59 7
11 20.25 4.38 19
12 20.47 4.34 2
13 20.85 4.26 100
14 22.18 4.00 4
15 22.52 3.94 2
16 22.73 3.91 12
17 23.26 3.82 1
18 23.62 3.76 1
19 23.91 3.72 17
20 24.16 3.68 5
21 24.41 3.64 1
22 24.86 3.58 4
23 25.54 3.49 6
24 25.85 3.44 11
25 26.35 3.38 8
The resistance of the crystal structure of the new idelalisib base form (Form E) according to our invention to mechanical stress was investigated with compression tests. The set pressure value (approx. 50 MPa) is comparable to the pressure values usually used when producing tablets. The x-ray powder diffractogram of a sample from a tablet of idelalisib base Form E produced using high pressure is presented in figure 2. It can be seen that the diffractogram is the same as that of the initial sample (before compression), in other words the pressing did not result in solid phase transformation in the sample.
A similar experiment was performed with idelalisib Form I according to patent application number WO 2013134288, the results can be seen in figure 3. In this case, in accordance with that stated in the application referred to, the diffraction peaks (indicated with arrows in figure 3) characteristic of idelalisib base Form II appeared in the diffractogram of the tablet obtained, in other words the sample partially transformed into a crystal structure that is not homogenous. On the basis of this idelalisib base Form I is less resistant to mechanical stress, the sample suffered solid phase transformation due to the effect of high-pressure compression. The phenomenon experienced in the case of Form I is not preferable, as during preparation formulation (e.g. tableting) the active substance is subjected to pressure of this order, as a result of which the crystal structure of the active substance in the preparation will not be homogenous.
The water sorption isotherms of the idelalisib base Form E recorded at 25 °C are presented in figure 4. It can be seen that the substance does not display hygroscopicity: in the relative humidity range of 0-85% the maximum water absorption is under 0.15%. According to the measurement results the hygroscopicity of idelalisib base Form E in the examined range is lower than that of Form I and Form II according to patent application number WO 2013134288, and is also preferably lower than that of the two new solvent-free forms (Form IV and Form VIII) presented in patent application number WO 2015014315. The lower hygroscopicity experienced in the case of Form E is also preferable from the points of view of stability and preparation formulation.
More specifically the subject of our invention also relates to the acetonitrile solvate of the crystalline idelalisib base (Form E-S), the significance of which is that the idelalisib Form E crystalline form according to the invention may be produced via this.
The characteristic x-ray powder diffraction peaks characteristic of the Form E-S acetonitrile solvate are the following: 2Θ (±0.2° 2Θ): 6.81; 7.94; 8.65; 12.47; 20.99. More specifically it can be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2° 2Θ): 6.81;
7.94; 8.65; 11.99; 12.47; 13.13; 15.17; 20.99; 25.09; 29.02. Even more specifically it can be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2° 2Θ): 6.81; 7.94; 8.65;
11.99; 12.47; 13.13; 13.57; 15.17; 15.93; 17.02; 17.20; 17.85; 18.46; 19.07; 19.23; 19.45; 20.27; 20.99; 21.92; 22.11; 22.45; 22.74; 23.07; 23.49; 24.04; 24.25; 25.09; 25.79; 26.37;
27.00; 27.44; 27.68; 28.10; 28.58; 29.02; 29.44; 29.86; 30.29; 30.56; 31.14; 32.04; 32.45;
32.71; 33.11; 34.03; 34.65. The characteristic x-ray powder diffractogram of this may be seen in figure 5, and the 2% or greater intensity peaks are summarised in the following table 2.
Table 2 The x-ray powder diffraction data of the idelalisib base acetonitrile solvate (Form E-
S) (relative intensities > 2%)
22 22.74 3.91 30
23 23.07 3.85 20
24 23.49 3.78 21
25 24.04 3.70 96
26 24.25 3.67 29
27 25.09 3.55 48
28 25.79 3.45 17
29 26.37 3.38 44
30 27.00 3.30 16
31 27.44 3.25 19
32 27.68 3.22 16
33 28.10 3.17 13
34 28.58 3.12 9
35 29.02 3.07 22
36 29.44 3.03 10
37 29.86 2.99 4
38 30.29 2.95 9
39 30.56 2.92 2
40 31.14 2.87 2
41 32.04 2.79 8
42 32.45 2.76 7
43 32.71 2.74 9
44 33.11 2.70 10
45 34.03 2.63 4
46 34.65 2.59 3
The subject of the invention also relates to a method for the production of the Form E-S acetonitrile solvate of 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin- 4(3H)-one (idelalisib) in such a way that 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6- ylamino)propyl]quinazolin-4(3H)-one is dissolved in acetonitrile, the solution is stirred, the crystalline substance precipitated during stirring is the acetonitrile solvate Form E-S of 3- phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one.
The subject of the invention also relates to a method for the production 3-phenyl-5-fluoro-2- [l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one (idelalisib) Form E, in such a way that the Form E-S acetonitrile solvate form according to the invention is dried. Furthermore, the subject of the invention relates to a pharmaceutical preparation containing idelalisib Form E and pharmaceutically acceptable additives.
The subject of the invention also relates to a medical preparation containing a therapeutically effective amount of idelalisib base Form E according to the invention and, optionally, one or more excipients used in the production of medical preparations. Furthermore, a method for the production of a medical preparation, characterised by that the idelalisib base Form E according to the invention is mixed with an appropriate amount of medically acceptable carrier and, optionally, other medically suitable excipients, and is then placed in a galenic formulation.
The medial preparations according to the invention are preferably administered orally. Orally administered preparations may include, for example, tablets, capsules, dragees, solutions, elixirs, suspensions and emulsions.
The medical preparations according to the invention may contain the usual medical carriers and/or excipients. Carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting point wax, PEG, cocoa butter, etc. In the case of capsules it is frequently the material of the capsule that serves as the carrier and so in such a case there is no need for a separate carrier. Orally administered preparations also include sachets and lozenges. Tablets, powders, capsules, pills, sachets and lozenges are especially suitable solid preparation forms.
An especially preferable medical preparation is the film-coated tablet containing idelalisib in the tablet core. According to a preferable embodiment of the method the tablet core contains the following excipients: microcrystalline cellulose, hydroxypropyl cellulose (E463), croscarmellose-sodium, carboxymethyl starch sodium and magnesium stearate. The tablets may be produced by mixing the active substance with carrier materials with suitable characteristics in the appropriate ratio, and by pressing the desired shape and size tablets from the mixture.
Powders are produced by mixing the finely powdered active substance with finely powdered carrier material. Liquid preparations include solutions, suspensions and emulsions, from which, optionally, the active substance is released in a delayed way.
The medical preparations according to the invention are preferably produced in the form of dose units. The dose units contain the desired amount of active substance. The dose units may be distributed in packaged form, which contains separated amounts of the preparations (e.g. packaged tablets, capsules, powder in vials or ampules). The dose unit relates to the capsule, the tablet, sachet, lozenge as well as to the packaging containing a sufficient number of unit doses.
The subject of the invention also relates to a method for the production of the above medical preparations, in such a way that the idelalisib base Form E according to the invention is mixed with medically suitable solid or liquid diluents and/or excipients, and the mixture is placed into a galenic form.
The medical preparations according to the invention are produced using the usual methods of pharmaceutical production. If necessary, the medical preparations according to the invention may also contain further medical active substances with the compounds or a mixture of compounds according to the invention. The subject of the invention also relates to the use of the compounds according to the present invention as a medical active substance.
The subject of the present invention relates to the use of the idelalisib base Form E according to the invention for the production of a medical preparation serving for the treatment of cancer diseases.
The subject of the invention also relates to the use of the idelalisib base Form E according to the invention on its own or in combination with the active substance rituximab for the treatment of cancer diseases. The treated cancer disease may include leukaemia, preferably chronic lymphocytic leukaemia or follicular lymphoma.
The advantage of the invention is that the compounds according to the invention are substances with uniform morphology and preferable crystalline forms. Accordingly, these substances have preferable and reproducible characteristics in terms of dissolution rate, bioavailability, chemical stability, hygroscopicity and processability (filtration features, drying, tableting, etc.).
The active substances according to the invention may be advantageously produced using reproducible processes at industrial scales.
EXAMPLES
Measurement conditions used
Dynamic vapour sorption analysis (DVS)
SMS DVS Advantage DVSA1-STD dynamic vapour sorption
Device:
analyser
Atmosphere: nitrogen
Total gas flow rate: 200 mL/min
Solvent: water
Temperature: 25 °C
Regulation: Open cycle
Step size: 5 % RH
Stability criterion: 0.002 %/min Phases: DMDT Window: 5 min
Minimum stability time 30 min
Maximum phase time: 360 min
Data saving frequency: 1 min
Measurement range: 0% RH→ 85% RH
X-ray powder diffraction measurement conditions
In the case of all crystalline forms presented here the x-ray diffraction data of the new idelalisib base forms (and their various solvates) according to our invention were obtained under the following measurement conditions:
Device: PANalytical Empyrean X-ray powder diffractometer Sampling: Transmission
X-ray
Type: Empyrean Long Fine Focus High Resolution tube
Anode: Cu
Wavelength: Ka (1.541874 A)
Optics
Divergence slit: Fixed slit 1/2 °
Mirror: Focussing elliptical mirror
Soller slit: 0.04 rad
Diffusion inhibitor slit: Fixed slit 1/2 °
Diffraction ray optics
Diffusion inhibitor slit: Programmable slit in fixed mode: 1/2
Soller slit: 0.04 rad
Sample table
Type: Reflection-transmission spinner stage
Sample rotation: 1 rotation/min Detector
Type: PrXcel 3D 1 x 1 area detector
Mode: Scanning line detector (ID) operation mode
Active length: 3.3473°
Sample preparation: unpowdered samples placed between Mylar sheets
Measurement settings
Temperature: room temperature
Accelerating voltage: 45 kV
Anode heating current: 40 mA
Scanning: continuous gonio (Θ/Θ) scan
Measurement range: 2.0000-34.9964° 2Θ
Step gap: 0.0131° 2Θ
Step duration: 109.650 s
Measurement cycles: 1
Measurement time: -20 min
Conditions of the pressing tests
The resistance against mechanical stresses of the crystal structure of the new idelalisib base form according to our invention and of the polymorphs known from the literature was studied using pressing tests. Tablets were formed from the powder samples using a Specac Atlas 15T hydraulic press with a Star pressure gauge (15 tonne). The pressure applied was approx. 50 MPa. The crystal structure of the tablets produced was studied without powdering using x-ray powder diffraction, under the give measurement conditions.
Further details of the solution according to our invention are presented in the following examples without restricting the scope of protection of the invention in any way to the examples.
A mixture of 16.4 g (49.13 mmol) (5)-2-(l-amino-propyl)-5-fluor-3-phenyl-quinazolin- 4(3H)-one hydrochloride (II), 9.9 g (63.9 mmol) 6-chloropurine, 330 ml isopropyl alcohol (IPA) and 20.5 ml ( 14.9 g; 147.4 mmol) triethylamine (TEA) at an internal temperature of 82- 84 °C is stirred for 63 hours. The orange coloured solution is cooled to 45-50 °C, then evaporated in a vacuum (50 °C, 30-35 mbar). The evaporation residue is dissolved in 200 ml of dichloromethane (DCM), then washed in 2x 50 ml of water. The organic phase is dried with 10 g of magnesium sulphate (stirred for 1 hour), and cleared with 0.6 g of active carbon. The drying agent and clearing carbon are filtered out, then washing is performed with 2x20 ml of DCM, the solvent is removed in a vacuum. 100 ml of acetonitrile (ACN) is added to the residue resin-type material at room temperature. A homogenous solution is obtained after stirring, and a few minutes after continued stirring the crystallization of the idelalisib Form E- S acetonitrile solvate starts. After two hours of stirring the precipitated material is filtered, and then washed with small amounts of ACN being added to cover the substance until the filtrate becomes colourless (approx. 6x 5 ml). The material obtained is the acetonitrile solvate of idelalisib (Form E-S).
Example 2: The production of the idelalisib base Form E-S acetonitrile solvate (method "B")
A mixture of 16.4 g (49.1 mmol) (5)-2-(l-amino-propyl)-5-fluor-3-phenyl-quinazolin-4(3H)- one hydrochloride (II), 9.9 g (63.9 mmol) 6-chloropurine, 330 ml isopropyl alcohol (IPA) and
20.5 ml (14.9 g; 147.4 mmol) triethylamine (TEA) at an internal temperature of 82-84 °C is stirred for 63 hours. The orange coloured solution is cooled to 45-50 °C, then evaporated in a vacuum (50 °C, 30-35 mbar) so that 77 g of mixture remains in the flask. It is cooled to room temperature, 1 g of clearing carbon is added which its filtered out along with the precipitated TEA HQ (approx. 10 g), the filtered substance is washed with 10 ml of IPA. 60 ml of water is added to the solution. The mixture is brought to the boil and further water is added drop by drop in order to obtain a clear solution. Leave to cool. Crystallization starts at about 40 °C. After room temperature is reached the solution is stirred for 2 hours, the precipitated substance is filtered out and then washed with an IPA:water = 1: 1 mixture, then dried for 5 hours at 100 °C in a vacuum drying cabinet. 7 ml/g of ACN is added to the crystalline material obtained. After stirring a homogenous solution is obtained, which after continued stirring starts to crystalize after a few minutes. After two hours of stirring the precipitated material is filtered, and then washed with small amounts of ACN being added to cover the substance (approx. 3 x 15 ml). The material obtained is the acetonitrile solvate of idelalisib (Form E-S).
Example 3: The production of the idelalisib base (I) Form E polymorph
(I)
The idelalisib Form E-S acetonitrile solvate obtained in either of examples 1 or 2 is dried in a drying cabinet at 100 °C for 15 hours. Form E idelalisib polymorph is obtained as an off- white crystalline material.
Mp: 208-210 °C.
Element analysis: calculated: C22H18FN7O (415.43): C 63.61%, H 4.37%, N 23.60%;
measured: C 63.51%, H 4.28%; N 23.09%
Claims
1. 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one Form E polymorph, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 1 1.56; 12.80; 14.96; 20.85.
2. The Form E polymorph according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 1 1.56; 12.80; 14.96; 15.70; 18.24; 19.34; 20.25; 20.85; 22.73; 23.91 ; 32.42.
3. The Form E polymorph according to claim 1 or 2, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 1 1.56; 11.73; 12.80; 13.71 ; 14.96; 15.55; 15.70; 17.57; 18.24; 19.34; 20.25; 20.47; 20.85; 22.18; 22.52; 22.73; 23.26; 23.62; 23.91 ; 24.16; 24.41 ; 24.86; 25.54; 25.85; 26.35; 27.04; 27.24; 27.40; 30.63; 30.86; 31.44; 31.71 ; 32.01 ; 32.42; 32.81 ; 33.67.
4. The acetonitrile solvate Form E-S of 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6- ylamino)propyl]quinazolin-4(3H)-one Form E-S, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 6.81 ; 7.94; 8.65; 12.47; 20.99.
5. The acetonitrile solvate Form E-S according to claim 4, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 6.81 ; 7.94; 8.65; 11.99; 12.47; 13.13; 15.17; 20.99; 25.09; 29.02.
6. The acetonitrile solvate Form E-S according to claim 4 or 5, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2° 2Θ): 6.81 ; 7.94; 8.65; 11.99; 12.47; 13.13; 13.57; 15.17; 15.93; 17.02; 17.20; 17.85; 18.46; 19.07; 19.23; 19.45; 20.27; 20.99; 21.92; 22.11 ; 22.45; 22.74; 23.07; 23.49; 24.04; 24.25; 25.09; 25.79; 26.37; 27.00; 27.44; 27.68; 28.10; 28.58; 29.02; 29.44; 29.86; 30.29; 30.56; 31.14; 32.04; 32.45; 32.71 ; 33.11 ; 34.03; 34.65.
7. Method for the production of idelalisib Form E according to any of claims 1 to 3, in such a way that the Form E-S acetonitrile solvate according to any of claims 4 to 6 is dried.
8. Method for the production of the Form E-S acetonitrile solvate according to any of claims 4 to 6, in such a way that 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)- one is dissolved in acetonitrile, the solution is stirred, the crystalline material precipitated during stirring is the Form E-S acetonitrile solvate form of 3-phenyl-5-fluoro-2-[l(5)-(9H-purin-6- ylamino)propyl]quinazolin-4(3H)-one.
9. Method for the production of a pharmaceutical preparation, characterised by that the Form E polymorph according to any of claims 1 to 3 is mixed with excipients usually used in the preparation of medicines to produce a pharmaceutical preparation.
10. The use of the compound according to any of claims 1 to 3 in the treatment or prevention of cancer dieases.
11. The compound according to claim 10, where the cancer disease is leukaemia, preferably chronic lymphocytic leukaemia or follicular lymphoma.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HU1500577A HU231016B1 (en) | 2015-11-30 | 2015-11-30 | New polymorph and solvate of idelalisib |
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WO2019178596A1 (en) | 2018-03-16 | 2019-09-19 | Johnson Matthey Public Limited Company | Pyridine or n,n-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
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WO2005113556A1 (en) * | 2004-05-13 | 2005-12-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
WO2013134288A1 (en) * | 2012-03-05 | 2013-09-12 | Gilead Calistoga Llc | Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one |
CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
WO2015014315A1 (en) * | 2013-08-01 | 2015-02-05 | 杭州普晒医药科技有限公司 | Inhibitor crystalline form and preparation method and use thereof |
-
2015
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WO2005113556A1 (en) * | 2004-05-13 | 2005-12-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
WO2013134288A1 (en) * | 2012-03-05 | 2013-09-12 | Gilead Calistoga Llc | Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one |
WO2015014315A1 (en) * | 2013-08-01 | 2015-02-05 | 杭州普晒医药科技有限公司 | Inhibitor crystalline form and preparation method and use thereof |
CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2019178596A1 (en) | 2018-03-16 | 2019-09-19 | Johnson Matthey Public Limited Company | Pyridine or n,n-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
US11358966B2 (en) | 2018-03-16 | 2022-06-14 | Johnson Matthey Public Limited Company | Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
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HUP1500577A2 (en) | 2017-06-28 |
HU231016B1 (en) | 2019-11-28 |
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