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WO2023121574A1 - Novel polymorph of ruxolitinib hemifumarate and method of preparation - Google Patents

Novel polymorph of ruxolitinib hemifumarate and method of preparation Download PDF

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Publication number
WO2023121574A1
WO2023121574A1 PCT/TR2021/051471 TR2021051471W WO2023121574A1 WO 2023121574 A1 WO2023121574 A1 WO 2023121574A1 TR 2021051471 W TR2021051471 W TR 2021051471W WO 2023121574 A1 WO2023121574 A1 WO 2023121574A1
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WO
WIPO (PCT)
Prior art keywords
ruxolitinib
hemifumarate
hemihydrate
crystalline
crystalline form
Prior art date
Application number
PCT/TR2021/051471
Other languages
French (fr)
Inventor
Philipp Daniel Haas
Hartwig Andreas Steckel
Esen BELLUR ATİCİ
Okşan SOYER CAN
Original Assignee
Deva Holding Anonim Sirketi
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Publication date
Application filed by Deva Holding Anonim Sirketi filed Critical Deva Holding Anonim Sirketi
Priority to PCT/TR2021/051471 priority Critical patent/WO2023121574A1/en
Publication of WO2023121574A1 publication Critical patent/WO2023121574A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid

Definitions

  • the present invention relates to a novel crystalline polymorphic form of ruxolitinib hemifumarate designated as Form II and a process for its preparation.
  • the invention further relates to pharmaceutical compositions comprising Form II and use of Form II in the treatment of cancer.
  • Ruxolitinib is a janus kinase inhibitor (JAK inhibitor) with selectivity for subtypes JAK1 and JAK2, which is approved for treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow; polycythemia vera (PCV), when there has been an inadequate response to or intolerance of hydroxyurea; and steroid- refractory acute graft-versus-host disease.
  • JAK inhibitor janus kinase inhibitor
  • PCV polycythemia vera
  • Ruxolitinib is chemically known as (7?)-3-(4-(7J/-pyrrolo[2,3- ]pyrimidin-4-yl)-lJ/- pyrazol-l-yl)-3 -cyclopentylpropanenitrile and represented by the following structural formula:
  • Ruxolitinib and process for the preparation thereof was first disclosed in W02007070514.
  • Ruxolitinib was developed and marketed by Incyte Corp in the US under the brand name JAKAFI®, and by Novartis elsewhere in the world, under the brand name JAKAVI®, JAKAFI®, JAKAVI® presented as immediate release tablet containing phosphate salt of ruxolitinib.
  • W02007070514A1 describes trifluoroacetate salt of ruxolitinib.
  • ruxolitinib namely ruxolitinib phosphate, ruxolitinib sulfate and ruxolitinib maleate have been reported in W02008157208 A2.
  • W02016074650A1 discloses salts of ruxolitinib with benzoic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, citric acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulfonic acid, L-tartaric acid and p-toluenesulfonic acid, and method of preparation of these salts.
  • This patent also discloses ruxolitinib with fumaric acid and a method of preparation thereof.
  • WO2017125097A1 describes ruxolitinib hemifumarate salt.
  • ruxolitinib hemifumarate corresponds to the following formula:
  • crystal modification 1 a crystalline form of ruxolitinib hemifumarate labelled as crystal modification 1 is described in WO2017125097.
  • the X-ray powder diffractogram (XRPD) of crystal modification 1 was shown in Figure 12 of WO2017125097.
  • the object of the present invention is to provide a new polymorphic form of ruxolitinib hemifumarate and process for the preparation of this novel polymorphic form of ruxolitinib hemifumarate.
  • Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of ruxolitinib hemifumarate.
  • Active pharmaceutical ingredients are individual components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
  • Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture.
  • Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. Difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.
  • composition is affected by polymorphic form of the pharmaceutically active substance.
  • invention relates to novel solid form of ruxolitinib.
  • This new polymorph of ruxolitinib besides being stable, meets the pharmaceutical requirements such as storage, shelflife, solubility and high purity.
  • Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline ruxolitinib hemifumarate (hemihydrate) Form II
  • Figure 2 shows the X-ray powder diffraction (XRPD) pattern of crystalline ruxolitinib hemifumarate (anhydrous) Form I
  • Figure 3 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline ruxolitinib hemifumarate (hemihydrate) Form II
  • Figure 4 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline ruxolitinib hemifumarate (anhydrous) Form I
  • Figure 5 shows the 3 H nuclear magnetic resonance ( r H NMR) spectrum of ruxolitinib hemifumarate
  • Figure 6 shows the 13 C nuclear magnetic resonance ( 13 C NMR) spectrum of ruxolitinib hemifumarate
  • FIG. 7 shows the differential scanning calorimetry (DSC) thermogram of ruxolitinib hemifumarate (hemihydrate) Form II
  • FIG. 8 shows the differential scanning calorimetry (DSC) thermogram of ruxolitinib hemifumarate (anhydrous) Form I
  • FIG. 9 shows the thermogravimetric analysis (TGA) of ruxolitinib hemifumarate (hemihydrate) Form II
  • FIG. 10 shows the thermogravimetric analysis (TGA) of ruxolitinib hemifumarate (anhydrous) Form I
  • the present invention relates to novel polymorph of ruxolitinib, namely ruxolitinib hemifumarate Form II.
  • a first aspect of the present invention relates to a novel polymorphic form of ruxolitinib hemifumarate. This new form hereinafter is referred as crystalline Form II of ruxolitinib.
  • Form II of ruxolitinib hemifumarate is hemihydrate.
  • Form II is characterized by an XRPD pattern having characteristic peaks at 5.4 ⁇ 0.2, 16.9 ⁇ 0.2 and 21.4 ⁇ 0.2 degree 2-theta.
  • Form II of ruxolitinib hemifumarate can be characterized by an XRPD pattern with characteristic peaks at 6.2 ⁇ 0.2, 11.0 ⁇ 0.2, 16.1 ⁇ 0.2, 12.1 ⁇ 0.2, 14.7 ⁇ 0.2, 15.4 ⁇ 0.2, 18.5 ⁇ 0.2, 18.9 ⁇ 0.2, 23.5 ⁇ 0.2, 24.1 ⁇ 0.2, 24.4 ⁇ 0.2, 25.6 ⁇ 0.2, 26.3 ⁇ 0.2 and 29.1 ⁇ 0.2 degree 2-theta.
  • Form II is characterized by an XRPD pattern, as shown in Figure 1.
  • Form II is also characterized by an Infrared (IR) spectrum, as shown in Figure 3 and characterized by differential scanning calorimetry (DSC) thermogram, as shown in Figure 7.
  • IR Infrared
  • DSC differential scanning calorimetry
  • a second aspect of the present invention relates to a process for preparing novel polymorphic Form II of ruxolitinib hemifumarate.
  • the Form II of ruxolitinib hemifumarate according to the present invention may be obtained by: a) dissolving ruxolitinib in a suitable solvent and/or solvent mixture, b) adding fumaric acid and/or its solution into the ruxolitinib solution at step (a) c) heating and stirring the reaction solution at step (b) at a suitable temperature, d) cooling the solution to room temperature, e) filtering and isolating the obtained solid, f) washing the obtained solid as pure crystalline ruxolitinib hemifumarate hemihydrate designated as Form II with a suitable organic solvent.
  • suitable solvent in step (a) and step (f) is selected from, water, methanol, ethanol, 2-propanol, 1 -propanol, 1 -butanol, 2-butanol, tert-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3 -pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, dieth
  • the suitable temperature used in step (c) is selected from room temperature to reflux temperature of the solvent used.
  • a third aspect of the present invention relates to crystalline anhydrous form of ruxolitinib hemifumarate designated as Form I.
  • Form I is characterized by an XRPD pattern, as shown in Figure 2.
  • Form I is also characterized by an IR spectrum, as shown in Figure 4 and characterized by a DSC thermogram, as shown in Figure 8.
  • a fourth aspect of the present invention relates to a process for preparing Form II of ruxolitinib hemifumarate involving Form I of ruxolitinib hemifumarate.
  • a fifth aspect of the present invention relates to a process for preparing Form I of ruxolitinib hemifumarate involving Form II of ruxolitinib hemifumarate hemihydrate.
  • Form II is stable without polymorphic conversion under normal conditions and under heating up to 90 °C.
  • Crystalline Form II of ruxolitinib hemifumarate hemihydrate starts to lose water above 120 °C and converts to crystalline anhydrous Form I.
  • the process of the present invention affords ruxolitinib hemifumarate Form II in high purity and high yield.
  • the ruxolitinib hemifumarate Form II is obtained having purity greater than 99% by area percentage in high performance liquid chromatography (HPLC).
  • Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.
  • Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the drug substance.
  • the changes in solid state form of the drug substance may be resulted from the conditions of manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of drug substance.
  • a solvent e.g., wet granulation, polymorphs in solution, and polymorphs in suspension
  • These variations comprising polymorphic transformations, hydrate / solvate formations and dehydration / desolvation reactions in the solid-state form of the drug substance, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of the drug substance has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of drug substance should be used in pharmaceutical formulations.
  • crystalline stability of ruxolitinib hemifumarate Form II was investigated under the following conditions: a sample was kept in an open flask at 90 °C for 10 days, packed samples were kept at 40 °C under 75% relative humidity (RH) and at 25 °C under 60% relative humidity (RH) for 6 months.
  • the crystalline stability referred here is the stability of a polymorphic form of drug substance with respect to polymorph transformations, hydration, dehydration, or amorphization through time under these conditions.
  • Crystalline Form II showed crystalline stability under dry heating at 90 °C for 10 days, at 40 °C / 75% RH and at 25 °C / 60% RH for 6 months.
  • the chemical stability of crystalline ruxolitinib hemifumarate Form II is also important and its stability in finished product at room temperature storage can be predicted from short-term storage under accelerated conditions at high temperature and humidity.
  • samples of obtained crystalline ruxolitinib hemifumarate Form II were kept under dry heating in open flask at 90 °C for 10 days in an oven, and in LDPE pack at 40 °C & 75% RH and at 25 °C & 60% RH for 6 months in stability chambers to test chemical stability.
  • the chemical stability of the samples was determined by HPLC method.
  • Table 1 shows the stability results of ruxolitinib hemifumarate Form II prepared according to the present invention. Form II samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts. Table 1. Ruxolitinib hemifumarate hemihydrate Form II stability test results
  • Table 2 shows the stability results of ruxolitinib hemifumarate Form I under the same conditions.
  • Form I samples also stayed stable under all conditions without any change in the polymorphic form, without any significant change in the impurity profile and without increase in the impurity amounts.
  • Form II in terms of stability. Both are physically and chemically stable under normal and accelerated stability conditions.
  • a sixth aspect of the present invention relates to pharmaceutical compositions comprising crystalline ruxolitinib hemifumarate hemihydrate Form II along with a pharmaceutically acceptable carrier.
  • NMR and 13 C NMR analyses were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-de) as a solvent.
  • DMSO-de deuterated dimethyl sulfoxide
  • Samples were measured as neat by ATR (attenuated total reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm -1 with 20 scans and 4 cm -1 resolution.
  • DSC Differential scanning calorimetry thermograms were obtained using a differential scanning calorimeter (TA instruments DSC 250, USA) by using following instrument parameters: Start temperature: 25 °C, final temperature: 350 °C, heating rate: 10 °C/min.
  • thermograms were obtained by using a thermogravimetric analzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C, final temperature: 120 °C, heating rate: 10 °C/min, isothermal: 15 min.
  • X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters:
  • Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethanol (2 mL), and the mixture was heated to 60 °C.
  • water (20 mL) was added, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h.
  • Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethyl acetate (5 mL) and water (0.5 mL), and the mixture was heated to 77 °C. Fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) was added into ruxolitinib solution at 77 °C and the mixture was stirred for 2 - 3 h at 77 °C. Afterwards, n-hexane (15 mL) was added and the mixture was further stirred under heating for 1 h. Then, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h.
  • Ruxolitinib hemifumarate (1.1 g, 3.02 mmol, Form I) was dissolved in ethanol (5 mL) at reflux temperature (65 - 70 °C). After complete dissolution, water (25 mL) was added and the mixture was stirred for 2 - 3 h at 65 - 70 °C. Afterwards, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h.
  • Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethanol (2 mL), and the mixture was heated to 60 °C.
  • Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethyl acetate (5 mL), and the mixture was heated to 77 °C. Fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) was added into ruxolitinib solution at 77 °C and the mixture was stirred for 2 - 3 h at 77 °C. Afterwards, n- hexane (15 mL) was added and the mixture was further stirred under heating for 1 h. Then, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h.
  • Ruxolitinib hemifumarate hemihydrate (Form II) was dried in vacuo at 150 - 160 °C for 1 h to obtain ruxolitinib hemifumarate (Form I) as an off-white crystalline solid (100%, HPLC purity: 99.65%, water content (KF): 0.04%). This experiment was done by using 1 g and 10 g ruxolitinib hemifumarate hemihydrate (Form II) and both afforded ruxolitinib hemifumarate (Form I).

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Abstract

The present invention relates to a new crystalline polymorphic form of ruxolitinib hemifumarate hemihydrate, namely Form II, and methods for its preparation. The new crystalline polymorph Form II of ruxolitinib hemifumarate hemihydrate is characterized by an XRPD pattern having characteristic peaks (2theta ± 0.2º) at 5.4, 16.9 and 21.4. The present invention also provides pharmaceutical compositions comprising Form II of ruxolitinib hemifumarate hemihydrate, and medical use of Form II.

Description

NOVEL POLYMORPH OF RUXOLITINIB HEMIFUMARATE AND METHOD
OF PREPARATION
Technical Field
The present invention relates to a novel crystalline polymorphic form of ruxolitinib hemifumarate designated as Form II and a process for its preparation.
The invention further relates to pharmaceutical compositions comprising Form II and use of Form II in the treatment of cancer.
Background Art
Ruxolitinib is a janus kinase inhibitor (JAK inhibitor) with selectivity for subtypes JAK1 and JAK2, which is approved for treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow; polycythemia vera (PCV), when there has been an inadequate response to or intolerance of hydroxyurea; and steroid- refractory acute graft-versus-host disease.
Ruxolitinib is chemically known as (7?)-3-(4-(7J/-pyrrolo[2,3- ]pyrimidin-4-yl)-lJ/- pyrazol-l-yl)-3 -cyclopentylpropanenitrile and represented by the following structural formula:
Figure imgf000002_0001
Ruxolitinib and process for the preparation thereof was first disclosed in W02007070514.
Ruxolitinib was developed and marketed by Incyte Corp in the US under the brand name JAKAFI®, and by Novartis elsewhere in the world, under the brand name JAKAVI®, JAKAFI®, JAKAVI® presented as immediate release tablet containing phosphate salt of ruxolitinib.
Several salts of ruxolitinib including various crystalline forms are disclosed in applications W02007070514, W02008157208 A2, W02016074650A1, WO2017125097A1, WO2016026974A1, WO2016026975 Al and W02017008772A1. W02007070514A1 describes trifluoroacetate salt of ruxolitinib.
Pharmaceutically acceptable salts of ruxolitinib, namely ruxolitinib phosphate, ruxolitinib sulfate and ruxolitinib maleate have been reported in W02008157208 A2.
W02016074650A1 discloses salts of ruxolitinib with benzoic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, citric acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulfonic acid, L-tartaric acid and p-toluenesulfonic acid, and method of preparation of these salts. This patent also discloses ruxolitinib with fumaric acid and a method of preparation thereof.
WO2017125097A1 describes ruxolitinib hemifumarate salt.
The structure of ruxolitinib hemifumarate corresponds to the following formula:
Figure imgf000003_0001
Ruxolitinib hemifumarate
In particular, a crystalline form of ruxolitinib hemifumarate labelled as crystal modification 1 is described in WO2017125097. The X-ray powder diffractogram (XRPD) of crystal modification 1 was shown in Figure 12 of WO2017125097.
The discovery of a new polymorph of an active ingredient provides an opportunity to improve its characteristics, increasing the possibilities available to a formulation specialist when developing a new pharmaceutical form, a drug with a particular release profile or a specific dissolution degree.
Based on these considerations, there still appears a need for new polymorphs of ruxolitinib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically novel polymorphs of ruxolitinib with good chemical purity and improved stability characteristics, which may further improve the characteristics of ruxolitinib in finished medicinal product. Summary of the invention
The object of the present invention is to provide a new polymorphic form of ruxolitinib hemifumarate and process for the preparation of this novel polymorphic form of ruxolitinib hemifumarate.
Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of ruxolitinib hemifumarate.
Technical Problem
Active pharmaceutical ingredients (APIs) are individual components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce these APIs.
Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture.
Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. Difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.
The relationship between polymorphic forms of pharmaceutically active substance and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active substance.
Discovery of new salts and polymorphic forms of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, therefore, development of new salts and polymorphic forms are always encouraged.
According to the need, studies have been done to develop novel polymorph of ruxolitinib having advantageous properties which are useful and suitable for the preparation of various pharmaceutical compositions. Solution to Problem
In an embodiment invention relates to novel solid form of ruxolitinib.
This new polymorph of ruxolitinib, besides being stable, meets the pharmaceutical requirements such as storage, shelflife, solubility and high purity.
Brief description of the drawings:
Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline ruxolitinib hemifumarate (hemihydrate) Form II
Figure 2 shows the X-ray powder diffraction (XRPD) pattern of crystalline ruxolitinib hemifumarate (anhydrous) Form I
Figure 3 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline ruxolitinib hemifumarate (hemihydrate) Form II
Figure 4 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline ruxolitinib hemifumarate (anhydrous) Form I
Figure 5 shows the 3H nuclear magnetic resonance (rH NMR) spectrum of ruxolitinib hemifumarate
Figure 6 shows the 13C nuclear magnetic resonance (13C NMR) spectrum of ruxolitinib hemifumarate
Figure 7 shows the differential scanning calorimetry (DSC) thermogram of ruxolitinib hemifumarate (hemihydrate) Form II
Figure 8 shows the differential scanning calorimetry (DSC) thermogram of ruxolitinib hemifumarate (anhydrous) Form I
Figure 9 shows the thermogravimetric analysis (TGA) of ruxolitinib hemifumarate (hemihydrate) Form II
Figure 10 shows the thermogravimetric analysis (TGA) of ruxolitinib hemifumarate (anhydrous) Form I
Description of embodiments
The present invention relates to novel polymorph of ruxolitinib, namely ruxolitinib hemifumarate Form II. A first aspect of the present invention relates to a novel polymorphic form of ruxolitinib hemifumarate. This new form hereinafter is referred as crystalline Form II of ruxolitinib. Form II of ruxolitinib hemifumarate is hemihydrate. Form II is characterized by an XRPD pattern having characteristic peaks at 5.4 ± 0.2, 16.9 ± 0.2 and 21.4 ± 0.2 degree 2-theta. Furthermore, Form II of ruxolitinib hemifumarate can be characterized by an XRPD pattern with characteristic peaks at 6.2 ± 0.2, 11.0 ± 0.2, 16.1 ± 0.2, 12.1 ± 0.2, 14.7 ± 0.2, 15.4 ± 0.2, 18.5 ± 0.2, 18.9 ± 0.2, 23.5 ± 0.2, 24.1 ± 0.2, 24.4 ± 0.2, 25.6 ± 0.2, 26.3 ± 0.2 and 29.1 ± 0.2 degree 2-theta.
Form II is characterized by an XRPD pattern, as shown in Figure 1.
Form II is also characterized by an Infrared (IR) spectrum, as shown in Figure 3 and characterized by differential scanning calorimetry (DSC) thermogram, as shown in Figure 7.
A second aspect of the present invention relates to a process for preparing novel polymorphic Form II of ruxolitinib hemifumarate.
The Form II of ruxolitinib hemifumarate according to the present invention may be obtained by: a) dissolving ruxolitinib in a suitable solvent and/or solvent mixture, b) adding fumaric acid and/or its solution into the ruxolitinib solution at step (a) c) heating and stirring the reaction solution at step (b) at a suitable temperature, d) cooling the solution to room temperature, e) filtering and isolating the obtained solid, f) washing the obtained solid as pure crystalline ruxolitinib hemifumarate hemihydrate designated as Form II with a suitable organic solvent.
Wherein suitable solvent in step (a) and step (f) is selected from, water, methanol, ethanol, 2-propanol, 1 -propanol, 1 -butanol, 2-butanol, tert-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3 -pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-di oxane, 2 -methoxy ethanol, A,A-di methyl form am ide (DMF), MA-dimethylacetamide (DMAc), A-methylpyrrolidone (NMP), pyridine, dimethyl sulfoxide (DMSO), sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptane, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.
The suitable temperature used in step (c) is selected from room temperature to reflux temperature of the solvent used.
A third aspect of the present invention relates to crystalline anhydrous form of ruxolitinib hemifumarate designated as Form I.
Form I is characterized by an XRPD pattern, as shown in Figure 2.
Form I is also characterized by an IR spectrum, as shown in Figure 4 and characterized by a DSC thermogram, as shown in Figure 8.
A fourth aspect of the present invention relates to a process for preparing Form II of ruxolitinib hemifumarate involving Form I of ruxolitinib hemifumarate.
A fifth aspect of the present invention relates to a process for preparing Form I of ruxolitinib hemifumarate involving Form II of ruxolitinib hemifumarate hemihydrate.
Form II is stable without polymorphic conversion under normal conditions and under heating up to 90 °C. Crystalline Form II of ruxolitinib hemifumarate hemihydrate starts to lose water above 120 °C and converts to crystalline anhydrous Form I.
The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner.
The process of the present invention affords ruxolitinib hemifumarate Form II in high purity and high yield. The ruxolitinib hemifumarate Form II is obtained having purity greater than 99% by area percentage in high performance liquid chromatography (HPLC).
Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.
Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the drug substance. The changes in solid state form of the drug substance may be resulted from the conditions of manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of drug substance. These variations comprising polymorphic transformations, hydrate / solvate formations and dehydration / desolvation reactions in the solid-state form of the drug substance, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of the drug substance has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of drug substance should be used in pharmaceutical formulations.
For this aspect, crystalline stability of ruxolitinib hemifumarate Form II was investigated under the following conditions: a sample was kept in an open flask at 90 °C for 10 days, packed samples were kept at 40 °C under 75% relative humidity (RH) and at 25 °C under 60% relative humidity (RH) for 6 months. The crystalline stability referred here, is the stability of a polymorphic form of drug substance with respect to polymorph transformations, hydration, dehydration, or amorphization through time under these conditions.
The crystalline stability of ruxolitinib hemifumarate Form II was investigated and determined by X-ray powder diffraction method. Results showed that any polymorphic transformation to another crystal form or any degradation in crystalline Form II did not occur. Crystalline Form II showed crystalline stability under dry heating at 90 °C for 10 days, at 40 °C / 75% RH and at 25 °C / 60% RH for 6 months.
The chemical stability of crystalline ruxolitinib hemifumarate Form II is also important and its stability in finished product at room temperature storage can be predicted from short-term storage under accelerated conditions at high temperature and humidity. In the present invention, samples of obtained crystalline ruxolitinib hemifumarate Form II were kept under dry heating in open flask at 90 °C for 10 days in an oven, and in LDPE pack at 40 °C & 75% RH and at 25 °C & 60% RH for 6 months in stability chambers to test chemical stability. The chemical stability of the samples was determined by HPLC method.
Table 1 shows the stability results of ruxolitinib hemifumarate Form II prepared according to the present invention. Form II samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts. Table 1. Ruxolitinib hemifumarate hemihydrate Form II stability test results
Figure imgf000009_0001
Table 2 shows the stability results of ruxolitinib hemifumarate Form I under the same conditions. Form I samples also stayed stable under all conditions without any change in the polymorphic form, without any significant change in the impurity profile and without increase in the impurity amounts.
Table 2. Ruxolitinib hemifumarate Form I stability test results
Figure imgf000009_0002
It can be concluded that there is no difference between ruxolitinib hemifumarate Form I and
Form II in terms of stability. Both are physically and chemically stable under normal and accelerated stability conditions.
A sixth aspect of the present invention relates to pharmaceutical compositions comprising crystalline ruxolitinib hemifumarate hemihydrate Form II along with a pharmaceutically acceptable carrier. Instrumental parameters:
NMR:
NMR and 13C NMR analyses were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-de) as a solvent.
FTIR:
Samples were measured as neat by ATR (attenuated total reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm-1 with 20 scans and 4 cm-1 resolution.
DSC:
Differential scanning calorimetry (DSC) thermograms were obtained using a differential scanning calorimeter (TA instruments DSC 250, USA) by using following instrument parameters: Start temperature: 25 °C, final temperature: 350 °C, heating rate: 10 °C/min.
TGA:
Thermogravimetric analysis (TGA) thermograms were obtained by using a thermogravimetric analzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C, final temperature: 120 °C, heating rate: 10 °C/min, isothermal: 15 min.
PXRD Method of Analysis:
X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters:
The measurement conditions were as follows:
Radiation: Cu (1.5406 A)
Filter for KP: Nickel
Voltage: 40.0 kV
Current: 30.0 mA
Auto slit: not used
Divergence slit: 1.0°
Scatter slit: 1.0° Receiving slit: 0.30 mm with a Graphite monochromator
Drive axis: Theta-2Theta
Scan range: 3.00 - 40.00°
Scan mode: continuous scan
Scan speed: 1.07min
Sampling pitch: 0.02°
Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLES
Preparation of ruxolitinib hemifumarate hemihydrate (ruxolitinib / fumaric acid / water ratio = 1 / 0.5 / 0.5; MW: 373.41 g/mol; theoretical water content: 2.41%; Form II)
Example 1:
Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethanol (2 mL), and the mixture was heated to 60 °C. Hot fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) solution prepared in ethanol (3 mL) was added into ruxolitinib solution at 60 °C and the mixture was stirred for 2 - 3 h at 60 °C. Afterwards, water (20 mL) was added, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h. Product crystals were filtered, washed with water, and then dried in vacuo at 40 - 50 °C to obtain ruxolitinib hemifumarate hemihydrate as an off- white crystalline solid (1.45 g, 83%, HPLC purity: 99.64%, water content (KF): 2.66%, hemihydrate, Form II).
Example 2:
Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethyl acetate (5 mL) and water (0.5 mL), and the mixture was heated to 77 °C. Fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) was added into ruxolitinib solution at 77 °C and the mixture was stirred for 2 - 3 h at 77 °C. Afterwards, n-hexane (15 mL) was added and the mixture was further stirred under heating for 1 h. Then, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h. Product crystals were filtered, washed with n-hexane, and then dried in vacuo at 40 - 50 °C to obtain ruxolitinib hemifumarate hemihydrate as an off-white crystalline solid (1.65 g, 94%, HPLC purity: 99.60%, water content (KF): 2.70%, TGA: 2.705% total loss, hemihydrate, Form II).
Example 3:
Ruxolitinib hemifumarate (1.1 g, 3.02 mmol, Form I) was dissolved in ethanol (5 mL) at reflux temperature (65 - 70 °C). After complete dissolution, water (25 mL) was added and the mixture was stirred for 2 - 3 h at 65 - 70 °C. Afterwards, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h. Product crystals were filtered, washed with water, and then dried in vacuo at 40 - 50 °C to obtain ruxolitinib hemifumarate hemihydrate as an off-white crystalline solid (0.88 g, 78%, HPLC purity: 99.74%, water content (KF): 2.68%, hemihydrate, Form II).
Preparation of ruxolitinib hemifumarate (ruxolitinib / fumaric acid ratio: 1 / 0.5; MW: 364.40 g/mol; Form I)
Example 4:
Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethanol (2 mL), and the mixture was heated to 60 °C. Hot fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) solution prepared in ethanol (3 mL) was added into ruxolitinib solution at 60 °C and the mixture was stirred for 2 - 3 h at 60 °C. Afterwards, heating stopped and the mixture was allowed to cool to 20 - 25 °C. At this temperature, water (20 mL) was added to the mixture and stirred for 12 - 16 h. Product crystals were filtered, washed with water, and then dried in vacuo at 40 - 50 °C to obtain ruxolitinib hemifumarate as an off-white crystalline solid (1.25 g, 73%, HPLC purity: 99.56%, water content (KF): 0.32%, anhydrous, Form I).
Example 5:
Ruxolitinib (1.45 g, 4.70 mmol, 1.0 equiv.) was dissolved in ethyl acetate (5 mL), and the mixture was heated to 77 °C. Fumaric acid (0.32 g, 2.8 mmol, 0.6 equiv.) was added into ruxolitinib solution at 77 °C and the mixture was stirred for 2 - 3 h at 77 °C. Afterwards, n- hexane (15 mL) was added and the mixture was further stirred under heating for 1 h. Then, heating stopped and the mixture was stirred at 20 - 25 °C for 12 - 16 h. Product crystals were filtered, washed with n-hexane, and then dried in vacuo at 40 - 50 °C to obtain ruxolitinib hemifumarate as an off-white crystalline solid (1.51 g, 88%, HPLC purity: 99.60%, water content (KF): 0.35%, anhydrous, Form I). Example 6:
Ruxolitinib hemifumarate hemihydrate (Form II) was dried in vacuo at 150 - 160 °C for 1 h to obtain ruxolitinib hemifumarate (Form I) as an off-white crystalline solid (100%, HPLC purity: 99.65%, water content (KF): 0.04%). This experiment was done by using 1 g and 10 g ruxolitinib hemifumarate hemihydrate (Form II) and both afforded ruxolitinib hemifumarate (Form I).

Claims

1. Crystalline Form II of ruxolitinib hemifumarate hemihydrate.
2. The crystalline Form II of ruxolitinib hemifumarate hemihydrate of claim 1 characterized with an XRPD pattern showing at least one characteristic peak (2 -theta ± 0.2°) at 5.4, 16.9 and 21.4; and further characterized by having XRPD peaks (2theta ± 0.2°) at 6.2, 9.8, 11.0, 16.1, 12.1, 14.7, 15.4, 18.5, 18.9, 23.5, 24.1, 24.4, 25.6, 26.3, and 29.1.
3. The crystalline Form II of ruxolitinib hemifumarate hemihydrate of claim 1 characterized by an XPRD pattern having 2-theta values as shown in Fig. 1.
4. The crystalline Form II of ruxolitinib hemifumarate hemihydrate of claim 1, characterized by IR spectrum as shown in Fig. 3.
5. The crystalline Form II of ruxolitinib hemifumarate hemihydrate of claim 1, characterized by a DSC thermogram as shown in Fig. 7.
6. The crystalline Form II of ruxolitinib hemifumarate hemihydrate of claim 1, characterized by a TGA thermogram as shown in Fig. 9.
7. A method of preparation of crystalline ruxolitinib hemifumarate hemihydrate of claim 1, comprising crystalline anhydrous Form I of ruxolitinib hemifumarate.
8. The pharmaceutical composition comprising crystalline Form II of ruxolitinib hemifumarate hemihydrate according to any one of the claims 1 to 6.
9. The use of crystalline Form II of ruxolitinib hemifumarate hemihydrate according to any one of the claims 1 to 8 in the manufacture of a medicament for the treatment of myelofibrosis.
10. A method of treating myelofibrosis comprising administering a therapeutically effective amount of a crystalline Form II of ruxolitinib hemifumarate hemihydrate, wherein the crystalline Form II of ruxolitinib hemifumarate hemihydrate is characterized by an XPRD pattern having 2-theta values as shown in Fig. 1.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016026974A1 (en) * 2014-08-21 2016-02-25 Ratiopharm Gmbh Oxalate salt of ruxolitinib
CA2928286A1 (en) * 2015-04-28 2016-10-28 Signa S.A. De C.V. Solid form of ruxolitinib phosphate
WO2017125097A1 (en) * 2016-01-22 2017-07-27 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile salts and preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016026974A1 (en) * 2014-08-21 2016-02-25 Ratiopharm Gmbh Oxalate salt of ruxolitinib
CA2928286A1 (en) * 2015-04-28 2016-10-28 Signa S.A. De C.V. Solid form of ruxolitinib phosphate
WO2017125097A1 (en) * 2016-01-22 2017-07-27 Zentiva, K.S. Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile salts and preparation thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ARANA YI CECILIA ET AL: "Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis", FUTURE ONCOLOGY, FUTURE MEDICINE LTD., LONDON, GB, vol. 11, no. 5, 1 March 2015 (2015-03-01), GB , pages 719 - 733, XP009547248, ISSN: 1479-6694, DOI: 10.2217/fon.14.272 *

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