WO2020072870A1 - Formes co-cristallines du baricitinib - Google Patents

Formes co-cristallines du baricitinib

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Publication number
WO2020072870A1
WO2020072870A1 PCT/US2019/054644 US2019054644W WO2020072870A1 WO 2020072870 A1 WO2020072870 A1 WO 2020072870A1 US 2019054644 W US2019054644 W US 2019054644W WO 2020072870 A1 WO2020072870 A1 WO 2020072870A1
Authority
WO
WIPO (PCT)
Prior art keywords
baricitinib
crystal
fumaric acid
dcm
solvate
Prior art date
Application number
PCT/US2019/054644
Other languages
English (en)
Inventor
Padmini Kavuru
Original Assignee
Johnson Matthey Public Limited Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Johnson Matthey Public Limited Company filed Critical Johnson Matthey Public Limited Company
Publication of WO2020072870A1 publication Critical patent/WO2020072870A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to co-crystal forms of baricitinib; particularly with fumaric acid as the co-crystal former (coformer) in solvated and anhydrous forms. Further, the present disclosure is also related to processes for the preparation of the solvated and anhydrous forms of baricitinib co-crystals with fumaric acid. Further, the present disclosure also relates to pharmaceutical compositions comprising the forms of baricitinib co-crystals with fumaric acid, and methods for treating disease using the forms.
  • Baricitinib having the chemical designation ⁇ 1 -(ethyl sulfonyl)-3- [4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl- ]azetidin-3-yl ⁇ acetonitrile, is a Janus kinase (JAK) inhibitor.
  • JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function.
  • JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression.
  • STATs Signal Transducers and Activators of Transcription
  • Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
  • Baricitinib has the following structure:
  • Olumiant Baricitinib is commercially marketed in Europe and in the U.S. under the name Olumiant. In the U.S., it is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have responded inadequately to one or more TNF antagonist therapies. Olumiant may be used as monotherapy or in combination with methotrexate or other DMARDs.
  • Baricitinib is described in U.S. Patent No. 8158616. Solid forms of baricitinib are described in U.S. Patent Nos. 9827230 (amorphous hybrid nanoparticles), 9938283 (crystalline form comprising 3% water) and 10377757 (crystalline forms I and II, and crystalline phosphate salt forms A, B and C), and U.S. Publication No. 20170129895 (amorphous). Methods of treating rheumatoid arthritis and psoriasis using baricitinib are described in U.S. Patent No. 8420629. Processes for preparing baricitinib and intermediates are described in U.S. Patent Nos.
  • the present invention is directed to a baricitinib co-crystal with fumaric acid/DCM solvate and to an anhydrous baricitinib co-crystal with fumaric acid.
  • the present disclosure is also related to processes for the preparation of these forms of baricitinib co-crystal with fumaric acid.
  • the present invention also relates to pharmaceutical compositions comprising a form of baricitinib co-crystal with fumaric acid and to methods for treating disease using a form of baricitinib co-crystal with fumaric acid.
  • Figure 1 represents the experimental and calculated XRPD patterns of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 2 is a TGA plot of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 3 is a DSC plot of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 4 is a X H NMR spectra of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 5 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus that of baricitinib and fumaric acid.
  • Figure 6 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus a physical mixture of baricitinib and fumaric acid.
  • Figures 7 A and 7B together represent the asymmetric unit of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 7 A depicts the interaction between baricitinib and fumaric acid in Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 7B depicts the relationship between baricitinib and DCM in Form I baricitinib co-crystal with fumaric acid/DCM solvate (only one molecule of DCM shown).
  • Figures 8A and 8B together show the inter-molecular hydrogen bonding between baricitinib molecules and between baricitinib molecules and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 8A shows the inter- molecular hydrogen bonding between baricitinib molecules in Form I baricitinib co- crystal with fumaric acid/DCM solvate (fumaric acid not shown).
  • Figure 8B shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate (DCM not shown).
  • Figure 9 represents the comparison of XRPD patterns of Form I baricitinib co crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.
  • Figure 10 represents a comparison of XRPDs for wet cake and dried precipitate of Form II baricitinib co-crystal with fumaric acid (prepared according to Example 7), and the calculated XRPD for Form II baricitinib co-crystal with fumaric acid.
  • Figure 11 contains TGA and DSC plots of Form II baricitinib co-crystal with fumaric acid.
  • Figure 12 is a X H NMR spectra of Form II baricitinib co-crystal with fumaric acid.
  • Figure 13 represents crystals of Form II baricitinib co-crystal with fumaric acid examined by PLM.
  • Figure 14 shows the asymmetric unit of Form II baricitinib co-crystal with fumaric acid.
  • Figure 15 shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form II baricitinib co-crystal with fumaric acid.
  • Figure 16 represents a comparison of XRPDs for wet cake and dried precipitate of Form II baricitinib co-crystal with fumaric acid (prepared according to Example 8), and the calculated XRPD for Form II baricitinib co-crystal with fumaric acid.
  • a specific temperature or temperature range such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration
  • “co-crystal” and“co-crystal systems” refer to solid materials composed of two or more different components that are solid at room temperature and in particular stoichiometric ratios which interact through non-covalent interactions which can be designed utilizing supramolecular synthon approach.
  • the co-crystal in which at least one of the components is baricitinib and the coformer is a second pharmaceutically acceptable compound, is called a pharmaceutical baricitinib co-crystal with the coformer.
  • the term“pharmaceutical composition” is intended to encompass a pharmaceutically effective amount of the baricitinib in the co-crystal of the invention and a pharmaceutically acceptable excipient.
  • the term“pharmaceutical compositions” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • excipient refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for bulking-up formulations that contain potent active ingredients (thus often referred to as“bulking agents,”“fillers,” or“diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the
  • the term“patient” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/or prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition.
  • the terms“treat,”“treating” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of symptoms of a disease.
  • Particular embodiments of the invention are directed to solvated and anhydrous forms of a baricitinib co-crystal with fumaric acid; more particularly to Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.
  • the forms are considered to have an isostructural relationship which lends to them looking identical.
  • Form I baricitinib co-crystal with fumaric acid/DCM solvate is a site disordered baricitinib co-cry stal/solvate, where the fumaric acid molecule that links two molecules of baricitinib is replaced by two dichloromethane molecules in approximately 15% of the unit cells.
  • Form II baricitinib co-crystal with fumaric acid has no solvent associated therewith, i.e., it is anhydrous.
  • the present disclosure is also related to processes for the preparation of Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.
  • Another embodiment according to the invention is a method of making a baricitinib co-crystal with fumaric acid, comprising dissolving baricitinib and fumaric acid in a solvent to form a clear solution, allowing the solution to evaporate to yield the baricitinib co-crystal with fumaric acid.
  • a further embodiment according to the invention is a method of making a baricitinib co-crystal with fumaric acid, comprising dissolving baricitinib and fumaric acid in a solvent to form a clear solution, adding an antisolvent thereto, and allowing the baricitinib co-crystal with fumaric acid to precipitate from the solvent-anti solvent mixture.
  • the aforesaid method uses as the solvent, for example dimethylsulfoxide (DMSO) and uses as the antisolvent, for example methanol or water.
  • the antisolvent for example methanol or water.
  • the mole ratio of the baricitinib to fumaric acid is 1 : 1.5-3.5.
  • the mole ratio of the baricitinib to fumaric acid is 1 : 1-1.5.
  • a further embodiment according to the invention is a method for the preparation of a baricitinib co-crystal with fumaric acid/DCM solvate comprising:
  • BCTmmol:MeOHmL:DCMmL is about 1 :22:28 to about 1 :25:40;
  • the aforesaid method wherein the baricitinib co-crystal with fumaric acid prepared is Form I.
  • the aforesaid method wherein Form I is a baricitinib co-crystal with fumaric acid/DCM solvate.
  • the aforesaid method wherein Form I baricitinib co-crystal with fumaric acid/DCM solvate consists of one molecule of baricitinib, half a molecule of fumaric acid that is disordered in the cocrystal, and 0.14 molecules of disordered DCM.
  • BCT baricitinib dissolved in dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • step (b) stirring the combined solutions of step (a) overnight (8-10 hr) at room temperature (RT) to yield the baricitinib co-crystal with fumaric acid;
  • step (c) isolating the baricitinib co-crystal with fumaric acid formed in step (b).
  • the aforesaid method of preparation embodiment wherein in the combining the fumaric acid in MeOH is added to the baricitinib in DMSO.
  • the aforesaid method wherein the combining is at about 50 °C.
  • the aforesaid method wherein the isolating of the baricitinib co-crystal with fumaric acid is by filtering.
  • the aforesaid method wherein the isolated baricitinib co-crystal with fumaric acid prepared is Form II.
  • Form II baricitinib co-crystal with fumaric acid consists of one molecule of baricitinib and half a molecule of fumaric acid that is disordered in the cocrystal.
  • the present invention also relates to pharmaceutical compositions comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid, and methods for treating disease using these forms.
  • Pharmaceutical compositions comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid may be prepared according to U.S. Patent No. 8420629, which is incorporated herein by reference in its entirety.
  • the dosage of the pharmaceutical compositions may be varied over a wide range. Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of
  • a dosage of the pharmaceutical composition of the invention is available as 2 mg tablets.
  • the recommended dose of baricitinib is 2 mg once daily and may be used as monotherapy or in combination with methotrexate or other DMARDs.
  • the present disclosure provides for a method of treating a disease comprising administering to a patient, in need thereof, a pharmaceutical composition comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate or Form II baricitinib co- crystal with fumaric acid.
  • Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more TNF antagonist therapies.
  • the °2Q values and the relative intensity values are generated by performing a peak search on the measured data and the r -spacing values are calculated by the instrument from the °2Q values using Bragg’s equation.
  • the relative intensity for the measured peaks may vary because of sample preparation, orientation and instrument used, for example.
  • DSC data are collected using a TA Instruments Q10 DSC. Approximately, samples (2-8 mg) are placed in unsealed but covered hermetic alodined aluminum sample pans and scanned from about 30 to about 300 °C at a rate of about 10 °C/min under a nitrogen purge of about 50 mL/min. Some of the DSC runs are generated on a TA Instruments Q2000 equipped with an auto-sampler and RSC40. The sampling is conducted at a ramp rate of about 10 °C/min from 20 °C to 320 °C using Tzero hermetic sealed aluminum sample pans in T4P (or T3) mode.
  • TGA measurements are recorded using TA Q500 instrument. Approximately, 2-5 mg samples are placed in a pin holed sealed hermetic alodined aluminum DSC pan, pre- tared with an aluminum pan. TGA investigations are performed at a heating rate of 10.0 °C/min over a temperature range of from about 30 to about 300 °C, with purging with nitrogen at a flow rate of 60 mL/min.
  • 'H-NMR data is collected using a Bruker Avance 300 MHz NMR equipped with TopSpin software. Samples are prepared by dissolving the compound in deuterated dimethylsulfoxide with 0.05% (v/v) tetramethylsilane (TMS). The number of scans is 16 for 'H-NMR.
  • IR analysis is done by employing solid samples for FTIR using KBr pellet.
  • the pellet is prepared by mixing KBr and the sample in 1 : 150 ratio (approximately 2-5 mg of the sample with 350 mg of KBr).
  • Omnic software is used for the analysis and the samples are collected with 32 scans.
  • Crystalline morphology of samples is analyzed using an Olympus BX53 polarized light microscope (PLM) equipped with a PAXcam 3 digital microscope camera.
  • PLM Olympus BX53 polarized light microscope
  • Examples below provide embodiments of the preparation of co-crystal forms of baricitinib with fumaric acid.
  • Figure 1 represents the experimental and calculated XRPD patterns of Form I baricitinib co-crystal with fumaric acid/DCM solvate obtained by the instant method.
  • Form I baricitinib co-crystal with fumaric acid/DCM solvate is characterized by its XRPD pattern peaks and their corresponding intensities that are listed in Table I below. Table I
  • the angle measurements are ⁇ 0.2° 2Q.
  • Key defining peaks or solid-state Form I baricitinib co-crystal with fumaric acid/DCM solvate include 7.8, 10.2, 15.9, 19.2, 19.9,
  • the TGA plot ( Figure 2) shows a weight loss of about 2.5% from about 100 °C through about 175 °C for Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • the DSC plot ( Figure 3) shows a small thermal event at about 151 °C and another thermal event at about 207 °C for Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 4 is an 'H NMR spectra for Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 5 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus that of baricitinib and fumaric acid.
  • Figure 6 is directed to FT-IR spectra comparison of Form I baricitinib co crystal with fumaric acid/DCM solvate versus a physical mixture of baricitinib and fumaric acid.
  • Figures 7A and 7B together represent the asymmetric unit of Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 7 A depicts the interaction between baricitinib and fumaric acid in Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 7B depicts the relationship between baricitinib and DCM in Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figures 8A and 8B together show the inter-molecular hydrogen bonding between baricitinib molecules and between baricitinib molecules and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate.
  • Figure 8A shows the inter- molecular hydrogen bonding between baricitinib molecules in Form I baricitinib co crystal with fumaric acid/DCM solvate (fumaric acid not shown).
  • Figure 8B shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate (DCM not shown).
  • the reaction mixture is stirred overnight (18- 20 h).
  • the solids are filtered and the wet cake is rinsed with 10 mL of water and the final rinse with 15 mL of TBME.
  • the sample is double bagged and dried in the oven at 45 °C over the weekend.
  • the wet cake and dried precipitate are analyzed by XRPD, and those XRPDs are compared to the calculated XRPD for Form II baricitinib co-crystal with fumaric acid. See Figure 10.
  • Form II baricitinib co-crystal with fumaric acid is characterized by its XRPD pattern peaks and their corresponding intensities that are listed in Table II below.
  • the angle measurements are ⁇ 0.2° 2Q.
  • Key defining peaks or solid-state Form II baricitinib co-crystal with fumaric acid include 7.8, 10.2, 13.8, 22.1 and 27.8 ° 2Q degrees.
  • Figure 11 shows the TGA plot that shows ⁇ 1 % weight loss when heated to 200 °C for Form II baricitinib co-crystal with fumaric acid, and the DSC plot that shows a thermal event at about 212 °C.
  • Figure 12 is directed to the 'H NMR for Form II baricitinib co-crystal with fumaric acid. Crystals of Form II baricitinib co-crystal with fumaric acid are examined by PLM ( Figure 13).
  • Single crystals of Form II baricitinib co-crystal with fumaric acid are obtained by the instant method, and the single crystal parameters for Form II baricitinib co-crystal with fumaric acid as determined by SCXRD are:
  • Figure 14 shows the asymmetric unit of Form II baricitinib co-crystal with fumaric acid.
  • Figure 15 shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form II baricitinib co-crystal with fumaric acid.
  • the precipitate is filtered and the wet cake is rinsed with 10-15 mL of water.
  • the sample is double bagged and dried in the oven at 45 °C over the weekend.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des co-cristaux de baricitinib comprenant du baricitinib et de l'acide fumarique dans des formes solvatées et anhydres. La présente invention concerne également des procédés de préparation des co-cristaux de baricitinib avec de l'acide fumarique. En outre, la présente invention concerne également des compositions pharmaceutiques comprenant les co-cristaux de baricitinib avec de l'acide fumarique et des méthodes de traitement d'une maladie faisant appel aux co-cristaux de baricitinib avec de l'acide fumarique.
PCT/US2019/054644 2018-10-05 2019-10-04 Formes co-cristallines du baricitinib WO2020072870A1 (fr)

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US62/741,969 2018-10-05

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