WO2016206662A1 - Ibrutinib hemisulphate - Google Patents
Ibrutinib hemisulphate Download PDFInfo
- Publication number
- WO2016206662A1 WO2016206662A1 PCT/CZ2016/000072 CZ2016000072W WO2016206662A1 WO 2016206662 A1 WO2016206662 A1 WO 2016206662A1 CZ 2016000072 W CZ2016000072 W CZ 2016000072W WO 2016206662 A1 WO2016206662 A1 WO 2016206662A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ibrutinib
- ibmtinib
- sulphuric acid
- hemisulphate
- preparation
- Prior art date
Links
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title abstract description 40
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title abstract description 39
- 229960001507 ibrutinib Drugs 0.000 title abstract description 39
- 238000002360 preparation method Methods 0.000 abstract description 13
- 150000003839 salts Chemical class 0.000 abstract description 12
- 239000007787 solid Substances 0.000 abstract description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 10
- 235000011149 sulphuric acid Nutrition 0.000 abstract description 10
- 239000001117 sulphuric acid Substances 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- 239000012458 free base Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 239000002552 dosage form Substances 0.000 abstract description 3
- 238000009472 formulation Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to a novel solid form of l-[(3i?)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl] iperidin-l-yl]prop-2-en-l-one of formula (I),
- ibrutinib (CAS no. 936563-96-1) ,belongs to the group of kinase inhibitors that can be used for the treatment of lymphomas.
- Imbruvica Ibrutinib was approved by The Food and Drug Administration (FDA) for the treatment of centrocytic lymphoma.
- the patent WO2013/184572 deals, besides preparation methods, with the pharmaceutical composition of crystalline and solvated forms of ibrutinib for oral administration and mentions pharmaceutically acceptable salts of this drug without any further description or example of production thereof.
- Further use of ibrutinib for the treatment of cancer, inflammatory and autoimmune diseases, together with a description of pharmaceutical compositions mentioning its pharmaceutically acceptable salts without further description or example of production thereof is mentioned in the patent WO2014/004707.
- the solubility of the crystalline free base of ibrutinib in water is very low, even if aqueous solutions with different pH are used. It is clear that novel solid forms of this active pharmaceutical ingredient are needed for the preparation of dosage forms with higher solubility and bioavailability.
- the invention provides a novel crystalline solid form of ibrutinib in the form of a pharmaceutically acceptable salt with sulphuric acid and methods of its preparation.
- This salt is prepared by a reaction of ibrutinib in the free base form (formula I) with sulphuric acid in a suitable solvent or mixtures of solvents.
- the prepared novel crystalline solid form has suitable physical-chemical characteristics for use in the pharmaceutical industry and formulation of new dosage forms.
- the salt of ibrutinib with sulphuric acid is in the solid phase and in crystalline form; in the DSC record it exhibits the melting point of approximately 121°C.
- the ibrutinib sulphate is ibrutinib hemisulphate exhibiting the following characteristic diffraction peaks with the use of CuKct radiation: 4.18; 7.96; 14.51; 17.69; and 21.2 ⁇ 0.2° 2-theta.
- the molar ratio of ibrutinib : sulphuric acid is in the range of 10:1 to 1:3, preferably 2:1.
- Salts of pharmaceutically active substances generally have higher solubility and bioavailability values than their corresponding basic forms.
- This invention provides a salt of ibrutinib in a crystalline solid phase.
- the invention consists in a novel solid form of ibrutinib with sulphuric acid that can be prepared in a crystalline form in adequate yields with high chemical purity.
- the prepared novel solid form of ibrutinib may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its preparation. Therefore, the invention relates to a crystalline or amorphous form of ibrutinib sulphate in any ratio.
- This novel solid form is suitable for preparation of ibrutinib with high chemical and optical purity.
- the preparation of the novel form of ibrutinib (formula (I)) is based on a reaction of the free base of ibrutinib with sulphuric acid.
- the reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof. Aliphatic C1-C4 alcohols, esters or their mixtures are preferred.
- the most commonly used solvents are acetone, ethanol, isopropanol, acetonitrile, tetrahydrofuran or mixtures thereof.
- the final product is typically precipitated or crystallized at temperatures in the range of - 30°C to the boiling point of the solvent.
- the crystalline form of ibrutinib hemisulphate (according to Example 2) is characterized by the reflections presented in Table 1.
- Table 1 includes reflections whose relative intensity value is higher than 1 percent.
- the characteristic diffraction peaks of ibrutinib hemisulphate according to this invention are: 4.18; 7.96; 14.51; 17.69; and 21.2 ⁇ 0.2° 2-theta.
- An example of the X-ray powder pattern is shown in Figure 1.
- the melting point of the crystalline form of ibrutinib hemisulphate, prepared according to Example 2, is 121°C (DSC).
- ibrutinib sulphate prepared according to Example 2 is shown in Fig. 2.
- the molar ratio of ibrutinib: sulphuric acid can be in the range of 10:1 to 1:3, preferably 2:1.
- a 10mm mask and a 1/4° fixed anti- dispersion slit were used.
- the irradiated area of the sample is 10 mm, programmable divergence slits were used.
- ATR (Ge - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 cm “1 and the spectral resolution of 4.0 cm “1 .
- the data were obtained at 64 spectrum accumulations.
- the OMNIC 6.2 software was used to process the spectra.
- the record of the novel solid form of ibrutinib hemisulphate was measured using a Discovery DSC device made by TA Instruments.
- the sample charge in a standard Al pot 40 was between 4-5 and 5 mg and the heating rate was 5°C/min.
- As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.
- Example 1 The free base of ibrutinib was prepared according to the procedure mentioned in the patent (WO2008/039218).
- Example 2 Preparation of ibrutinib hemisulphate l-[(3i?)-3-[4-Amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1- yl]prop-2-en-l-one (Ibrutinib) in the amount of 2.124 g (4.82-10 "3 mol) was dissolved in 110 ml of acetone. 0.134 ml (2.41 -10 "3 mol) of sulphuric acid (96 %) was added to this solution. After 30 min, the originally clear solution turned into a white suspension. The obtained suspension was further stirred at the room temperature for 2 hours.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ2015-442A CZ2015442A3 (cs) | 2015-06-26 | 2015-06-26 | Ibrutinib hemisulfát |
CZPV2015-442 | 2015-06-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016206662A1 true WO2016206662A1 (en) | 2016-12-29 |
Family
ID=56507367
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CZ2016/000072 WO2016206662A1 (en) | 2015-06-26 | 2016-06-27 | Ibrutinib hemisulphate |
Country Status (2)
Country | Link |
---|---|
CZ (1) | CZ2015442A3 (cs) |
WO (1) | WO2016206662A1 (cs) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3501609A1 (en) | 2017-12-08 | 2019-06-26 | Zentiva K.S. | Pharmaceutical compositions comprising ibrutinib |
CN110317203A (zh) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | 一种依鲁替尼和羧酸的共无定型物及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008039218A2 (en) * | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2013184572A1 (en) * | 2012-06-04 | 2013-12-12 | Pharmacyclics, Inc. | Crystalline forms of a bruton's tyrosine kinase inhibitor |
WO2016050422A1 (en) * | 2014-10-01 | 2016-04-07 | Ratiopharm Gmbh | Acid addition salt of ibrutinib |
-
2015
- 2015-06-26 CZ CZ2015-442A patent/CZ2015442A3/cs unknown
-
2016
- 2016-06-27 WO PCT/CZ2016/000072 patent/WO2016206662A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008039218A2 (en) * | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2013184572A1 (en) * | 2012-06-04 | 2013-12-12 | Pharmacyclics, Inc. | Crystalline forms of a bruton's tyrosine kinase inhibitor |
WO2016050422A1 (en) * | 2014-10-01 | 2016-04-07 | Ratiopharm Gmbh | Acid addition salt of ibrutinib |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3501609A1 (en) | 2017-12-08 | 2019-06-26 | Zentiva K.S. | Pharmaceutical compositions comprising ibrutinib |
CN110317203A (zh) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | 一种依鲁替尼和羧酸的共无定型物及其制备方法 |
CN110317203B (zh) * | 2019-07-08 | 2022-05-13 | 浙江工业大学 | 一种依鲁替尼和羧酸的共无定型物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CZ2015442A3 (cs) | 2017-01-04 |
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