WO2021259732A1 - Composés à composants multiples comprenant du zanubrutinib et un dérivé d'acide benzoïque - Google Patents

Composés à composants multiples comprenant du zanubrutinib et un dérivé d'acide benzoïque Download PDF

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WO2021259732A1
WO2021259732A1 PCT/EP2021/066261 EP2021066261W WO2021259732A1 WO 2021259732 A1 WO2021259732 A1 WO 2021259732A1 EP 2021066261 W EP2021066261 W EP 2021066261W WO 2021259732 A1 WO2021259732 A1 WO 2021259732A1
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zanubrutinib
crystalline form
range
compound
temperature
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PCT/EP2021/066261
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English (en)
Inventor
Verena Adamer
Arthur Pichler
Erwin Schreiner
Thomas GELBRICH
Andreas Krekeler
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Sandoz Ag
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    • 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

Definitions

  • the present invention relates to compounds, comprising (5)-7-(l-acryloylpiperidin-4-yl)-2-(4- phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[ 1 , 5 -c/]pyri mi dine-3 -carboxamide (INN: zanubrutinib) and a benzoic acid derivative selected from 4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid and to crystalline forms thereof. Also provided are processes of producing said compounds and their crystalline forms. Furthermore, the invention relates to pharmaceutical compositions comprising the compounds of the present invention and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions of the present invention can be used as medicaments, in particular for the treatment and/or prevention of B- cell proliferative diseases such as mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • Zanubrutinib is an orally available reversible inhibitor of Bruton’s Tyrosine kinase (BTK).
  • BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cell s, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.
  • BCR B-cell antigen receptor
  • zanubrutinb leads to inhibition of BTK activity and hence inhibits malignant B-cell proliferation and reduces tumor growth.
  • 2019 zanubrutinib has been approved by the US FDA for the second-line treatment of adult patients with relapsed and refractory mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • Zanubrutinib and its preparation are disclosed in WO 2014/173289 A2 (Compound 27).
  • a crystalline Form A of zanubrutinib is described in WO 2018/033853 A2.
  • the same Form A is also mentioned in WO 2019/108795 A1 as a result of Example 1, Step 16.
  • the marketed product BRUKINS ATM contains zanubrutinib Form A according to the quality product review published on the FDA website.
  • Different solid-state forms of an active pharmaceutical ingredient often possess different physical and chemical properties such as but not limited to dissolution rate, solubility, chemical stability, physical stability, hygroscopicity, melting point, morphology, flowability, bulk density and compressibility.
  • Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an API.
  • processing or handling of an API during the formulation process may be improved.
  • New solid-state forms of an API can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid-state forms.
  • zanubrutinib Form A suffers from certain drawbacks, e.g. it is practically insoluble in water and consists of irregularly shaped, cohesive particles with poor flow characteristics and a tendency to agglomerate. Also, as apparent from the description of WO 2018/033853 A2, in particular from Figure 2 of the document, Form A possesses a relatively low melting point with an onset temperature of only about 139°C. Finally, according to the teaching of WO 2018/033853 A2 Form A can only be produced from starting materials of high enantiomeric purity e.g. having an “ee value” of above 97%.
  • zanubrutinib e.g. a form of zanubrutinib which possesses improved physicochemical properties.
  • a solid-state form of zanubrutinib which is chemically and physically stable against temperature and/or moisture stress, has a low residual solvent content, possesses improved aqueous solubility and/or dissolution properties and/or possesses improved powder characteristics.
  • zanubrutinib can form multi-component compounds, which have improved properties relevant for pharmaceutical purposes.
  • the inventors of the present invention have identified multi-component compounds comprising zanubrutinib and benzoic acid derivatives selected from 4-hydroxybenzoic acid and 3,4-dihydroxybenzoic acid.
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention possess one or more unexpected improved physicochemical properties selected from the group consisting of dissolution rate, solubility, chemical stability, physical stability, chemical purity, residual solvent content, hygroscopicity, melting point, morphology, flowability, wettability, bulk density and compressibility.
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4- dihydroxybenzoate form of the present invention possess high melting points with onset temperatures of about 174°C and 187°C (see Example 5, Figure 3 and Figure 8), show low residual solvent contents (see Example 6, Figure 4 and Figure 9) exhibit high crystallinity (see Example 3, Figure 1 and Figure 6), are non-hygroscopic or at maximum slightly hygroscopic and show no hysterises between their sorption and desorption curves during a gravimetric moisture sorption experiment (see Example 7, Figure 5 and Figure 10 hereinafter) and are physically stable in aqueous media and upon exposure to high temperature and humidity conditions (see Examples 9 and 10).
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4- dihydroxybenzoate form of the present invention exhibit improved solubilities and dissolution rates in aqueous phosphate buffer pH 6.8, aqueous acetate buffer pH 4.5 and FaSSIF medium (see Example 11, Figure 13 - 15).
  • FaSSIF Fasted state simulated small intestinal fluid SDS Sodium dodecyl sulfate
  • room temperature refers to a temperature in the range of from 20 to 30°C.
  • zanubrutinib refers to the compound having the chemical name ( S )- 7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrimidine-3 -carboxamide and the chemical structure as depicted in Formula (I) disclosed herein above.
  • co-crystal refers to crystalline materials composed of two or more different molecular and/or ionic compounds in the same crystal lattice that are associated by nonionic and noncovalent bonds, wherein at least two of the individual molecular and/or ionic compounds are solids at room temperature.
  • zanubrutinib Form A refers to the crystalline form of zanubrutinib, which is disclosed in WO 2018/033853 A2.
  • Form A of zanubrutinib can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (5.4 ⁇ 0.2)°, (14.8 ⁇ 0.2)° and (21.4 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions.
  • standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature.
  • Standard conditions can mean a temperature of about 22°C.
  • standard conditions can additionally mean a measurement under 20-50% relative humidity.
  • reflection with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
  • a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering.
  • long-range order e.g.
  • the term “essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably in the range of ⁇ 0.1° 2-Theta.
  • a reflection that usually appears at 7.7° 2-Theta for example can appear between 7.5° and 7.9° 2-Theta, preferably between 7.6 and 7.8° 2-Theta on most X-ray diffractometers under standard conditions.
  • relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
  • a typical precision of the wavenumber values is in the range of ⁇ 4 cm 1 , preferably in the range of ⁇ 2 cm 1 .
  • a peak at 1678 cm 1 for example can appear between 1674 and 1682 cm 1 , preferably between 1676 and 1680 cm 1 on most infrared spectrometers under standard conditions.
  • Peak intensities can be derived from according figures, but one skilled in the art will appreciate that differences in peak intensities due to degree of crystallinity, sample preparation, measurement method and other factors can also occur in infrared spectroscopy. Peak intensities should therefore be taken as qualitative measure only.
  • solid-state form refers to any crystalline and/or amorphous phase of a compound.
  • Crystalline phases include anhydrous/non-solvated forms of a compound and their polymorphs; hydrates and solvates of a compound and their polymorphs; salts and co-crystals of a compound and their polymorphs and pseudopolymorphic forms; and any mixtures thereof.
  • the term “essentially free of any other solid-state form” with reference to the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form of the present invention means that the zanubrutinib 4- hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate form contains at most 20 w- %, preferably at most 10 w-%, more preferably at most 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w- % of any other solid-state form of zanubrutinib, based on the total weight of the composition.
  • the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate form of the present invention may be referred to herein as being characterized by a powder X-ray diffractogram or an FTIR spectrum "as shown in" a figure.
  • the person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations, for example relating to the exact reflection/peak positions and intensities.
  • a comparison of the graphical data in the figure herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
  • mother liquor refers to the solution remaining after crystallization of a solid from said solution.
  • a “predetermined amount” as used herein with regard to the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate form of the present invention refers to the initial amount of the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form used for the preparation of a pharmaceutical composition having a desired dosage strength of zanubrutinib.
  • the term “effective amount” in conjunction with the zanubrutinib 4- hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate form of the present invention encompasses an amount of the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form of the present invention which causes the desired therapeutic or prophylactic effect.
  • the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
  • pharmaceutically acceptable excipient refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, wetting agent, stabilizer or a manufacturing aid among others.
  • Figure 1 illustrates a representative PXRD of the zanubrutinib 4-hydroxybenzoate form according to the present invention.
  • the x-axis shows the scattering angle in °2-Theta
  • the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.
  • Figure 2 illustrates a representative FTIR spectrum of the zanubrutinib 4-hydroxybenzoate form according to the present invention.
  • the x-axis shows the wavenumbers in cm 1
  • the y-axis shows the relative intensity in percent transmittance.
  • Figure 3 illustrates a representative DSC curve of the zanubrutinib 4-hydroxybenzoate form according to the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.
  • Figure 4 illustrates a representative TGA curve of the zanubrutinib 4-hydroxybenzoate form according to the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the mass (loss) of the sample in weight percent (w-%).
  • Figure 5 illustrates representative GMS isotherms of the zanubrutinib 4-hydroxybenzoate form according to the present invention in the range of from 0 to 90% relative humidity.
  • the x- axis displays the relative humidity in percent (%) measured at a temperature of (25.0 ⁇ 0.1) °C, the y-axis displays the mass changes in weight percent (w-%).
  • the sorption cycles are marked by triangles, whereas the desorption cycles are marked by squares.
  • the sample weight at 0% relative humidity at the end of the desorption cycle was set as reference weight.
  • Figure 6 illustrates a representative PXRD of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention.
  • the x-axis shows the scattering angle in °2-Theta
  • the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.
  • Figure 7 illustrates a representative FTIR spectrum of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention.
  • the x-axis shows the wavenumbers in cm 1
  • the y-axis shows the relative intensity in percent transmittance.
  • Figure 8 illustrates a representative DSC curve of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.
  • Figure 9 illustrates a representative TGA curve of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the mass (loss) of the sample in weight percent (w-%).
  • Figure 10 illustrates representative GMS isotherms of the zanubrutinib 3,4-dihydroxybenzoate form of the present invention in the range of from 0 to 90% relative humidity.
  • the x-axis displays the relative humidity in percent (%) measured at a temperature of (25.0 ⁇ 0.1) °C, the y-axis displays the the mass change in weight percent (w-%).
  • the sorption cycles are marked by triangles, whereas the desorption cycles are marked by squares.
  • the sample weight at 0% relative humidity at the end of the desorption cycle was set as reference weight.
  • Figure 11 illustrates the single crystal structure of the zanubrutinib 4-hydroxybenzoic acid co crystal of the present invention.
  • Figure 12 illustrates the single crystal structure of the zanubrutinib 3,4-dihydroxybenzoic acid co-crystal of the present invention.
  • Figure 13 displays the dissolution curves of the zanubrutinib 4-hydroxybenzoate form of the present invention (black triangles), the zanubrutinib 3,4-dihydroxybenzoate form of the present invention (white triangles) and zanubrutinib Form A of WO 2018/033853 A2 (white squares) in phosphate buffer pH 6.8 measured at 37°C.
  • the x-axis shows the time in hours
  • the y-axis the zanubrutinib concentration of the solution in mg/mL.
  • Figure 14 displays the dissolution curves of the zanubrutinib 4-hydroxybenzoate form of the present invention (black triangles), the zanubrutinib 3,4-dihydroxybenzoate form of the present invention (white triangles) and zanubrutinib Form A of WO 2018/033853 A2 (white squares) in acetate buffer pH 4.5 measured at 37°C.
  • the x-axis shows the time in hours
  • the y-axis the zanubrutinib concentration of the solution in mg/mL.
  • Figure 15 displays the dissolution curves of the zanubrutinib 4-hydroxybenzoate form of the present invention (black triangles), the zanubrutinib 3,4-dihydroxybenzoate form of the present invention (white triangles) and zanubrutinib Form A of WO 2018/033853 A2 (white squares) in FaSSIF medium measured at 37°C.
  • the x-axis shows the time in hours, the y-axis the zanubrutinib concentration of the solution in mg/mL.
  • Figure 16 displays a flowchart of the manufacturing process for hard gelatin capsules comprising the zanubrutinib 4-hydroxybenzoate form of the present invention or the zanubrutinib 3,4-dihydroxybenzoate form of the present invention
  • the present invention relates to a compound comprising zanubrutinib and a benzoic acid derivative characterized by having the chemical structure as depicted in Formula
  • the compound of the present invention as defined above is crystalline. More preferably, the compound is a co-crystal, a salt or a mixture of a co-crystal and a salt and most preferably the compound is a co-crystal.
  • the invention relates to a crystalline form comprising zanubrutinib and 4- hydroxybenzoic acid characterized by the chemical structure as depicted in Formula (Ila),
  • n is in the range of from 0.8 to 1.2, preferably of from 0.9 to 1.1, even more preferably of from 0.95 to 1.05 and most preferably n is 1.0.
  • the crystalline form of the present invention as defined above is a co-crystal, a salt or a mixture of a co-crystal and a salt and most preferably the crystalline form is a co-crystal.
  • the zanubrutinib 4-hydroxybenzoate form of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing crystalline solids. Such methods comprise but are not limited to PXRD, SXRD, FTIR, DSC, TGA and GMS.
  • the zanubrutinb 4-hydroxybenzoate form of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them.
  • the zanubrutinb 4-hydroxybenzoate form of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
  • the invention relates to a crystalline form comprising zanubrutinib and 4- hydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of (7.7 ⁇ 0.2)°, (9.6 ⁇ 0.2)°, (12.2 ⁇ 0.2)°, (13.6 ⁇ 0.2)°, (17.2 ⁇ 0.2)°, (18.9 ⁇ 0.2)°, (19.9 ⁇ 0.2)°, (20.3 ⁇ 0.2)°, (22.0 ⁇ 0.2)° and (24.4 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of (7.7 ⁇ 0.1)°, (9.6 ⁇ 0.1)°, (12.2 ⁇ 0.1)°, (13.6 ⁇ 0.1)°, (17.2 ⁇ 0.1)°, (18.9 ⁇ 0.1)°, (19.9 ⁇ 0.1)°, (20.3 ⁇ 0.1)°, (22.0 ⁇ 0.1)° and (24.4 ⁇ 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention in another embodiment relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4- hydroxybenzoic acid characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 4- hydroxybenzoic acid characterized by having an FTIR spectrum essentially the same as shown in Figure 2 of the present invention, when measured at a temperature in the range of from 20 to 30°C with a diamond ATR cell.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having an onset at a temperature of (187 ⁇ 5)°C, preferably of (187 ⁇ 3)°C, more preferably of (187 ⁇ 2)°C and most preferably of (187 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a maximum at a temperature of (187 ⁇ 5)°C, preferably of (187 ⁇ 3)°C, more preferably of (187 ⁇ 2)°C and most preferably of (187 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by having a TGA curve showing a mass loss of not more than 0.5 w-%, preferably of not more than 0.4 w-%, more preferably of not more than 0.3 w-% based on the weight of the crystalline form, when heated from 25 to 180°C at a rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by showing a mass change of not more than 0.5 w- %, preferably of not more than 0.4 w-%, more preferably of not more than 0.3 w-% and most preferably of not more than 0.2 w-%, based on the weight of the crystalline form, when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ⁇ 0.1)°C.
  • the present invention relates to a crystalline form comprising zanubrutinib and 4-hydroxybenzoic acid characterized by exhibiting an orthorhombic unit cell having space group P2i2i2i.
  • the present invention relates to a composition comprising the zanubrutinib 4- hydroxybenzoate form as defined in any one of the above described embodiments, characterized in that the composition is essentially free of any other solid-state form of zanubrutinib.
  • a composition comprising the zanubrutinib 4-hydroxybenzoate form of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid-state form of zanubrutinib, based on the total weight of the composition.
  • the any other solid-state form of zanubrutinib is Form A of WO 2018/033853 A2.
  • Form A of zanubrutinib exhibits a PXRD comprising amongst others a characteristic reflection at (5.4 ⁇ 0.2)° 2-Theta, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. Therefore, the absence of reflections at 2-Theta angles in the range of (5.4 ⁇ 0.2)° in the PXRD confirms the absence of form A of zanubrutinib in the composition.
  • the present invention relates to a composition
  • a composition comprising the zanubrutinib 4-hydroxybenzoate form as defined in any one of the above described embodiments, characterized by having a PXRD comprising no reflections at 2-Theta angles in the range of (5.4 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention in another embodiment, relates to a composition
  • a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the zanubrutinib 4-hydroxybenzoate form as defined in any one of the above described embodiments, based on the total weight of the composition.
  • the remaining material may comprise other solid-state form(s) of zanubrutinib and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
  • the present invention relates to a process for the preparation of the zanubrutinib 4-hydroxybenzoate form or the composition comprising the zanubrutinib 4- hydroxybenzoate form as defined in any one of the above described aspects and their corresponding embodiments comprising:
  • Zanubrutinib free base can for example be prepared according to the procedures provided in WO 2014/173289 A2, WO 2018/033853 A2 and WO 2019/108795 Al, all of the douments which are herewith incorporated by reference.
  • Zanubrutinib, which is used as starting material in step (a) of the above described process, may be applied as crystalline and/or amorphous material.
  • a solution comprising zanubrutinib free base, 4- hydroxybenzoic acid and a solvent mixture comprising ethyl acetate and ethanol is provided.
  • the volume ratio of ethyl acetate and ethanol is about 9: 1 (volume: volume) and the molar ratio of zanubrutinib and 4-hydroxybenzoic acid is in the range of from about 1.0: 1.0 to 1.0: 3.0 (zanubrutinib: 4-hydroxybenzoic acid), preferably the molar ratio is in the range of from about 1.0: 1:0 to 1.0: 1.5 (zanubrutinib: 4-hydroxybenzoic acid) and most preferably the molar ratio is about 1.0: 1.1 (zanubrutinib: 4-hydroxybenzoic acid).
  • the applied zanubrutinib concentration in step (a) of the above described process may be in the range of from about 200 to 400 g/L, preferably of from about 200 to 350 g/L and most preferably the applied zanubrutinib free base concentration is about 300 g/L. Dissolution may be accelerated by increasing the temperature of the mixture provided in step (a) to about 40 to 70°C or by heating the mixture under reflux.
  • seed crystals comprising the zanubrutinib 4-hydroxybenzoate form are added in order to promote crystallization and/or to control particle size distribution.
  • the amount of seed crystals employed may be in the range of from about 1 to 20 w-%, preferably of from about 1 to 10 w-% and most preferably of from about 1 to 5 w-%, based on the weight of applied zanubrutinib starting material. Seed crystals may be prepared according to Example 1 hereinafter.
  • the crystals are separated from the mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
  • the isolated crystals are washed with a solvent comprising ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate and ethanol is about 9: 1 (volume: volume).
  • the obtained crystals are dried. Drying may be performed at a temperature in the range of from about 20 to 80°C, preferably in the range of from about 20 to 60°C and most preferably drying is performed at 40 °C. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably of from about 2 to 48 hours, more preferably of from about
  • Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less.
  • the invention relates to a crystalline form comprising zanubrutinib and 3,4- dihydroxybenzoic acid characterized by the chemical structure as depicted in Formula (lib), Formula (lib), wherein n is in the range of from 0.8 to 1.2, preferably of from 0.9 to 1.1, even more preferably of from 0.95 to 1.05 and most preferably n is 1.0 and m is in the range of from 0.0 to 0.3.
  • the crystalline form of the present invention as defined above is a co-crystal, a salt or a mixture of a co-crystal and a salt and most preferably the crystalline form is a co-crystal.
  • the invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a PXRD comprising reflections at 2-Theta angles of (10.7 ⁇ 0.2)°, (12.4 ⁇ 0.2)°, (13.8 ⁇ 0.2)°, (17.2 ⁇ 0.2)°, (18.7 ⁇ 0.2)°, (19.3 ⁇ 0.2)°, (19.9 ⁇ 0.2)°, (21.8 ⁇ 0.2)°, (23.8 ⁇ 0.2)° and (26.9 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a PXRD comprising reflections at 2- Theta angles of (10.7 ⁇ 0.1)°, (12.4 ⁇ 0.1)°, (13.8 ⁇ 0.1)°, (17.2 ⁇ 0.1)°, (18.7 ⁇ 0.1)°, (19.3 ⁇ 0.1)°, (19.9 ⁇ 0.1)°, (21.8 ⁇ 0.1)°, (23.8 ⁇ 0.1)° and (26.9 ⁇ 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention in another embodiment relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a PXRD essentially the same as shown in Figure 6 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4- dihydroxybenzoic acid characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4- dihydroxybenzoic acid characterized by having an FTIR spectrum essentially the same as shown in Figure 7 of the present invention, when measured at a temperature in the range of from 20 to 30°C with a diamond ATR cell.
  • the present invention relates a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having an onset at a temperature of (174 ⁇ 5)°C, preferably of (174 ⁇ 3)°C, more preferably of (174 ⁇ 2)°C and most preferably of (174 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a maximum at a temperature of (175 ⁇ 5)°C, preferably of (175 ⁇ 3)°C, more preferably of (175 ⁇ 2)°C and most preferably of (175 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by having a TGA curve showing a mass loss of not more than 0.9 w-%, preferably of not more than 0.6 w-%, more preferably of not more than 0.5 w-% and most preferably of not more than 0.4 w-%, based on the weight of the crystalline form, when heated from 25 to 170°C at a rate of 10 K/min.
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by showing a mass change of not more than 1.0 w-%, more preferably of not more than 0.9 w-%, based on the weight of the crystalline form, when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ⁇ 0.1)°C.
  • the present invention relates to a crystalline form comprising zanubrutinib and 3,4-dihydroxybenzoic acid characterized by exhibiting an orthorhombic unit cell having space group P2i2i2i.
  • the present invention relates to a composition comprising the zanubrutinib 3,4-dihydroxybenzoate form of the present invention as defined in any one of the above described embodiments, characterized in that the composition is essentially free of any other solid-state form of zanubrutinib.
  • a composition comprising the zanubrutinib 3,4- dihydroxybenzoate form of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid- state form of zanubrutinib, based on the total weight of the composition.
  • the any other solid-state form of zanubrutinib is Form A of WO 2018/033853 A2.
  • Form A of zanubrutinib exhibits a PXRD comprising amongst others a characteristic reflection at (5.4 ⁇ 0.2)° 2-Theta, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai, 2 radiation having a wavelength of 0.15419 nm. Therefore, the absence of reflections at 2-Theta angles in the range of (5.4 ⁇ 0.2)° in the PXRD confirms the absence of form A of zanubrutinib in the composition.
  • the present invention relates to a composition
  • a composition comprising the zanubrutinib 3,4-dihydroxybenzoate form of the present invention as defined in any one of the above described embodiments, characterized by having a PXRD comprising no reflections at 2-Theta angles in the range of (5.4 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention in another embodiment, relates to a composition
  • a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the zanubrutinib 3,4-dihydroxybenzoate form as defined in any one of the above described embodiments, based on the total weight of the composition.
  • the remaining material may comprise other solid-state form(s) of zanubrutinib and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
  • the present invention relates to a process for the preparation of the zanubrutinib 3,4-dihydroxybenzoate form or the composition comprising the zanubrutinib 3,4- dihydroxybenzoate form as defined in any one of the above described aspects and their corresponding embodiments comprising:
  • Zanubrutinib free base can for example be prepared according to the procedures provided in WO 2014/173289 A2, WO 2018/033853 A2 and WO 2019/108795 Al, all of the douments which are herewith incorporated by reference.
  • Zanubrutinib, which is used as starting material in step (a) of the above described process, may be applied as crystalline and/or amorphous material.
  • a solution comprising zanubrutinib free base, 3,4- dihydroxybenzoic acid and a solvent mixture comprising ethyl acetate and ethanol is provided.
  • the volume ratio of ethyl acetate and ethanol is about 9: 1 (volume: volume) and the molar ratio of zanubrutinib and 3,4-dihydroxybenzoic acid is in the range of from about 1.0: 1.0 to 1.0: 3.0 (zanubrutinib: 3,4-dihydroxybenzoic acid), preferably the molar ratio is in the range of from about 1.0: 1:0 to 1.0: 1.5 (zanubrutinib: 3,4-dihydroxybenzoic acid) and most preferably the molar ratio is about 1.0: 1.1 (zanubrutinib: 3,4-dihydroxybenzoic acid).
  • the applied zanubrutinib concentration in step (a) of the above described process may be in the range of from about 200 to 400 g/L, preferably of from about 200 to 350 g/L and most preferably the applied zanubrutinib free base concentration is about 300 g/L. Dissolution may be accelerated by increasing the temperature of the mixture provided in step (a) to about 40 to 70°C or by heating the mixture under reflux.
  • seed crystals comprising the zanubrutinib 3,4-dihydroxybenzoate form are added in order to promote crystallization and/or to control particle size distribution.
  • the amount of seed crystals employed may be in the range of from about 1 to 20 w-%, preferably of from about 1 to 10 w-% and most preferably of from about 1 to 5 w-%, based on the weight of applied zanubrutinib starting material. Seed crystals may be prepared according to Example 2 hereinafter.
  • the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
  • the isolated crystals are washed with a solvent comprising ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate and ethanol is about 9: 1 (volume: volume).
  • the obtained crystals are dried. Drying may be performed at a temperature in the range of from about 20 to 80°C, preferably in the range of from about 20 to 60°C and most preferably drying is performed at 40 °C. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably of from about 2 to 48 hours, more preferably of from about 4 to 24 hours and most preferably of from about 6 to 18 hours. Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less.
  • the present invention relates to the use of the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, preferably the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate form or the composition comprising one of the forms as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, preferably the zanubrutinib 4-hydroxybenzoate form, the zanubrutinib 3,4- dihydroxybenzoate form or the composition comprising one of the forms as defined in any one of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.
  • the predetermined and/or effective amount of the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid preferably of the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4-dihydroxybenzoate or the composition comprising one of the forms as defined in any one of the above described aspects and their corresponding embodiments is in the range of from 20 to 100 mg calculated as zanubrutinib free base.
  • the predetermined and/or effective amount is selected from the group consisting of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg and 100 mg calculated as zanubrutinib free base.
  • the predetermined and/or effective amount is 25 mg or 100 mg, calculated as zanubrutinib free base.
  • the predetermined and/or effective amount is 80 mg, calculated as zanubrutinib free base.
  • the at least one pharmaceutically acceptable excipient is selected from the group consisting of filler, disintegrant, flowability aid, glidant and solubilizer.
  • the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, colloidal silicon dioxide, sodium dodecyl sulfate, croscarmellose sodium and magnesium stearate.
  • the pharmaceutical composition of the present invention as described above is an oral solid dosage form.
  • the pharmaceutical composition of the present invention as described above is a capsule, preferably a hard gelatin capsule, more preferably a hard gelatin capsule with capsule size 0.
  • the pharmaceutical composition of the present invention as described above is a tablet, preferably a film-coated tablet.
  • the present invention relates to the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, preferably the zanubrutinib 4- hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form, the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form or the pharmaceutical composition comprising the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, in particular the zanubrutinib 4-hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form or the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament
  • the present invention relates to the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, preferably the zanubrutinib 4- hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form, the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form or the pharmaceutical composition comprising the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, in particular the zanubrutinib 4-hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form or the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of
  • the invention concerns a method of treating a B-cell proliferative disease said method comprising administering an effective amount of the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, preferably the zanubrutinib 4-hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form, the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form or the pharmaceutical composition comprising the compound comprising zanubrutinib and 4-hydroxybenzoic acid or 3,4-dihydroxybenzoic acid, in particular the zanubrutinib 4-hydroxybenzoate form, the zanubrutinib 3,4-dihydroxybenzoate form or the composition comprising the zanubrutinib 4-hydroxybenzoate form or the zanubrutinib 3,4- dihydroxybenzoate form as defined
  • the B-cell proliferative disease is a B-cell malignancy including but not limited to lymphoma, non-Hodgkin’s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), Hairy cell leukemia (HCC), Burkitt’ s-like leukemia or a combination of two or more thereof.
  • NHL non-Hodgkin’s lymphoma
  • DLBCL diffuse large B cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • W marginal zone lymphoma
  • HCC Hairy cell
  • the B-cell proliferative disease is a relapsed/refractory (R/R) B-cell malignancy including but not limited to mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM) or a combination of two or more thereof.
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • Zanubrutinib (1.50 g, 3.18 mmol, e.g. prepared according to Example 1 of WO 2019/108795 Al) and 4-hydroxybenzoic acid (0.49 g, 3.55 mmol) were dissolved in a mixture of ethyl acetate/ethanol (5 mL, 9/1 v/v) upon gentle heating. The resulting clear solution was stirred at room temperature, whereat a suspension was formed within a minute.
  • Example 2 Preparation of the crystalline zanubrutinib 3,4-dihydroxybenzoate form Zanubrutinib (1.49 g, 3.16 mmol, e.g. prepared according to Example 1 of WO 2019/108795 Al) and 3,4-dihydroxybenzoic acid (0.55 g, 3.57 mmol) were dissolved in a mixture of ethyl acetate/ethanol (5 mL, 9/1 v/v) upon gentle heating. The resulting clear solution was stirred at room temperature, whereat a suspension was formed within a minute.
  • Example 3 Powder X-ray diffraction
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention were investigated by powder X-ray diffraction, which was performed on a PANalytical Empyrean diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kal,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcellD detector.
  • the patterns were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.026° 2-Theta with 50s per step in the angular range of 2° to 40° 2-Theta at ambient conditions.
  • a typical precision of the 2-theta values is in the range of about ⁇ 0.2° 2-Theta, preferably of about ⁇ 0.1° 2-Theta .
  • a diffraction peak that appears for example at 7.7° 2-Theta can appear between 7.5 and 7.9° 2-Theta, preferably between 7.6 and 7.8° 2-Theta on most X-ray diffractometers under standard conditions.
  • a representative diffractogram of the zanubrutinib 4-hydroxybenzoate form according to the present invention is displayed in Figure 1 and the corresponding reflection list (peak list) from 2 to 30° 2-Theta is provided in Table 1 below.
  • Table 1 Reflection (peak) positions of the zanubrutinib 4-hydroxybenzoate form according to the present invention in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • a representative diffractogram of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention is displayed in Figure 6 and the corresponding reflection list (peak list) from 2 to 30° 2-Theta is provided in Table 2 below.
  • Table 2 Reflection (peak) positions of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • Example 4 Fourier transform infrared spectroscopy
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention were investigated by FTIR spectroscopy, which was performed on an MKII Golden GateTM Single Reflection Diamond ATR cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm 1 resolution at RT.
  • To record a spectrum a spatula tip of the sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded. A spectrum of the clean diamond was used as background spectrum.
  • a typical precision of the wavenumber values is in the range of ⁇ 4 cm x , preferably of ⁇ 2 cm '.
  • the infrared peak of the zanubrutinib 4-hydroxybenzoate form according to the present invention at 1678 cm 1 can appear between 1674 and 1682 cm 1 , preferably between 1676 and 1680 cm 1 on most infrared spectrometers under standard conditions.
  • Table 3 FTIRpeak list of the zanubrutinib 4-hydroxybenzoate form according to the present invention; a typical precision of the wavenumbers is in the range of ⁇ 4 cm 1 , preferably of ⁇ 2 cm 1 .
  • Table 4 FTIR peak list of the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention; a typical precision of the wavenumbers is in the range of ⁇ 4 cm 1 , preferably of ⁇ 2 cm 1 .
  • zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form according to the present invention were investigated by DSC, which was performed on a Mettler
  • TGA was performed on a Mettler TGA/DSC 1 instrument.
  • the samples (8.14 mg zanubrutinib 4-hydroxybenzoate form and 4.34 mg zanubrutinib 3,4-dihydroxybenzoate form) were each heated in a 100 microliter aluminium pan closed with an aluminium lid from 25 to 220°C at a rate of 10 K/min. The lid was automatically pierced at the beginning of the measurement. Nitrogen (purge rate 50 mL/min) was used as purge gas.
  • the TGA curves of the crystalline zanubrutinib 4-hydroxybenzoate form (see Figure 4) and the 3,4-dihydroxybenzoate form (see Figure 9) of the present invention both show almost no weight loss until they melt.
  • the zanubrutinib 4-hydroxybenzoate form shows a mass loss of only about 0.3 w-% up to a temperature of about 180°C
  • the zanubrutinib 3,4- dihydroxybenzoate form shows a mass loss of only about 0.0 w-% to 0.9 w-% up to a temperature of about 170°C.
  • Moisture sorption isotherms were recorded with an SPSx-Im moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (RH) of 30%. RH was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0%. Afterwards RH was increased from 0% to 90% in a sorption cycle and subsequently decreased to 0 % in a desorption cycle each in 5% steps. Finally, RH was increased to ambient relative humidity of 30% in 5% steps. The time per step was set to a minimum of 2 hours and a maximum of 6 hours.
  • the water uptakes in the sorption cycle between 0 and 90% are only about 0.2 w-% for the zanubrutinib 4-hydroxybenzoate form and only about 0.9 w-% for the zanubrutinib 3,4-dihydroxybenzoate form, respectively.
  • neither of the forms shows a significant hysteresis between the sorption and desorption curves, which indicates that no structural changes appear during the experiment. This assumption is strengthened by the fact that the samples still show the same PXRDs after the experiment.
  • zanubrutinib Form A shows a higher water uptake of about 1.5 w-% in the sorption cycle between 0 and 90% and a significant hysteresis between the sorption and the desorption curves.
  • Table 7 below provides a summary of the behaviours of the various forms during GMS experiments.
  • Non-hydrogen atoms were located in difference maps and refined anisotropically.
  • the hydrogen atoms bonded to C atoms fixed in idealized positions and the thermal displacement parameters of the former were set to 1.2U eq of the parent C atom.
  • the investigated zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4- dihydroxybenzoate form both don’t show any intermolecular proton transfers and are therefore co-crystals.
  • the water position in the structure model of the zanubrutinib 3,4- dihydroxybenzoate form is only partially occupied.
  • Example 9 Physical stability at increased temperature/humidity conditions
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention were stored in open vials in climate chambers at 30°C/65% RH and 40°C/75% RH respectively.
  • the samples were stored in open vials in an exsiccator with a saturated K 2 SO 4 solution at the bottom. Samples were taken at predefined time points of 1 day, 1 week, 2 weeks, 4 weeks, 9 weeks, 12 weeks and 24 weeks and subjected to PXRD to determine the physical stability of the forms. No phase changes took place at any conditions proofing the physical stability of both forms.
  • Example 10 Physical stability in aqueous media
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention were each slurried in water and aqueous HC1 solution (1M), respectively. About 35 mg of the respective form was magnetically stirred at RT in 2 mL of each media. Samples were taken at predefined timepoints of 60 min, 90 min and 6 days and investigated by powder X-ray diffraction. No phase changes took place at any conditions proofing the physical stability of both forms in the investigated media.
  • Example 11 Dissolution rates in phosphate buffer pH 6.8, acetate buffer pH 4.5 and FaSSIF medium
  • Powder dissolution experiments were carried out in phosphate buffer pH 6.8, acetate buffer pH 4.5 and FaSSIF medium at 37°C for zanubrutinib Form A of WO 2018/033853 A2, the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention. Particle sizes of the forms were kept as similar as possible to allow for proper comparison. The respective concentrations were determined by HPLC at a wavelengths of 241 nm (zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form) and 235 nm (Form A), respectively.
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention exhibit an increased solubility (> 2-fold) in phosphate puffer pH 6.8 over the whole range from 15 minutes to 24 hours compared to zanubrutinib Form A of WO 2018/033853 A2.
  • Table 8 Dissolution profiles of various zanubrutinib forms in phosphate buffer pH 6.8
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention exhibit an increased solubility in acetate buffer pH 4.5 over the whole range from 15 minutes to 24 hours compared to zanubrutinib Form A of WO 2018/033853 A2.
  • the zanubrutinib 4-hydroxybenzoate form and the zanubrutinib 3,4-dihydroxybenzoate form of the present invention exhibit an increased solubility in FaSSIF medium over the whole range from 15 minutes to 24 hours compared to zanubrutinib Form A of WO 2018/033853 A2.
  • Example 12 Hard gelatin capsule formulations comprising the crystalline zanubrutinib 4- hydroxybenzoate form or the crystalline zanubrutinib 3,4-dihydroxybenzoate form The capsules were manufactured according to the procedure displayed in the flowchart of figure 16 using the compositions of tables 11 and 12 below.
  • Table 12 Hard gelatin capsule formulation comprising the zanubrutinib 3,4-dihydroxybenzoate form
  • Example 13 Stress stability testing of hard gelatin capsule comprising the zanubrutinib 4- hydroxybenzoate form
  • Capsules prepared according to example 12 comprising the zanubrutinib 4-hydroxybenzoate form were subjected to stress conditions at 25°C/60%RH and 30°C/65%RH respectively. Samples were taken at predefined timepoints of 1 month, 2 months and 3.5 months.
  • the chemical stability was determined by HPLC at a wavelength of 241 nm while the physical stability was investigated by powder X-ray diffraction. As can be seen from the results summarized in table 13 below, the the zanubrutinib 4-hydroxybenzoate form was stable at all conditions.

Abstract

La présente invention concerne des composés, comprenant du (S)-7-(1-acryloylpipéridin-4-yl)-2-(4- phénoxyphényl)-4,5,6,7-tétrahydropyrazolo[1,5-α]pyrimidine-3-carboxamide (INN : zanubrutinib) et un dérivé d'acide benzoïque choisi parmi l'acide 4-hydroxybenzoïque et l'acide 3,4-dihydroxybenzoïque et leurs formes cristallines. L'invention concerne également des procédés de production desdits composés et de leurs formes cristallines. En outre, l'invention concerne des compositions pharmaceutiques comprenant les composés selon la présente invention et au moins un excipient pharmaceutiquement acceptable. Les compositions pharmaceutiques selon la présente invention peuvent être utilisées en tant que médicaments, en particulier pour le traitement et/ou la prévention des maladies prolifératives à cellules B telles que le lymphome à cellules du manteau (MCL).
PCT/EP2021/066261 2020-06-24 2021-06-16 Composés à composants multiples comprenant du zanubrutinib et un dérivé d'acide benzoïque WO2021259732A1 (fr)

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WO2018033853A2 (fr) 2016-08-16 2018-02-22 Beigene, Ltd. Forme cristalline de (s)-7-(1-acryloylpipéridin-4-yl)-2-(4-phénoxyphényle)-4,5,6,7-tétra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, sa préparation et ses utilisations
WO2018033135A1 (fr) * 2016-08-19 2018-02-22 Beigene, Ltd. Utilisation d'une combinaison comprenant un inhibiteur de btk pour le traitement de cancers
WO2019108795A1 (fr) 2017-11-29 2019-06-06 Beigene Switzerland Gmbh Traitement de lymphomes à cellules b indolentes ou agressives au moyen d'une combinaison comprenant des inhibiteurs de btk

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