WO2011140431A1 - Sels de la varénicline et leurs formes cristallines - Google Patents

Sels de la varénicline et leurs formes cristallines Download PDF

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Publication number
WO2011140431A1
WO2011140431A1 PCT/US2011/035503 US2011035503W WO2011140431A1 WO 2011140431 A1 WO2011140431 A1 WO 2011140431A1 US 2011035503 W US2011035503 W US 2011035503W WO 2011140431 A1 WO2011140431 A1 WO 2011140431A1
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WIPO (PCT)
Prior art keywords
varenicline
hydrobromide
solid
powder xrd
peaks
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PCT/US2011/035503
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English (en)
Inventor
Maytal Piran
Jacob Rendell
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceutical Usa, Inc.
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Publication of WO2011140431A1 publication Critical patent/WO2011140431A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the invention is directed to salts and solid state forms of Varenicline, process and formulation thereof.
  • Varenicline tartrate is marketed by Pfizer under the trade name of
  • CHANTIXTM as a partial agonist selective for certain subtypes of nicotinic receptors and indicated for smoking cessation.
  • Varenicline base and a variety of salts thereof, are disclosed in
  • Varenicline tartrate salt is described in U.S. Patent No. 6,558,435. Crystalline forms of Varenicline citrate and succinate salts are described in the US Patent Nos. 6,787,549 and 6,794,388, respectively. Varenicline L-tartrate and its crystalline forms A, B, and C are described in the U.S. Patent Nos. 6,890,927 and 7,265,119. Crystalline Varenicline HCl Forms I, II, and III are described in the PCT Publication No. WO2009109651. Crystalline forms of Varenicline tosylate are described in the PCT Publication No. WO20090143347. Crystalline forms of Varenicline sulfate and mesylate are described in the PCT
  • the invention provides new salts of Varenicline, such as acetate, hydrobromide, and hydrochloride, as well as their solid state forms, formulation therapy and processes for preparing them.
  • the invention provides new crystalline forms of Varenicline salts, such as tosylate and sulfate, as well as their formulation therapy and processes for preparing them.
  • the invention further provides a pharmaceutical composition comprising the crystalline forms of Varenicline salts described herein.
  • composition additionally comprises at least one pharmaceutically acceptable excipient.
  • the invention further provides the use of the salts and polymorphs described below for the manufacture of a medicament for the treatment of smoking addiction.
  • the invention further provides the use of the salts and polymorphs described below in the process of preparing Varenicline tartrate.
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern of crystalline Varenicline Tosylate_Form V.
  • Figure 2 shows a PXRD pattern of a mixture of crystalline Form I and
  • Figure 3 shows a PXRD pattern of dry crystalline Varenicline acetate
  • Figure 5 shows a PXRD pattern of crystalline Varenicline sulfate Form
  • Figure 6 shows a PXRD pattern of crystalline Varenicline sulfate Form
  • Figure 7 shows a PXRD pattern of crystalline Varenicline sulfate Form
  • Figure 8 shows a PXRD pattern of crystalline Varenicline acetate Form
  • Figure 9 shows a PXRD pattern of crystalline Varenicline acetate Form
  • Figure 10 shows a PXRD pattern of crystalline Varenicline sulfate
  • Figure 11 shows a PXRD pattern of crystalline Varenicline hydrobromide Form I
  • Figure 12 shows a PXRD pattern of crystalline Varenicline hydrobromide Form II.
  • Figure 13 shows a PXRD pattern of crystalline Varenicline Sulfate pure Form III.
  • Figure 14 shows a PXRD pattern of crystalline Varenicline
  • Figure 15 shows a solid-state 13 C NMR spectrum of Varenicline hydrobromide form I in the 0-200 ppm range.
  • Figure 16 shows a solid-state 13 C NMR spectrum of Varenicline hydrobromide form I in the 100-200 ppm range.
  • Figure 17 shows PXRD pattern of crystalline Varenicline
  • Figure 18 shows a solid-state 13 C NMR spectrum of Varenicline
  • Figure 19 shows a solid-state 13 C NMR spectrum of Varenicline
  • Figure 20 shows a solid-state 13 C NMR spectrum of Varenicline
  • Figure 22 shows a solid-state 13 C NMR spectrum of Varenicline HBr form II in the 0-200 ppm range.
  • Figure 23 shows a solid-state 13 C NMR spectrum of Varenicline HBr form II in the 100-200 ppm range.
  • Figure 24 shows PXRD pattern of crystalline Varenicline
  • hydrobromide form II measured after humidity stability test.
  • Figure 25 shows PXRD pattern of crystalline Varenicline Sulfate form
  • the invention provides new salts of Varenicline, such as acetate, hydrobromide, and hydrochloride, as well as their solid state forms, formulation therapy and processes for preparing them.
  • the invention provides new crystalline forms of Varenicline salts, such as tosylate and sulfate, as well as their formulation therapy and processes for preparing them.
  • the polymorphs of Varenicline salts of the invention are substantially free of any other polymorphic forms.
  • substantially free is meant that the crystal forms of the invention contain 20% (w/w) or less, 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, particularly 1% (w/w) or less, more particularly 0.5%> (w/w) or less, and most particularly 0.2%> (w/w) or less of any other polymorph.
  • the polymorphs of Varenicline salts of the invention contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of any other polymorph.
  • a crystal form may be referred to herein as being characterized by graphical data "as shown in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state nuclear magnetic resonance (NMR) spectra.
  • NMR solid state nuclear magnetic resonance
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.
  • chemical shift difference refers to the difference in chemical shifts between a reference signal and another signal in the same NMR spectrum. These chemical shift differences serve to provide an additional analytical measurement for a substance, for example a crystalline form of A
  • Varenicline salt according to the present invention which will compensate for a phenomenon that may occur in NMR spectroscopy wherein a shift in the solid-state NMR "fingerprint” is observed.
  • a shift in the NMR peaks may occur, for example as a result of variations in the instrumentation, the temperature, or the calibration method used in the NMR analysis.
  • This shift in the solid-state NMR "fingerprint" having chemical shift resonances at a certain positions, is such that even though the individual chemical shifts of signals have moved, all the peaks in the spectrum are moved by the same amount, such that the difference between chemical shifts of each signal and another selected signal is retained.
  • This chemical shift difference provides data that may be used as a reliable characterization of the material being analyzed even when there is a shift in the overall solid-state NMR "fingerprint”.
  • room temperature refers to a temperature between about 20 °C and about 30 °C, and preferably from about 20°C to about 25 °C.
  • the invention provides crystal forms of Varenicline tosylate, 7,8,9,10- tetrahydro- 6, 10 -methano -6H - pyrazino [2, 3-h] [3] benzapine tosylate, and methods of preparing the crystal form of Varenicline tosylate.
  • Varenicline tosylate Form I refers to a crystalline
  • Varenicline tosylate characterized by a powder X-ray diffraction (XRD) pattern having peaks at 10.1°, 13.0°, 16.7°, 18.7°, and 20.6° ⁇ 0.2° 2 ⁇ .
  • Form I can be prepared, for example, by combining Varenicline base, a Ci-C 6 alcohol and p-toluene sulfonic acid to obtain a mixture, heating and then cooling the obtained mixture, e.g., as indicated in PCT Publication No. WO20090143347.
  • Varenicline tosylate Form II refers to a crystalline
  • Varenicline tosylate characterized by a powder XRD pattern having peaks at 1 1.6°, 12.9°, 13.3°, 21.3 °, and 23.3° ⁇ 0.2° 2 ⁇ .
  • Form II can be prepared, for example, by combining Varenicline base, methanol, a C 6 -Ci2 aromatic hydrocarbon, and p-toluene sulfonic acid to obtain a mixture, heating and cooling the obtained mixture, e.g., as indicated in PCT Publication No. WO20090143347.
  • Varenicline sulfate Form I refers to a crystalline
  • Varenicline sulfate characterized by a powder XRD pattern having peaks at 15.1°, 15.4°, 16.8°, 17.7°, and 21.5° ⁇ 0.2 degrees two theta.
  • Form I can be prepared, for example, by combining Varenicline base and sulfuric acid solution to obtain a mixture, cooling and then heating the obtained mixture, e.g., as indicated in PCT application No. PCT/US 10/39446.
  • the salts and solid state forms of the present invention have certain advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • Varenicline Hydrobromide Form II as well as Varenicline Sulfate form IV of the present invention have improved stability under high humidity conditions.
  • Varenicline Hydrobromide Form I, Varenicline Hydrobromide Form II, and Varenicline Sulfate Form IV show no polymorphic conversion to other polymorphs under high humidity conditions, such as 100% relative humidity as shown in figure 17, figure 24, and figure 25.
  • the invention provides a crystalline form of
  • Varenicline tosylate designated Form V.
  • Form V can be characterized by a powder XRD pattern having peaks at 5.7°, 11.4°, 17.5°, 19.1°, and 19.6° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 1 ; and combinations thereof.
  • Varenicline tosylate Form V can further be characterized by a powder
  • Form V can be characterized by any combination of the above data.
  • the invention provides Varenicline acetate.
  • the Varenicline acetate can be isolated. Preferably it can be in a solid form. More preferably the Varenicline acetate is crystalline. [00052] In another embodiment, the invention provides a crystalline form of
  • Varenicline acetate designated Form I.
  • Form I can be characterized by a powder XRD pattern having peaks at 10.7°, 15.1°, 16.1°, 17.9°, and 20.3° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 3; and combinations thereof.
  • Varenicline acetate Form I can be further characterized by a powder
  • Form I can be characterized by any combination of the above data.
  • the invention provides a crystalline form of
  • Varenicline acetate designated Form II.
  • Varenicline acetate Form II can be characterized by a powder XRD pattern having peaks at 6.9°, 13.0°, 15.3°, 20.8°, and 23.5° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 9; and combinations thereof.
  • Varenicline acetate Form II can be further characterized by a powder
  • Form III can be characterized by any combination of the above data.
  • the invention provides a crystalline form of
  • Varenicline acetate designated Form III.
  • Varenicline acetate Form III can be characterized by a powder XRD pattern having peaks at 6.8°, 8.6°, 13.7°, 17.5°, and 20.7° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 8; and combinations thereof.
  • Varenicline acetate Form III can be further characterized by a powder
  • Form III can be characterized by any combination of the above data.
  • the invention also provides crystal forms of Varenicline sulfate.
  • the Varenicline sulfate is crystalline.
  • the invention provides a crystalline form of
  • Varenicline sulfate designated Form II.
  • Form II can be characterized by a powder XRD pattern having peaks at 5.5°, 16.3°, 16.8°, 19.9°, and 22.0° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 4; and combinations thereof.
  • Varenicline sulfate Form II can be further characterized by a powder
  • Varenicline sulfate Form II can be characterized by any combination of the above data.
  • the invention provides a crystalline form of
  • Varenicline sulfate designated Form III.
  • Form III can be characterized by a powder XRD pattern having peaks at 17.9°, 18.9°, 19.7°, 20.6°, and 24.4° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 5; a solid-state 13 C NMR spectrum with signals at 125.4,144.9 and 155.0 ⁇ 0.2 ppm;; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 9.9, 29.4 and 39.5 ⁇ 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm at about 115.5 ⁇ lppm.; a solid-state 13 C NMR spectrum is depicted in Figures 18; and any combinations thereof.
  • Varenicline sulfate Form III can be further characterized by a powder
  • Varenicline sulfate Form III can be characterized by any combination of
  • Varenicline sulfate form III is substantially pure, containing 10% or less of any other crystalline forms.
  • the substantially pure form III is free of peaks at: 5.4°, 16.4°, 17.9°, 20.2°, and 23.8° ⁇ 0.2° two theta.
  • the substantially pure form III can be characterized by a powder XRD pattern substantially as shown in figure 13.
  • the invention provides a crystalline form of
  • Varenicline sulfate designated Form IV.
  • Form IV can be characterized by a powder XRD pattern having peaks at 9.0°, 15.9°, 16.8°, 20.2°, and 25.7° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 6; a solid-state 13 C NMR spectrum with signals at 124.2,138.8 and 145.5 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 4.0, 18.6 and 25.3 ⁇ 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm at about 120.2 ⁇ lppm.; a solid-state 13 C NMR spectrum substantially as depicted in Figures 20; and combinations thereof.
  • Varenicline sulfate Form IV can be further characterized by a powder
  • Varenicline sulfate Form IV can be characterized by any combination of
  • the invention provides a crystalline form of
  • Varenicline sulfate designated Form V.
  • Form V can be characterized by a powder XRD pattern having peaks at 5.7°, 11.3°, 14.1°, 19.5°, and 25.7° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 7; and combinations thereof.
  • Varenicline sulfate Form V can be further characterized by a powder
  • Varenicline sulfate Form V can be characterized by any combination of the above data.
  • the invention provides a crystalline form of
  • Varenicline sulfate designated Form VI.
  • Form VI can be characterized by a powder XRD pattern having peaks at 5.6°, 8.0°, 10.0°, 11.2°, and 12.9° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 10; and combinations thereof.
  • Varenicline sulfate Form VI can be further characterized by a powder
  • Varenicline sulfate Form VI can be characterized by any combination of
  • the present invention provides Varenicline hydrobromide.
  • it can be in a solid form. More preferably the Varenicline hydrobromide is crystalline.
  • the invention provides a crystalline form of
  • Varenicline hydrobromide designated Form I.
  • Form I can be characterized by a powder XRD pattern having peaks at 10.7°, 16.0°, 16.5°, 20.3°, and 22.4° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 11; a solid-state 13 C NMR spectrum with signals at 124.7, 138.7, and 146.4 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 4.4, 18.4 and 26.1 ⁇ 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm at about 120.3 ⁇ lppm.; a solid-state 13 C NMR spectrum substantially as depicted in Figures 15; and any combinations thereof.
  • Varenicline hydrobromide Form I can be further characterized by a powder XRD pattern having additional peaks at 8.0, 14.9, 17.0, 19.4, 21.2 ⁇ 0.2° two theta.
  • Varenicline hydrobromide Form I can be further characterized by any one or more additional XRD peaks selected from 8.0, 10.1°, 13.5°, 14.9, 17.0, 19.1°, 19.4, 19.7°, 21.2, 21.5°, 24.5°, 25.1°, 25.8°, 26.4°, 27.3°, 29.4°, 29.7°, 30.3° and 31.9° ⁇ 0.2° two theta.
  • Varenicline hydrobromide Form I can be characterized by any combination of the above data.
  • the invention provides a crystalline form of
  • Varenicline hydrobromide designated Form II.
  • Form II can be characterized by a powder XRD pattern having peaks at 16.2°, 18.9°, 20.4°, 21.3°, and 23.7° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 12; a solid-state 13 C NMR spectrum with signals at 123.9,137.0 and 150.7 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 7.4, 20.5 and 34.2 ⁇ 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm at about 116.5 ⁇ lppm.; a solid-state 13 C NMR spectrum substantially as depicted in Figures 22; and any combinations thereof.
  • Varenicline hydrobromide Form II can be further characterized by a powder XRD pattern having additional peaks at 17.1°, 19.4°, 21.6°, 24.3°, 25.3° ⁇ 0.2° two theta.
  • Varenicline hydrobromide Form II can be further characterized by any one or more additional XRD peaks selected from 9.1°, 9.4°, 15.8°, 16.2°, 17.1°, 18.0°, 18.4°, 18.9°, 19.4°, 20.4°, 21.0°, 21.3°, 21.6°, 23.7°, 24.3°, 25.3°, 27.0°, 27.1°, 27.5°, and 29.5° ⁇ 0.2° two theta.
  • Varenicline hydrobromide Form II can be characterized by any combination of the above data.
  • the present invention provides Varenicline hydrochloride.
  • it can be in a solid form. More preferably the Varenicline hydrochloride is crystalline.
  • the invention provides a crystalline form of
  • Varenicline hydrochloride designated Form IV.
  • Form IV can be characterized by a powder XRD pattern having peaks at 7.8°, 10.8°, 16.0°, 19.8°, and 21.8° ⁇ 0.2° two theta; a powder XRD pattern substantially as shown in figure 14; and combinations thereof.
  • Varenicline hydrochloride Form IV can be further characterized by a powder XRD pattern having additional peaks at 10.0°, 11.8°, 19.4°, 23.5°, and 27.8 ⁇ 0.2° two theta.
  • Varenicline salts can be used to prepare Varenicline tartrate and formulation thereof, for example, by reacting any one of the above mentioned Varenicline salts with tartaric acid.
  • the above described forms of Varenicline salts can be used to prepare Varenicline tartrate by reacting any of the above mentioned Varenicline salt with a base to obtain free Varenicline free base, and to further reacting it with tartaric acid.
  • the present invention further encompasses 1) a pharmaceutical composition comprising any one or any combination of the solid state forms, as described above, and at least one pharmaceutically acceptable excipient, 2) the use of any one or any combination of the above-described solid state forms, in the manufacture of a pharmaceutical composition and 3) the use of the crystalline forms as describe above as a medicament, preferably for the treatment of smoking addiction.
  • the present invention also encompasses the use of any of the solid state forms described herein as a starting material, or an intermediate, in the preparation of Varenicline tartrate.
  • the pharmaceutical composition can be useful for the treatment of type 2 diabetes mellitus.
  • the solid state forms contain 20% or less, for example 10%> or less, or 5% or less, or 2% or less, or 1% or less of any other crystalline form of the respective Varenicline salt.
  • the present invention also provides crystalline forms as described above for use as a medicament, preferably for the treatment of smoking cessation.
  • X-Ray powder diffraction data was obtained by using methods known in the art using a SCINTAG powder X-ray diffractometer model X'TPvA 019 equipped with a solid-state detector. Copper radiation of 1.5418 A was used. A standard sample holder with zero background plate was used. The scanning parameters included: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05 deg.; and a rate of 3 deg/minute.
  • Injection volume 10 ⁇ .
  • Solid state NMR conditions Solid-state C NMR spectra were recorded with variable amplitude cross polarization, magic angle spinning, and high power proton decoupling using: BRUKER Avance 11+ spectrometer operating at 125MHz and ambient temperature (about 25°C).
  • a probe using 4mm o.d. zirconia rotors was employed.
  • the operation conditions were:
  • Recycle delay 10s 512 scans
  • the resultant mixture was cooled to 45-55°C, and filtered through a celite bed (20 g). The celite bed was washed with methanol (60 ml). To the filtrate obtained was charged p- toluene sulfonic acid (66 g) in organic layer at 45-55°C, and maintained for 15 minutes. The temperature was raised to 65-70°C, and maintained for 1 hour. The resultant mixture was cooled to 20-30°C, and maintained for 2 hours. The solid crystallized was filtered at 20-30°C, and the wet cake was washed with methanol (60 ml). The obtained product was dried under vacuum at 45-55°C.
  • VR (Varenicline) tosylate form II 130 mg was put into an open glass weighing bottle.
  • the bottle with the material was placed on the perforated shelf of a desiccator containing a container of 2-propanol (IP A) at the bottom, which served to provide a 2-propanol-saturated atmosphere inside the desiccator.
  • the desiccator containing the material was put into an oven set at 40°C, and stored there in the 2- propanol atmosphere for 1 week.
  • the sample was analyzed by powder XRD, and the obtained diffractogram is provided in figure 1.
  • VRN tosylate form I 130 mg was put into an open glass weighing bottle.
  • the bottle with the material was placed on the perforated shelf of a desiccator containing a container of 2-propanol at the bottom which served to provide an atmosphere inside the desiccator that was saturated with 2-propanol.
  • the desiccator containing the material was put into an oven set at 40°C, and stored there in the 2-propanol atmosphere for 1 week.
  • the sample was analyzed by powder XRD, and found to contain Form V, as shown in figure 2.
  • Example 5 Varenicline acetate form I
  • Varenicline base (1 g, 4.73 mmol) was dissolved at 25°C in toluene (23 mL) resulting in a clear yellow solution.
  • a mixture of acetic acid/toluene (25:75 w/w) (1.14 g, 4.73 mmol, 1 eq). Precipitation was observed after about 5 minutes, and stirring was continued for 16 hours. The mixture was then cooled to 5°C. The solid was isolated by filtration, and washed with cold (5°C) toluene (2x7.5 mL). Drying of the solid in a vacuum oven (35 mbar) at 60°C for 68 hours afforded Varenicline acetate form I (1.03 g, 80.5%> yield).
  • Varenicline base (1 g, 4.73 mmol) was dissolved at room temperature in ethyl acetate (36 mL) resulting in a clear yellow solution.
  • ethyl acetate 36 mL
  • acetic acid/ethyl acetate 25:75 w/w
  • Varenicline base (1.6 g, 7.6 mmol) was dissolved in ethanol (26 mL, 16V) at 25°C with stirring. The resulting solution was cooled to 5°C and sulfuric acid (8.9 g, 45.4 mmol, 50% aq. solution, 6 mol equivalents) was added. The mixture was allowed to warm up to room temperature, and stirring was continued for 4 hours leading to precipitation. The resulting solids were filtered and washed with cold ethanol (4x3.2 mL) to give Varenicline sulfate form II as a white solid.
  • Varenicline sulfate form II was dried in a vacuum oven (35 mbar) at 40°C for 8 hours to give Varenicline sulfate form III as a white solid (1.82 g).
  • Varenicline sulfate form I (0.3 g) was dissolved in a mixture of IPA:water (12.9: 1 v/v, 97 mL) at reflux with stirring. The resulting solution was cooled to -17 °C. After 2.5 hours the resulting solids were filtered and dried in a vacuum oven (35 mbar) at 40°C for 14 hours to give Varenicline sulfate form IV (0.23 g, 77%) as a white solid.
  • Example 12 Varenicline sulfate form V
  • Varenicline base (1.2 g, 5.7 mmol) was dissolved in methanol (17 mL, 14V) at 25°C with stirring. Sulfuric acid (1.39 g, 12.8 mmol, 20% aq. solution) was added. After ca. 15 minutes precipitation commenced. Stirring was continued for 2.5 hours. The suspension was cooled to 5°C with stirring for 0.5 hours and then the solids were filtered and dried in a vacuum oven (35 mbar) at 40°C for 15 hours to give Varenicline sulfate form V (1.21 g) as a white solid.
  • Varenicline base (0.8 g, 3.8 mmol) was dissolved in glacial acetic acid (2.27 g, 37.9 mmol, 10 eq) at 25°C to give an orange-red solution. Stirring was continued for 20 minutes and then the mixture was evaporated under reduced pressure to give an orange-red oil. The oil was triturated with methyl tert-butyl ether (10 mL) and the resulting mixture was stirred for 3.5 hours at 25°C, leading to precipitation. The precipitate was separated by filtering to give Varenicline acetate form III as a white solid.
  • Varenicline base (0.8 g, 3.8 mmol) was dissolved in glacial acetic acid (4.55 g, 75.7 mmol, 20 eq) at 25°C to give an orange-red solution. Stirring was continued for 25 minutes and then the mixture was azeotroped twice with toluene (2x20 mL). The resulting oil was triturated with n-heptane (20 mL) and stirring was continued for 2.25 hours at 25°C, leading to precipitation. The precipitate was separated by filtering to give Varenicline acetate form III as a white solid.
  • Varenicline base (1.5 g, 7.1 mmol) was dissolved in EtOAc (54 mL, 36V) at 25°C with stirring.
  • acetic acid (1.71 g, 7.1 mmol, 25% solution in EtOAc).
  • Precipitation commenced after ca. 5 minutes.
  • Stirring was continued at room temperature for 2 hours and then the precipitate were filtered, washed with cold EtOAc (7.5 mL) and dried in a vacuum oven (35 mbar) at 40°C for 24 hours to give Varenicline acetate form II (1.34 g, 69%).
  • Example 16 Varenicline sulfate form VI
  • Varenicline base (1.90 g, 8.99 mmol) was dissolved in MeOH (26.6 mL) and then cone, sulfuric acid (0.25 mL, 4.50 mmol, 0.5 mol eq, 96%) was added at room temperature with stirring, leading to immediate precipitation. Stirring was continued at ambient temperature for 3.5 hours, followed by cooling to 5 °C with continued stirring at this temperature for 20 min. The precipitate was separated by filtering to give VRN sulfate form VI (2.53 g) as a white solid.
  • Varenicline hydrobromide form I was placed in 100% relative humidity cell for 72 hours.
  • Figure 17 shows XRD comparison between Varenicline hydrobromide Form
  • Varenicline hydrobromide form II was placed in 100% relative humidity cell for 48 hours.
  • Figure 24 shows XRD comparison between Varenicline hydrobromide Form
  • Varenicline Sulfate form IV was placed in 100% relative humidity cell for 48 hours.
  • Figure 24 shows XRD comparison between Varenicline Sulfate Form IV before applying humidity conditions (lower diffractogram) and after applying humidity conditions (upper diffractogram).

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Abstract

La présente invention concerne des sels et des formes solides de la varénicline, des procédés de préparation desdits sels et formes solides de la varénicline, et des formulations les contenant.
PCT/US2011/035503 2010-05-06 2011-05-06 Sels de la varénicline et leurs formes cristallines WO2011140431A1 (fr)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US33193210P 2010-05-06 2010-05-06
US61/331,932 2010-05-06
US34534110P 2010-05-17 2010-05-17
US61/345,341 2010-05-17
US36060410P 2010-07-01 2010-07-01
US61/360,604 2010-07-01
US36589010P 2010-07-20 2010-07-20
US61/365,890 2010-07-20
US37087710P 2010-08-05 2010-08-05
US61/370,877 2010-08-05
US37513610P 2010-08-19 2010-08-19
US61/375,136 2010-08-19
US38446410P 2010-09-20 2010-09-20
US61/384,464 2010-09-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101781352B1 (ko) * 2016-09-23 2017-10-23 경동제약 주식회사 결정형의 바레니클린 신규염, 이의 제조방법 및 이를 포함하는 약학 조성물

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EP1044189A1 (fr) 1997-12-31 2000-10-18 Pfizer Products Inc. Composes azapolycycliques fusionnes avec un aryle
US6558435B2 (en) 2000-05-26 2003-05-06 Pfizer, Inc. Reactive crystallization method to improve particle size
US6787549B2 (en) 2001-05-14 2004-09-07 Pfizer Inc. Citrate salt of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US6794388B2 (en) 2001-11-29 2004-09-21 Pfizer Inc. Succinic acid salts of 5,7,14-triazatetracyclo[10.3.1.02,11.04,9] -hexadeca-1(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US6890927B2 (en) 2001-05-14 2005-05-10 Pfizer Inc Tartrate salts of 5,8, 14-triazateracyclo[10.3.1.02,11 04.9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
WO2009107476A1 (fr) * 2008-02-27 2009-09-03 久光製薬株式会社 Timbre médicamenteux
WO2009109651A1 (fr) 2008-03-06 2009-09-11 Medichem, S.A. Sels d'un dérivé de pyrazino[2,3-h][3]benzazépine
WO2009143347A2 (fr) 2008-05-22 2009-11-26 Teva Pharmaceutical Industries Ltd. Tosylate de varénicline, un intermédiaire dans le procédé de préparation du l-tartrate de varénicline
WO2010023561A1 (fr) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Procédé de fabrication de varénicline, intermédiaires de la varénicline et leurs sels pharmaceutiquement acceptables
WO2010151524A1 (fr) 2009-06-22 2010-12-29 Teva Pharmaceutical Industries Ltd Formes solides des sels de varénicline et leurs procédés de préparation

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EP1659114A2 (fr) 1997-12-31 2006-05-24 Pfizer Products Inc. Préparation de dérivés de quinazoline condensées avec Bicyclo[3.2.1]octane
US6410550B1 (en) 1997-12-31 2002-06-25 Pfizer Inc Aryl fused azapolycyclic compounds
EP1044189A1 (fr) 1997-12-31 2000-10-18 Pfizer Products Inc. Composes azapolycycliques fusionnes avec un aryle
US6558435B2 (en) 2000-05-26 2003-05-06 Pfizer, Inc. Reactive crystallization method to improve particle size
US6787549B2 (en) 2001-05-14 2004-09-07 Pfizer Inc. Citrate salt of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US6890927B2 (en) 2001-05-14 2005-05-10 Pfizer Inc Tartrate salts of 5,8, 14-triazateracyclo[10.3.1.02,11 04.9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US7265119B2 (en) 2001-05-14 2007-09-04 Pfizer Inc Tartrate salts of 5,8,14-triazatetracyclo[10.3.1.02,11.04.9]-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
US6794388B2 (en) 2001-11-29 2004-09-21 Pfizer Inc. Succinic acid salts of 5,7,14-triazatetracyclo[10.3.1.02,11.04,9] -hexadeca-1(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
WO2009107476A1 (fr) * 2008-02-27 2009-09-03 久光製薬株式会社 Timbre médicamenteux
WO2009109651A1 (fr) 2008-03-06 2009-09-11 Medichem, S.A. Sels d'un dérivé de pyrazino[2,3-h][3]benzazépine
WO2009143347A2 (fr) 2008-05-22 2009-11-26 Teva Pharmaceutical Industries Ltd. Tosylate de varénicline, un intermédiaire dans le procédé de préparation du l-tartrate de varénicline
WO2010023561A1 (fr) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Procédé de fabrication de varénicline, intermédiaires de la varénicline et leurs sels pharmaceutiquement acceptables
WO2010151524A1 (fr) 2009-06-22 2010-12-29 Teva Pharmaceutical Industries Ltd Formes solides des sels de varénicline et leurs procédés de préparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101781352B1 (ko) * 2016-09-23 2017-10-23 경동제약 주식회사 결정형의 바레니클린 신규염, 이의 제조방법 및 이를 포함하는 약학 조성물

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