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.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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Citations (3)

• 2015
  • 2015-06-26 CZ CZ2015-442A patent/CZ2015442A3/cs unknown
• 2016
  • 2016-06-27 WO PCT/CZ2016/000072 patent/WO2016206662A1/en not_active Ceased

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