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WO2018126040A1 - Formes solides cristallines de (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol - Google Patents

Formes solides cristallines de (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol Download PDF

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Publication number
WO2018126040A1
WO2018126040A1 PCT/US2017/068764 US2017068764W WO2018126040A1 WO 2018126040 A1 WO2018126040 A1 WO 2018126040A1 US 2017068764 W US2017068764 W US 2017068764W WO 2018126040 A1 WO2018126040 A1 WO 2018126040A1
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compound
crystalline form
xrpd
set out
methyl
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PCT/US2017/068764
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English (en)
Inventor
Lloyd F. Mackenzie
Jeffery R. Raymond
Curtis Harwig
Ana FERNANDEZ CASARES
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Aquinox Pharmaceuticals (Canada) Inc.
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Publication of WO2018126040A1 publication Critical patent/WO2018126040A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention is generally directed to crystalline forms of (1 S,3S,4f?)-4-
  • compositions comprising the crystalline forms.
  • inositol phosphatase activators represent a complementary, alternative approach to reduce PIP 3 levels.
  • PIP 3i SHIP1 phosphoinositol phosphatases that degrade PIP 3i SHIP1 is a particularly ideal target for development of therapeutics for treating immune and hemopoietic disorders because of its
  • SHIP1 modulators have been described in Ong et ai, Blood (2007), 110(6) 1942-1949, Yang et al., Org. Lett. (2005) 7(6) 1073-1076 and Meimetis et al., Eur. J. Org. Chem. (2012), 27, 5195-5207 and PCT Published Patent Applications Nos.
  • One such small molecule SHIP1 modulator is (1 S,3S,4 )-4-((3aS,4 ,5S,7aS)- 4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1 /-/-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol (referred to herein as Compound A).
  • Compound A has antiinflammatory activity as a SHIP1 modulator and is described in U.S. Patent Nos.
  • Compound A has the molecular formula of C2 0 H 3 5NO2, a molecular weight of 321.5 g/mole and has the follow
  • Compound A is useful in treating disorders and conditions that benefit from SHIP1 modulation, such as cancers, inflammatory disorders and conditions and immune disorders and conditions. Compound A is also useful in the preparation of a medicament for the treatment of such disorders and conditions.
  • the present invention is generally directed to crystalline forms of Compound A, processes for their preparation, pharmaceutical compositions containing them and methods of using the crystalline forms and their compositions.
  • this invention is directed to a first crystalline form of
  • Compound A referred to herein as Compound A Form A.
  • this invention is directed to a second crystalline form of Compound A, referred to herein as Compound A Form B.
  • this invention is directed to compositions comprising a pharmaceutically acceptable excipient, carrier and/or diluent and Compound A Form A.
  • this invention is directed to compositions comprising a pharmaceutically acceptable excipient, carrier and/or diluent and Compound A Form B.
  • this invention is directed to a method for modulating SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form A or an effective amount of a composition comprising Compound A Form A to the mammal in need thereof.
  • this invention is directed to a method for modulating SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form B or an effective amount of a composition comprising Compound A Form B to the mammal in need thereof.
  • this invention is directed to a method for treating a disease, disorder or condition associated with SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form A or an effective amount of a composition comprising Compound A Form A to the mammal in need thereof.
  • this invention is directed to a method for treating a disease, disorder or condition associated with SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form B or an effective amount of a composition comprising Compound A Form B to the mammal in need thereof.
  • this invention is directed to methods for the preparation of Compound A Form A.
  • this invention is directed to methods for the preparation of Compound A Form B.
  • Figure 1 illustrates the X-Ray Powder Diffraction pattern of amorphous
  • Figure 2 illustrates the X-Ray Powder Diffraction pattern
  • Figure 3 illustrates the DSC thermogram of Compound A Form A.
  • Figure 4 illustrates the TGA thermogram of Compound A Form A.
  • FIG. 5 illustrates the TGA/MS analysis of Compound A Form A.
  • Figure 6 illustrates the molecular structure of Compound A Form A, as determined from XRPD analysis.
  • Figure 7 illustrates the crystal packing (along the [100] direction) and the hydrogen bond scheme for Compound A Form A.
  • Figure 8 illustrates the Rietveld (Quantitative Phase) Analysis of Compound A Form A.
  • Figure 8(A) is the experimental HR-XRPD pattern superimposed with calculated HR-XRPD pattern;
  • Figure 8(B) is the difference between the experimental HR-XRPD pattern and the calculated HR-XRPD pattern;
  • Figure 8(C) is the simulated XRPD pattern (based on the crystal model); and
  • Figure 8(D) is the expected Bragg reflections (triangles on baseline).
  • Figure 9 illustrates the X-Ray Powder Diffraction pattern of Compound A
  • Figure 10 illustrates the DSC thermogram of Compound A Form B.
  • FIG. 11 illustrates the TGA thermogram of Compound A Form B.
  • Figure 12 illustrates the TGA/MS analysis of Compound A Form B.
  • the present invention is generally directed to crystalline forms of Compound A, processes for their preparation, pharmaceutical compositions containing them and methods of using the crystalline forms.
  • amorphous forms which can be characterized by only short range ordering. These compounds may be challenging to develop, as the amorphous form is often unstable relative to a crystalline form and may convert under certain conditions to any crystalline form, not necessarily the most stable one.
  • molecules of Compound A in the crystalline form have both short and long range ordering and have different physical properties as compared to the amorphous form.
  • Solid state physical properties of a material affect the ease with which the material is handled during processing into a pharmaceutical product, such as a tablet or capsule formulation.
  • the physical properties affect the types of excipients, for example, to be added to a formulation for a pharmaceutical compound.
  • the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous and liquid milieus, including gastric juices, thereby having therapeutic consequences.
  • the solid state form of a pharmaceutical compound may also affect its storage requirements. From a physicochemical perspective, the crystalline form of a pharmaceutical compound is the preferred form.
  • Organization of the molecules in an ordered fashion to form a crystal lattice provides improved chemical stability, flowability, and other powder properties including reduced moisture sorption. All of these properties are of importance to the manufacturing, formulation, storage and overall manageability of a pharmaceutical drug product.
  • Solid form of a substance.
  • One solid form may give rise to different thermal behavior from that of the amorphous material or other solid forms. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermo-gravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic solid forms from others.
  • TGA thermo-gravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic solid form may also give rise to distinct physical properties that may be detectable by X-ray powder diffraction (XRPD), solid state 3 C-Nuclear Magnetic Resonance spectroscopy, and infrared or Raman spectrometry.
  • XRPD X-ray powder diffraction
  • solid state 3 C-Nuclear Magnetic Resonance spectroscopy solid state 3 C-Nuclear Magnetic Resonance spectroscopy
  • Raman spectrometry infrared or Raman spectrometry
  • Compound A exists in an amorphous form, referred to herein as amorphous Compound A.
  • This invention is therefore directed to stable crystalline forms of Compound A, i.e., Compound A Form A and Compound A Form B, whose properties can be influenced by controlling the conditions under which Compound A is obtained in solid form.
  • the characteristics and properties of Compound A Form A and Compound A Form B are each described detail below.
  • Compound A Form A is provided, characterized by the selection of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or twenty-one X-ray powder diffraction peaks selected from the group consisting of 8.943°, 9.536°, 10.497°, 11.951 °, 13.097°, 13.335°, 14.047°, 16.091 °, 16.654°, 17.940°, 18.135°, 18.496°, 18.960°, 19.724°, 20.143°, 20.461 °, 21.1 17°, 24.320°, 24.695°, 25.572°, and 25.959° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form A is characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 1 :
  • Compound A Form A is characterized by an XRPD substantially according to Figure 2.
  • Compound A Form A is characterized by an XRPD containing at least one of the following peaks: 8.943°, 9.536°, 10.497°, and 11.951 ° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form A is characterized by an XRPD containing at least two of the following peaks: 8.943°, 9.536°, 10.497°, and 11.951 ° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form A is characterized by a DSC thermogram substantially according to Figure 3.
  • Compound A Form A is characterized by a TGA thermogram substantially according to Figure 4.
  • Compound A Form A is characterized by a DSC thermogram with an endothermic event with an onset at 181.3 °C ⁇ 0.3 °C, more preferably ⁇ 0.2 °C, most preferably ⁇ 0.1 °C, and a characterizing endothermic peak at 182.7 °C ⁇ 0.3 °C, more preferably ⁇ 0.2 °C, most preferably ⁇ 0.1 °C. From the analysis of the DSC thermogram, it was concluded that Compound A Form A is anhydrous. Residual chloroform was present (0.9% w/w) in the crystal as shown in the TGA/MS analysis ( Figure 5).
  • Compound A Form A is anhydrous and is stable as indicated by the DSC thermogram in Figure 3, which shows a sharp peak near the melting point.
  • Compound A Form A was stable for 2 days under accelerated aging conditions (Method C).
  • Method C Based on XRPD data, Compound A Form A crystallizes in an orthorhombic crystal system P 2i2i2i space group with four monomers, hydrogen bonded, in the asymmetric unit, as seen in Figure 7. The crystal is held together by a network of intermolecular hydrogen bonds which likely provides the unexpected high stability/melting point of Compound A.
  • Rietveld analysis ( Figure 8) indicates the presence of only one polymorph in the Compund A Form A crystalline material.
  • Compound A Form A is in a substantially pure form, and preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure means the form contains at least about 80 %, 85 %, 90 %, 95 %, 96 %, 97 %, 98 %, or 99 % of the Compound A Form A.
  • substantially free from other amorphous, crystalline and/or polymorphic forms means that no more than about 20 %, 15 %, 10 %, 5 %, 4 %, 3 %, 2 %, 1 % of these other amorphous, crystalline and/or polymorphic forms are present.
  • a method for the preparation of Compound A Form A including the steps of preparing a suspension of amorphous Compound A in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, 1 ,4-dioxane, terf-butyl methyl ether, tetrahydrofuran, acetonitrile, chloroform, cyclohexane, heptane, toluene, p-xylene, cumene, isopropyl acetate, anisole, 1 ,2-dimethoxyethane, and dichloromethane, or mixtures thereof, and crystallizing Compound A Form A by methods known to those skilled in the art, such as, but not limited to, cooling crystallization, crystallization by slurry conversion, evaporative crystallization by anti-solvent addition, vapor diffusion into liquid crystallization, vapor diffusion onto a solid crystallization, and crystall
  • the solvent is selected from the group consisting of water, acetonitrile, chloroform, ethanol, isopropanol, te/f-butyl methyl ether, heptane, isopropyl acetate, and anisole, and mixtures thereof.
  • the solvent is chloroform.
  • a second solvent selected from the group consisting of water, acetonitrile and tetrahydrofuran is used in an amount between 5 % and 95 % (v/v) with an amount of first solvent between 95 % and 5 % (v/v), preferably between 10 % and 35 % (v/v) with an amount of first solvent between 90 % and 65 % (v/v), more preferably between 15 % and 30 % (v/v) with an amount of first solvent between 85 % and 70 % (v/v), and most preferably between 20 % and 25 % (v/v), with an amount of first solvent between 80 % and 75 % (v/v).
  • water, acetonitrile, or tetrahydrofuran is used as a second solvent.
  • the first solvent/second solvent pairs are selected from the group consisting of water/tetrahydrofuran (20:80, v/v), and water/acetonitrile (10:90, v/v) were used.
  • Compound A Form B characterized by the selection of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty X-ray powder diffraction peaks selected from the group consisting of 6.321 °, 9.110°, 12.290°, 12.756°, 13.779°, 14.656°, 17.224°, 18.1 11 °, 19.051 °, 20.321 °, 22.059°, 23.869°, 24.644°, 25.844°, 26.870°, 28.641 °, 31.196°, 33.572°, 35.320°, and 36.896° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form B can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 3:
  • Compound A Form B is characterized by an XRPD substantially according to Figure 9.
  • Compound A Form B is characterized by an XRPD pattern containing at least one of the following peaks: 6.321 °, 9.110°, 12.290°, and 12.756° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form B is characterized by an XRPD containing at least two of the following peaks: 6.321 °, 9.1 10°, 12.290°, and 12.756° 2 ⁇ ⁇ 0.3° 2 ⁇ , more preferably ⁇ 0.2° 2 ⁇ , even more preferably ⁇ 0.1 ° 2 ⁇ , most preferably ⁇ 0.05° 2 ⁇ .
  • Compound A Form B is characterized by a DSC substantially according to Figure 10.
  • Compound A Form B is characterized by a TGA substantially according to Figure 1 1.
  • Compound A Form B of the present invention is characterized by DSC with an endothermic event with an onset at 172.3 °C ⁇ 0.3 °C, more preferably ⁇ 0.2 °C, most preferably ⁇ 0.1 °C and a characterizing endothermic peak at 176.5 °C ⁇ 0.3 °C, more preferably ⁇ 0.2 °C, most preferably ⁇ 0.1 °C. From thermal analysis, it is concluded that solid Compound A Form B is a methanol solvate.
  • Compound A Form B is a methanol solvate as in the TGA/MS Analysis of Figure 12
  • Compound A Form B is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to a form which contains at least about 80 %, 85 %, 90 %, 95 %, 96 %, 97 %, 98 %, or 99 % of Compound A Form B.
  • substantially free from other amorphous, crystalline and/or polymorphic forms means that no more than about 20 % 15 %, 10 %, 5 %, 4 %, 3 %, 2 %, 1 % of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.
  • a method for the preparation of Compound A Form B comprising the steps of preparing a suspension of Compound A in a mixture of solvents selected from the group consisting of methanol and water and crystallizing Compound A Form B by cooling crystallization, crystallization by slurry conversion, evaporative crystallization by anti-solvent addition, vapor diffusion into liquid crystallization, vapor diffusion onto a solid crystallization, or crystallization by wet milling.
  • the solvent is a mixture of water and methanol. In a more preferred embodiment, the solvent is a 9: 1 (v/v) mixture of methanol and water.
  • Compound A Form A and Compound A Form B may be formulated as a pharmaceutical composition in a manner similar to the pharmaceutical compositions disclosed in U.S. Patent Nos. 7,601 ,874 and 7,999,010.
  • Such pharmaceutical compositions comprise Compound A Form A or Compound A Form B and one or more pharmaceutically acceptable carriers, wherein the Compound A Form A or Compound A Form B is present in the composition in an amount that is effective to treat the condition of interest.
  • the pharmaceutical compositions of the present invention include Compound A Form A or Compound A Form B in an amount ranging from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to an effective amount of Compound A Form A or Compound A Form B, diluents, dispersing and surface-active agents, binders, lubricants, and/or delayed releases agents.
  • One skilled in this art may further formulate Compound A Form A or Compound A Form B in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA (current edition, the relevant sections of which are incorporated herein by reference in their entirety). Utility and Methods of Administration
  • Compound A Form B have activity as SHIP1 modulators and therefore may be used to treat any of a variety of diseases, disorders or conditions in a mammal, preferably a human, that would benefit from SHIP1 modulation.
  • diseases, disorders or conditions are disclosed in PCT Published Patent Application Nos. WO 2014/143561 and WO 2014/158654.
  • an embodiment of the invention is a method modulating SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form A or Compound A Form B or an effective amount of a composition comprising Compound A Form A or Compound A Form B to the mammal in need thereof.
  • Another embodiment is a method for treating a disease, disorder or condition associated with SHIP1 activity in a mammal comprising administering an effective amount of Compound A Form A or Compound A Form B or an effective amount of a composition comprising Compound A Form A or Compound A Form B to the mammal in need thereof.
  • Such methods include administering to a mammal, preferably a human, Compound A Form A or Compound A Form B in an amount sufficient to treat the disease, disorder or condition.
  • “treat” includes prophylactic
  • systemic administration includes oral and parenteral methods of administration.
  • suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other
  • the crystalline forms of Compound A of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
  • Representative crystalline forms of Compound A of the invention were prepared according to Methods A to C, as described below and subsequently analyzed. Representative crystalline forms of Compound A were aged by Method C and subsequently analyzed. It will be appreciated that in the following general methods, solvents used, relative amounts of solvents, and other parameters such as cooling rates, temperatures, times, etc. can be altered to suit needs, up or down by up to 50 % without significant change in expected results.
  • the concentration of the Compound A in solution was determined by HPLC-DAD analysis using a calibration curve made from two independent stock solutions of the Compound A prepared in 0.1 % TFA in water/acetonitrile (50:50).
  • Samples collected from the crystallization conditions were subjected, as is, to accelerated aging conditions of 40 °C and 75 % relative humidity for 48 hours, via standard methods known to one skilled in the art and analyzed by XRPD.
  • Amorphous Compound A was prepared by freeze-drying a THF/water (80:20, v/v) solution of Compound A. Amorphous Compound A material was further used, as is, in crystallization experiments.
  • Amorphous Compound A (20 mg) was suspended in a chloroform (100 ⁇ ) in a 1.8 mL HPLC vial. The mixture was kept at room temperature, with stirring (magnetic stirring bar), for about two weeks under ambient conditions. Solids were then separated from the liquid by centrifugation and some of the solids were harvested from the vials and placed in a 96-well plate for wet analysis. The remaining solid was dried in the vial under vacuum (at room temperature and 200 mbar) and analyzed by XRPD, DSC and TGA as well as subjected to aging studies (Method C).
  • Compound A Form B was generated through a modified Method A procedure.
  • Amorphous Compound A (37.5 mg) was suspended in methanol/water (200 ⁇ _,
  • Dry solid sample from Example 2 was transferred into a boron-glass capillary with 0.3 mm outer diameter, 8 mm length.
  • the capillary was mounted on the goniometer head and placed in the D8 Advance Bruker-AXS Diffractometer equipped with solid state LynxEye detector. The capillary was spinning during data recording, at 15 rpm.
  • the XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings.
  • Data collection for Compound A Form A was carried out, in transmission mode, at ambient conditions (-23 °C and -100 kPa) using CuK ⁇ radiation (1.54056 A), monochromatized by germanium crystal, in the 2 ⁇ region between 4° and 45° 2 ⁇ , with an exposure time of 90 s for each frame and 0.016° 2 ⁇ increments. No additional corrections were made during data collection.
  • Peak selection was performed using DIFFRAC p,us EVA software package
  • Peak width The algorithm uses 5 to 57 data points centered on the point of interest, and a peak is selected from the second derivate if the peak width lays within the range FWHM ⁇ Peak width ⁇ 4 x FWHM. Peak widths for 1 Form A and 1 Form B were 0.2 and 0.3°, respectively.
  • Threshold Based on the comparison of the computed maximum of the peak with the middle of the chord joining 2 inflection points of both sides of maximum. According to Equation 1 , a peak was accepted if l P was greater than the intensity at chord center (l M ) plus a factor comprising a threshold value of
  • Form A is indicative of diffractograms generated from material for Compound A Form A performed by alternative crystallization methods.
  • the diffractogram presented in Figure 1 was recorded on D8 Discover Bruker- AXS diffractometer using Cu K a radiation (1.54178 A) equipped with 2D GADDS detector in transmission mode.
  • the sample of amorphous Compound A was placed in the flat transmission sandwich-like 4.5 mm diameter sample holder protected by X-Ray transparent mylar foil.
  • Data collection was carried out in two frames 1.5 ⁇ 2 ⁇ ⁇ 21.5° and 19.5 ⁇ 2 ⁇ ⁇ 41.5° and separately integrated with step size 0.04°.
  • the final powder pattern was obtained by merging both frames using area between 19.5 ⁇ 2 ⁇ ⁇ 21.5° as common share. Peaks were analyzed as described above.
  • Example 3 High Throughput X-Ray Diffraction Spectrometry Experimental Conditions A sample from Example 3, was transferred to a T2 high-throughput XRPD setup. Plates were mounted on a Bruker GADDS diffractometer equipped with a Hi- Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d spacings.
  • Data collection for Compound A Form B was carried out, in transmission mode, at ambient conditions (-23 °C and -100 kPa) using monochromatic CuK a i radiation (1.54056 A) in two 2 ⁇ ranges (1.5 ⁇ 2 ⁇ ⁇ 21.5° and 19.5 ⁇ 2 ⁇ ⁇ 41.5°) with an exposure time of 90 s for each frame. No additional corrections were made during data collection.
  • the XRPD diffractogram from Example 5 is shown in Figure 9 for Compound A Form B, and is indicative of diffractograms generated from material for Compound A Form B performed by alternative crystallization methods.
  • Quantitative Phase Analysis (sometimes called also Standardless Phase Analysis, Multiphase Rietveld Phase Quantification, Rietveld Quantitative Analysis or Rietveld XRD Quantification) is a powerful method for determining the quantities of different polymorphs in multiphase mixtures.
  • the method relies on the simple relationship: where W is the relative weight fraction of phase p in a mixture of n phases, and S, Z, M, and V are, respectively, the Rietveld scale factor, the number of formula units per cell, the mass of the formula unit (in atomic mass units) and the unit cell volume (in A 3 ).
  • phase analysis allows for the determination of the weight (or volume) and quantity of crystalline and amorphous phases which are present in the sample.
  • TGA/MS Analysis Mass loss due to solvent or water loss from the crystals, from Examples 2 and 3, was determined by TGA/SDTA analysis. Monitoring of the sample weight, during heating in a TGA/SDTA851 e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve for each sample.
  • the TGA/SDTA curves for Compound A Form A and Compound A Form B are in Figures 4 and 1 1 , respectively and are indicative of TGA/SDTA data generated from material for Compound A Form A and Compound A Form B performed by alternative crystallization methods.
  • the TGA/SDTA851e was calibrated for temperature with indium and aluminum. Samples, from Examples 2 and 3, were weighed into 100 ⁇ _ aluminum crucibles and sealed.
  • TGA/MS data for Compound A Form A is in Figure 5 and Compound A Form B is in Figure 12 and are indicative of TGA/MS data generated from material for Compound A Form A and Compound A form B, respectively, performed by alternative crystallization methods.

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Abstract

La présente invention concerne de manière générale des formes cristallines de (1 S, 3 S , 4 R)-4-((3a S, 4 R , 5 S, 7a S)-4-(aminométhyl ) -7 a-méthyl-1-méthylèneoctahydro -1 H-inden-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol et des procédés pour leur préparation.
PCT/US2017/068764 2016-12-28 2017-12-28 Formes solides cristallines de (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol WO2018126040A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
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