WO2012125993A1 - Formes à l'état solide de base rilpivirine et sels de rilpivirine - Google Patents

Formes à l'état solide de base rilpivirine et sels de rilpivirine Download PDF

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Publication number
WO2012125993A1
WO2012125993A1 PCT/US2012/029619 US2012029619W WO2012125993A1 WO 2012125993 A1 WO2012125993 A1 WO 2012125993A1 US 2012029619 W US2012029619 W US 2012029619W WO 2012125993 A1 WO2012125993 A1 WO 2012125993A1
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Prior art keywords
rilpivirine
xrd pattern
powder xrd
peaks
solid
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PCT/US2012/029619
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English (en)
Inventor
Jacob Rendell
Ariel Mittelman
Motti Erlich
Marina Ratkaj
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2012125993A1 publication Critical patent/WO2012125993A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention relates to solid state forms of Rilpivirine base, salts of Rilpivirine, solid state forms of Rilpivirine salts, processes for preparing the solid state forms, and pharmaceutical compositions thereof.
  • Rilpivirine, (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2- ylamino)benzonitrile has the following chemical structure:
  • Rilpivirine is reported to be a non-nucleoside reverse transcriptase inhibitor, for the treatment of HIV infection, developed by Tibotec.
  • Different salts of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts may provide a basis for improving formulation, for example, by facilitating better processing or handling
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis - "TGA” or differential scanning calorimetry - “DSC”), powder X-ray diffraction (XRD or PXRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • XRD powder X-ray diffraction
  • infrared absorption fingerprint and solid state NMR spectrum.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
  • the present invention provides new solid state forms of Rilpivirine base. These solid state forms can be used to prepare Rilpivirine salts, and formulations thereof.
  • the present invention provides new salts of Rilpivirine; solid state forms of the salts; and formulations comprising one or more of these solid state forms.
  • the solid state forms of the present invention can be used to prepare Rilpivirine base, other solid state forms of the same salt or other different salts of Rilpivirine, and formulations thereof.
  • the present invention provides new solid state forms of Rilpivirine hydrochloride.
  • the solid state forms of the present invention can be used to prepare Rilpivirine base, other different solid state forms of Rilpivirine hydrochloride or other different salts, and formulations thereof.
  • the invention further provides the use of the Rilpivirine base or salts, and the solid state forms described below for the manufacture of a medicament for the treatment of HIV infection, and provides for a method of treatment of HIV infection comprising administering a therapeutically effective dose of one or more of the solid state forms described herein to a person suffering from an HIV infection.
  • Figure 1 provides a powder XRD pattern of crystalline Form E of Rilpivirine HC1.
  • Figure 2 provides a powder XRD pattern of crystalline Form H of Rilpivirine HC1.
  • Figure 3 provides a powder XRD pattern of crystalline Form J of Rilpivirine HC1.
  • Figure 4 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine sulfate.
  • Figure 5 provides a powder XRD pattern of crystalline Form 3 of Rilpivirine phosphate.
  • Figure 6 provides a powder XRD pattern of crystalline Form Zl of Rilpivirine hydrochloride.
  • Figure 7 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine phosphate.
  • Figure 8 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine HBr.
  • Figure 9 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine p- toluensulfonate.
  • Figure 10 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine methanesulfonate .
  • Figure 11 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine maleate.
  • Figure 12 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine succinate.
  • Figure 13 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine L- malate.
  • Figure 14 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine methanesulfonate .
  • Figure 15 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine benzenesulfonate.
  • Figure 16 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine ethanesulfonate.
  • Figure 17 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine sulfate.
  • Figure 18 provides a powder XRD pattern of polymorphically pure crystalline Form 3 of Rilpivirine phosphate.
  • Figure 19 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine succinate.
  • Figure 20 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine maleate.
  • Figure 21 provides a powder XRD pattern of crystalline Form 2 of Rilpivirine HBr.
  • Figure 22 provides a powder XRD pattern of crystalline Form 1 of Rilpivirine malonate.
  • Figure 23 provides a powder XRD pattern of amorphous Rilpivirine L-tartrate.
  • Figure 24 provides a powder XRD pattern of amorphous Rilpivirine citrate.
  • Figure 25 provides a powder XRD pattern of crystalline Form IV of Rilpivirine acetate.
  • Figure 26 provides a powder XRD pattern of crystalline Form V of Rilpivirine base.
  • Figure 27 provides a powder XRD pattern of crystalline Form 3 of Rilpivirine maleate.
  • Figure 28 provides a powder XRD pattern of crystalline Form 3 of Rilpivirine succinate.
  • Figure 29 provides a powder XRD pattern of crystalline Form Z2 of Rilpivirine hydrochloride.
  • Figure 30 provides a powder XRD pattern of crystalline Form 3 of Rilpivirine sulfate.
  • Figure 31 provides a solid state 13 C NMR spectrum of Rilpivirine HC1 Form Zl the 0-180 ppm range.
  • Figure 32 provides a solid state 13 C NMR spectrum of Rilpivirine HC1 Form Zl the 90-180 ppm range.
  • Figure 33 provides a solid state C NMR spectrum of Rilpivirine HC1 Form Z2 in the 0-180 ppm range.
  • Figure 34 provides a solid state 13 C NMR spectrum of Rilpivirine HC1 Form Z2 in the 90-180 ppm range.
  • Figure 35 provides a solid state 1 C NMR spectrum of Rilpivirine HC1 Form E in the 0-180 ppm range.
  • Figure 36 provides a solid state 13 C NMR spectrum of Rilpivirine HC1 Form E in the 90-180 ppm range.
  • Figure 37 provides a solid state 13 C NMR spectrum of Rilpivirine acetate Form IV in the 0-180 ppm range.
  • Figure 38 provides a solid state 13 C NMR spectrum of Rilpivirine acetate Form IV in the 90-180 ppm range.
  • Figure 39 provides a solid state 1 C NMR spectrum of Rilpivirine maleate Form 1 in the 0-180 ppm range.
  • Figure 40 provides a solid state 13 C NMR spectrum of Rilpivirine maleate Form 1 in the 90-180 ppm range.
  • Figure 41 provides a solid state 13 C NMR spectrum of Rilpivirine phosphate Form 3 in the 0-180 ppm range.
  • Figure 42 provides a solid state 13 C NMR spectrum of Rilpivirine phosphate Form 3 in the 90-180 ppm range.
  • Figure 43 provides a solid state 1 C NMR spectrum of Rilpivirine succinate Form 1 in the 0-190 ppm range.
  • Figure 44 provides a solid state 13 C NMR spectrum of Rilpivirine succinate Form 1 in the 90-190 ppm range.
  • Figure 45 provides a solid state 13 C NMR spectrum of Rilpivirine succinate Form 3 in the 0-190 ppm range.
  • Figure 46 provides a solid state C NMR spectrum of Rilpivirine succinate Form 3 in the 90-190 ppm range.
  • Figure 47 provides a powder XRD pattern of crystalline Form 4 of Rilpivirine phosphate.
  • Figure 48 provides a powder XRD pattern of crystalline Form 5 of Rilpivirine phosphate.
  • Figure 49 provides a powder XRD pattern of crystalline Form 4 of Rilpivirine sulfate.
  • Figure 50 provides a powder XRD pattern of crystalline Form 5 of Rilpivirine sulfate.
  • Figure 51 provides a powder XRD pattern of crystalline Form 4 of Rilpivirine maleate.
  • Figure 52 provides a solid state 13 C NMR spectrum of Rilpivirine maleate Form 3 in the 0-180 ppm range.
  • Figure 53 provides a solid state 13 C NMR spectrum of Rilpivirine maleate Form 3 in the 90-180 ppm range.
  • Figure 54 provides a microscope picture of Rilpivirine HC1 Form Z2.
  • Figure 55 provides a microscope picture of Rilpivirine succinate Form 1.
  • Figure 56 provides a microscope picture of Rilpivirine maleate Form 3.
  • Figure 57 provides a microscope picture of Rilpivirine sulfate Form 3.
  • Figure 58 provides a DSC endotherm of Rilpivirine phosphate Form 3.
  • Figure 59 provides a DSC endotherm of Rilpivirine HBr Form 2. DETAILED DESCRIPTION OF THE INVENTION
  • the present application relates to new Rilpivirine salts, their polymorphic forms, and formulations thereof.
  • the salts and solid state forms of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, morphology or crystal habit, bulk/tap density, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • the salts and solid state forms of the present invention exhibit relatively high solubility and small particle size.
  • solubility can be enhanced by reducing the particle size, for example, by milling.
  • the mechanical stress may lead to decrease in the degree of crystallinity that can lead to lower chemical stability.
  • obtaining crystals with low particle size directly from crystallization without milling, as shown in the present invention is advantageous for drug substances.
  • the polymorphs of the present invention possess narrow particle size dispersion, a non-needle shape crystal habit, and an improved bulk/tap density. All these features increase the ease of handling and processing.
  • the salts and solid state forms of the present invention can be also used as intermediates when purifying Rilpivirine HC1, or other salts of Rilpivirine, for example, by removing impurities such as Z-Rilpivirine or impurities originating from ADPA ((E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride).
  • ADPA (E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride).
  • a crystal form may be referred to herein as substantially free of any other solid forms.
  • the expression “substantially free” will be understood to mean that the crystalline form contains 20% or less, 10%> or less, 5% or less, 2% or less, or 1% or less of any other solid form of the subject compound as measured, for example, by powder X-ray diffraction (PXRD).
  • polymorphs of the Rilpivirine salts described herein as substantially free of any other solid forms would be understood to contain greater than 80%> (w/w), greater than 90%> (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject form of the Rilpivirine salt. Accordingly, in some embodiments of the invention, the described polymorphs of the Rilpivirine salt may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10%> (w/w) of one or more other solid forms of Rilpivirine salts.
  • a solid state 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 NMR spectra.
  • 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 factors are well known to the skilled person.
  • a solid state form may be referred to herein as being characterized by data selected from two or more different data groupings, for example, by a powder XRD pattern having a group of specific peaks; or by a powder XRD pattern as shown in a figure depicting a diffractogram, or by "a combination thereof (or “combinations thereof,” or "any
  • any combination thereof contemplate that the skilled person may characterize a crystal form using a combination of characteristic analytical data.
  • the skilled person may characterize a crystal form using a group of four or five characteristic powder XRD peaks, and supplement that characterization with an additional feature observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity, or even the absence of a peak at some position in the powder XRD pattern.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • the solvent is water, the solvate is often referred to as a "hydrate.”
  • the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
  • chemical shift difference refers to the difference in chemical shifts between a reference signal and another signal in the same NMR spectrum.
  • the reference signal in the solid state 13 C NMR spectrum in the range of 100 to 190 ppm from chemical shift value of another signal (referred to as the observed signal) in the same 13 CNMR spectrum in the range of 100 to 190 ppm.
  • the solid state forms of the present invention can be dried. Drying may be carried out, for example, at elevated temperature under reduced pressure.
  • the crystalline form can be dried, for example, at a temperature from about 40°C to about 80°C, or about 40°C to about 50°C, for example, about 40°C.
  • the drying can be carried out under reduced pressure (i.e., less than 1 atmosphere, for example, about 10 mbar to about 100 mbar, or about 10 mbar to about 25 mbar).
  • the drying can be carried out over a suitable period, for example, of about 8 hours to about 36 hours, or about 10 hours to about 24 hours, for example, about 16 hours. Drying can be carried out overnight.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
  • the expression “room temperature” may be used interchangeably herein with the expression “ambient temperature.” Typically, room temperature is from about 15°C to about 30°C, or about 20°C to about 25°C, or about 25°C.
  • Rilpivirine HC1 Form A refers to crystalline Rilpivirine HC1 as characterized and prepared in US publication US2011/0008434.
  • the present invention provides a Rilpivirine hydrochloride trifluoroethanol solvate.
  • the present invention provides a crystalline Rilpivirine HC1, designated Form E.
  • Form E can be characterized by data selected from: a powder XRD pattern with peaks at 8.2°, 14.6°, 15.2°, 17.8°, and 24.2° ⁇ 0.3° 2 ⁇ ; a powder XRD pattern as shown in Figure 1; a solid-state 13 C NMR spectrum with signals at 133.2, 137.0 and 151.3 ⁇ 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 90 to 180 ppm of 35.7, 39.5 and 53.8 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 35 or 36; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at about 97.5 ⁇ 1 ppm.
  • Form E can be characterized by a powder XRD pattern having peaks at 8.2°, 14.6°, 15.2°, 17.8°, and 24.2° ⁇ 0.3° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 8.9°, 16.6°, 18.9°, 21.2°, and 22.8° 2 ⁇ ⁇ 0.3° 2 ⁇ .
  • the present invention provides a Rilpivirine hydrochloride benzyl alcohol solvate.
  • the present invention provides a crystalline Rilpivirine HC1, designated Form H.
  • Form H can be characterized by a powder XRD pattern with peaks at 12.9°, 15.3°, 19.7°, 24.6°, and 28.8° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 2; or by combinations thereof.
  • Form H can be characterized by a powder XRD pattern having peaks at 12.9°, 15.3°, 19.7°, 24.6°, and 28.8° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four or five peaks selected from 9.8°, 14.7°, 18.9°, 20.9°, and 27.3° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the Form H can be a benzyl alcohol solvate.
  • the present invention provides a form of Rilpivirine HC1, designated Form J.
  • Form J can be characterized by a powder XRD pattern with peaks at 12.9°, 20.3°, 22. ⁇ , and 28.6° ⁇ 0.3° 2 ⁇ ; or by a powder XRD pattern as shown in figure 3; or by combinations thereof.
  • Form J can be characterized by a powder XRD pattern having peaks at 12.9°, 20.3°, 22.1°, and 28.6° ⁇ 0.3° 2 ⁇ and also having any one, or two peaks selected from 18.6° and 24.8° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides a Rilpivirine hydrochloride THF solvate.
  • Form Zl a crystalline Rilpivirine hydrochloride THF solvate, designated Form Zl .
  • Form Zl can be characterized by data selected from: a powder XRD pattern with peaks at 8.2°, 8.8°, 16.3°, 17.5°, and 23.7° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 6; a solid-state 13 C NMR spectrum with signals at 118.1, 133.6 and 137.1 ⁇ 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 90 to 180 ppm of 19.7, 35.2 and 38.7 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 31 or 32; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 98.4 ⁇ 1 ppm.
  • Form Zl can be characterized by a powder XRD pattern having peaks at 8.2°, 8.8°, 16.3°, 17.5°, and 23.7° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 14.5°, 18.4°, 18.9°, 21.2°, and 25.2° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • Form Zl can be characterized by a powder XRD pattern having peaks at 8.2°, 8.8°, 16.3°, 17.5°, and 23.7° ⁇ 0.3° 2 ⁇ .
  • Form Zl characterized by powder XRD peaks at 8.2°, 8.8°, 16.3°, 17.5°, and 23.7° ⁇ 0.3° 2 ⁇ can be further characterized by one or more additional powder XRD peaks at 14.5°, 18.4°, 18.9°, 21.2°, and 25.2° 2 ⁇ ⁇ 0.3° 2 ⁇ .
  • the present invention provides a Rilpivirine hydrochloride acetone solvate.
  • the present invention provides a crystalline Rilpivirine hydrochloride acetone solvate, designated Form Z2.
  • Form Z2 can be characterized by data selected from: a powder XRD pattern with peaks at 8.3°, 16.4°, 17.7°, 19.0° and 23.9° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 29; a solid-state 13 C NMR spectrum with signals at 133.5, 137.1 and 151.2 ⁇ 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 90 to 180 ppm of 35.5, 39.1 and 53.2 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 33 or 34; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 98.0 ⁇ 1 ppm.
  • Form Z2 can be characterized by a powder XRD pattern having peaks at 8.3°, 16.4°, 17.7°, 19.0° and 23.9° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 19.9°, 21.3°, 21.6°, 22.0°, and 22.7° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine sulfate.
  • Form 1 provides a crystalline Rilpivirine sulfate, designated Form 1.
  • Form 1 can be characterized by a powder XRD pattern with peaks at 5.0°, 12.0°, 18. ⁇ , 19.1°, and 21.4° ⁇ 0.2° 2 ⁇ ; by a powder XRD pattern as shown in figure 4; or by combinations thereof.
  • Form 1 can be characterized by a powder XRD pattern having peaks at 5.0°, 12.0°, 18. ⁇ , 19.1°, and 21.4° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 14.6°, 15.0°, 22. ⁇ , 27.3°, and 32.0° 2 ⁇ ⁇ 0.2°2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine sulfate, designated Form 2.
  • Rilpivirine sulfate Form 2 can be characterized by a powder XRD pattern with peaks at 11.8°, 15.6°, 19.6°, 21.3°, and 31.7° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 17; or by combinations thereof.
  • Rilpivirine sulfate Form 2 can be characterized by a powder XRD pattern having peaks at 11.8°, 15.6°, 19.6°, 21.3°, and 31.7° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four or five peaks selected from 6.0°, 16.8°, 23.3°, 25.2°, and 27.3° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine sulfate, desig
  • Rilpivirine sulfate Form 3 can be characterized by a powder XRD pattern with peaks at 6.4°, 14.6°, 17.6°, 18.5°, and 32.2° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 30; or by combinations thereof.
  • Rilpivirine sulfate Form 3 can be characterized by a powder XRD pattern having peaks at 6.4°, 14.6°, 17.6°, 18.5°, and 32.2° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four or five peaks selected from 6.1°, 16.8°, 21.9°, 23.3°, and 27.4° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine sulfate, designated Form 4.
  • Rilpivirine sulfate Form 4 can be characterized by a powder XRD pattern with peaks at 8.5°, 9.0°, 11.9°, 12.3°, and 14.5° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 49; or by combinations thereof.
  • Rilpivirine sulfate Form 4 can be characterized by a powder XRD pattern having peaks at 8.5°, 9.0°, 11.9°, 12.3°, and 14.5° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four or five peaks selected from 15.5°, 19.0°, 19.3°, 20. F, and 24.7° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine sulfate, designated Form 5.
  • Rilpivirine sulfate Form 5 can be characterized by a powder XRD pattern with peaks at 5.9°, 10.5°, 12.6°, 15.6°, and 16.8° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 50; or by combinations thereof.
  • Rilpivirine sulfate Form 5 can be characterized by a powder XRD pattern having peaks at 5.9°, 10.5°, 12.6°, 15.6°, and 16.8° ⁇ 0.2° 2 ⁇ and also having any one, two, three, or four peaks selected from 17.5°, 18.9°, 23.5°, and 29.9° ⁇ 0.2°2 ⁇ .
  • the present invention provides Rilpivirine phosphate.
  • the present invention provides a crystalline Rilpivirine phosphate, designated Form 3.
  • This form can be anhydrous.
  • this form was found to be polymorphically stable, as exemplified in the Examples below. In particular, this form is stable under heating, and under mechanical stress.
  • Rilpivirine phosphate Form 3 can be characterized by data selected from: a powder XRD pattern with peaks at 5.3°, 11.8°, 16. ⁇ , 21.0°, and 29.0° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern with peaks at 5.3°, 11.8°, 16.1°, 20.2°, and 22.3° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 5 or 18; a solid-state 13 C NMR spectrum with signals at 132.6, 136.7 and 139.6 ⁇ 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 90 to 180 ppm of 35.4, 39.5 and 42.4 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 41 or 42; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 97.2
  • Rilpivirine phosphate Form 3 can be characterized by a powder XRD pattern having peaks at 5.3°, 11.8°, 16. ⁇ , 21.0°, and 29.0° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 10.4°, 13.0°, 14.3°, 18.7°, and 19.8° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • Rilpivirine phosphate Form 3 can be characterized by a powder XRD pattern having peaks at 5.3°, 11.8°, 16. ⁇ , 20.2°, and 22.3° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four or five peaks selected from 11.8°, 10.3°, 14.3°, 21.0°, and 23.9° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • Rilpivirine phosphate Form 3 can be polymorphically pure, i.e., Rilpivirine phosphate Form 3 can be substantially free of any other polymorphic form.
  • Rilpivirine phosphate Form 3 can be substantially free of Rilpivirine phosphate Form 2, characterized hereinafter.
  • the present invention also provides a crystalline Rilpivirine phosphate, designated Form 2.
  • Rilpivirine phosphate Form 2 can be characterized by a powder XRD pattern with peaks at 4.9°, 10.8°, 14.1°, 16.6°, and 18.7° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 7; or by combinations thereof.
  • Rilpivirine phosphate Form 2 can be characterized by a powder XRD pattern having peaks at 4.9°, 10.8°, 14.1°, 16.6°, and 18.7° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 12.6°, 15.8°, 19.8°, 22.9°, and 23.4° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine phosphate, designated Form 4.
  • Rilpivirine phosphate Form 4 can be characterized by a powder XRD pattern with peaks at 4.5°, 5.7°, 8.9°, 11.5°, and 15.1° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 47; or by combinations thereof.
  • Rilpivirine phosphate Form 4 can be characterized by a powder XRD pattern having peaks at 4.5°, 5.7°, 8.9°, 11.5°, and 15.1° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 16.5°, 16.8°, 17.3°, 19.7°, and 21.5° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine phosphate, designated Form 5.
  • Rilpivirine phosphate Form 5 can be characterized by a powder XRD pattern with peaks at 5.8°, 11.6°, 16.6°, 16.9°, and 17.4° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 48; or by combinations thereof.
  • Rilpivirine phosphate Form 5 can be characterized by a powder XRD pattern having peaks at 5.8°, 11.6°, 16.6°, 16.9°, and 17.4° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 19.7°, 21.6°, 24.2°, 26.7°, and 31.0° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine HBr.
  • the present invention provides a crystalline Rilpivirine HBr, designated Form 1.
  • this form was found to be polymorphically stable, as exemplified in Example 41.
  • Rilpivirine HBr Form 1 can be characterized by a powder XRD pattern with peaks at 8.7°, 14.4°, 15.6°, 17.5°, and 23.8° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 8; or by combinations thereof.
  • Rilpivirine HBr Form 1 can be characterized by a powder XRD pattern having peaks at 8.7°, 14.4°, 15.6°, 17.5°, and 23.8° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 14.0°, 16.3°, 19.4°, 22.5°, and 24.6° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides a crystalline Rilpivirine HBr, designated Form 2.
  • Rilpivirine HBr Form 2 can be characterized by a powder XRD pattern with peaks at 10.7°, 14.2°, 21.8°, 23.8°, and 25.0° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 21; or by combinations thereof.
  • Rilpivirine HBr Form 2 can be characterized by a powder XRD pattern having peaks at 10.7°, 14.2°, 21.8°, 23.8°, and 25.0° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 9.8°, 14.8°, 19.2°, 20.8°, and 25.4° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine
  • the present invention provides a crystalline Rilpivirine
  • Rilpivirine p-toluenesulfonate Form 1 can be characterized by a powder XRD pattern with peaks at 9.4°, 18.6°, 19.7°, 21.3°, and 21.9° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 9; or by combinations thereof.
  • Rilpivirine p-toluenesulfonate Form 1 can be characterized by a powder XRD pattern having peaks at 9.4°, 18.6°, 19.7°, 21.3°, and 21.9° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 23.2°, 24.2°, 28.0°, 28.6°, and 37.6° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention provides Rilpivirine mesylate (methanesulfonate) .
  • the present invention provides a crystalline Rilpivirine mesylate, designated Form 1.
  • Rilpivirine mesylate Form 1 can be characterized by a powder XRD pattern with peaks at 10.5°, 11.2°, 11.9°, 15.4°, and 16.4° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 10; or by combinations thereof.
  • Rilpivirine mesylate Form 1 can be characterized by a powder XRD pattern having peaks at 10.5°, 11.2°, 11.9°, 15.4°, and 16.4° ⁇ 0.2° 2 ⁇ and also having any one, two, three, four, or five peaks selected from 17.4° ⁇ 0.2° 2 ⁇ , 20.7° ⁇ 0.2° 2 ⁇ , 24.8° ⁇ 0.3° 2 ⁇ , 24.1° ⁇ 0.2° 2 ⁇ , and 27.5° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine mesylate, designated Form 2.
  • Rilpivirine methanesulfonate Form 2 can be characterized by a powder XRD pattern with peaks at 6.2°, 10.0°, 12. F, 16.4°, and 19.8° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 14; or by combinations thereof.
  • Rilpivirine mesylate Form 2 can be characterized by a powder XRD pattern having peaks at 6.2°, 10.0°, 12. ⁇ , 16.4°, and 19.8° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, or four peaks selected from 20.4° ⁇ 0.2° 2 ⁇ , 20.9° ⁇ 0.2° 2 ⁇ , 21.8° ⁇ 0.3° 2 ⁇ , and 24.9° 2 ⁇ ⁇ 0.3° 2 ⁇ .
  • the present invention provides Rilpivirine maleate.
  • the Rilpivirine maleate can be a tetrahydrofuran solvate.
  • Rilpivirine maleate Form 1 provides a crystalline Rilpivirine maleate, designated Form 1.
  • Rilpivirine maleate Form 1 can be characterized by data selected from: a powder XRD pattern with peaks at 8.7°, 11.8°, 20.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 97.1 ⁇ 1 ppm.
  • Rilpivirine maleate Form 1 can be characterized by a powder XRD pattern having peaks at 8.7°, 11.8°, 20.1°, 21.2°, and 23.4° 2 ⁇ ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 16.8°, 17.0°, 18.3°, 19.1°, and 24.8° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the Rilpivirine maleate Form 1 can be a tetrahydrofuran solvate.
  • the present invention also provides a crystalline Rilpivirine maleate, designated Form 2.
  • Rilpivirine maleate Form 2 can be characterized by a powder XRD pattern with peaks at 6.4°, 13.6°, 17.0°, 18.9°, and 24.1° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 20; or by combinations thereof.
  • Rilpivirine maleate Form 2 can be characterized by a powder XRD pattern having peaks at 6.4°, 13.6°, 17.0°, 18.9°, and 24. ⁇ ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 7.6°, 12.5°, 15.5°, 20.4° and 21.9° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine maleate, designated Form 3.
  • Form 3 a crystalline Rilpivirine maleate
  • Rilpivirine maleate Form 3 can be characterized by data selected from: a powder XRD pattern with peaks at 6.3°, 9.2°, 11.9°, 15.2°, and 22. F ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 27; solid-state 13 C NMR spectrum with signals at about 104.3, 129.0 and 167.2 ⁇ 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 90 to 180 ppm, of about 7.7, 32.4 and 70.6 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum is depicted in Figures 52 and 53; and by combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at about 96.6 ⁇ 1 ppm.
  • Rilpivirine maleate Form 3 can be characterized by a powder XRD pattern having peaks at 12.9°, 15.3°, 19.7°, 24.6°, and 28.8° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 11.1°, 12.5°, 24.6°, 27.2°, and 27.8° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine maleate, designated Form 4.
  • Rilpivirine maleate Form 4 can be characterized by a powder XRD pattern with peaks at 8.5°, 10.5°, 16.0°, 18. ⁇ , and 27.0° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 51 ; or by combinations thereof.
  • Rilpivirine maleate Form 4 can be characterized by a powder XRD pattern having peaks at 8.5°, 10.5°, 16.0°, 18.1°, and 27.0° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 6.2°, 12.4°, 15.0°, 15.3°, and 22.5° ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine succinate.
  • the Rilpivirine succinate can be a THF solvate.
  • the present invention provides a crystalline Rilpivirine succinate, designated Form 1.
  • this form was found to be polymorphically stable, as exemplified in Example 43.
  • Rilpivirine succinate Form 1 can be characterized by data selected from: a powder XRD pattern with peaks at 5.3°, 9.3°, 14.3°, 18.5°, and 18.7° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 12; a solid-state 13 C NMR spectrum with signals at 130.7, 133.7 and 136.8 ⁇ 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 90 to 180 ppm of 38.9, 41.9 and 45.0 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 43 or 44; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 91.8 ⁇ 1 ppm.
  • Rilpivirine succinate Form 1 can be characterized by a powder XRD pattern having peaks at 5.3°, 9.3°, 14.3°, 18.5°, and 18.7° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 10.6°, 12.7°, 19.7°, 22.8°, and 23.0° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the Rilpivirine succinate Form 1 can be a tetrahydrofuran solvate.
  • the present invention also provides a crystalline Rilpivirine succinate, designated Form 2.
  • Rilpivirine succinate Form 2 can be characterized by a powder XRD pattern with peaks at 14.2°, 21.0°, 23. F, 23.6°, and 25.2° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 19; or by combinations thereof.
  • Rilpivirine succinate Form 2 can be characterized by a powder XRD pattern having peaks at 14.2°, 21.0°, 23.1°, 23.6°, and 25.2° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 6.6°, 22.8°, 29.1°, and 35.8° ⁇ 0.2° 2 ⁇ .
  • the present invention also provides a crystalline Rilpivirine succinate, designated Form 3.
  • Rilpivirine succinate Form 3 can be characterized by data selected from: a powder XRD pattern with peaks at 5.3°, 5.6°, 10.6°, 12.6°, and 23.1° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 28; a solid-state 13 C NMR spectrum with signals at 131.2, 134.1 and 162.4 ⁇ 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 90 to 180 ppm of 37.9, 40.8 and 69.1 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 45 or 46; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 93.3 ⁇ 1 ppm.
  • Rilpivirine succinate Form 3 characterized by a powder XRD pattern with peaks at 5.3°, 5.6°, 10.6°, 12.6°, and 23.1° ⁇ 0.2° 2 ⁇ can be further characterized by a powder XRD pattern having an additional one, two, three, four or five peaks selected from 9.6°, 14,7°, 18,4°, 19.4°, and 26.9° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention provides Rilpivirine L-malate.
  • Rilpivirine L-malate Form 1 provides a crystalline Rilpivirine L-malate, designated Form 1.
  • Rilpivirine L-malate Form 1 can be characterized by a powder XRD pattern with peaks at 5.4°, 9.2°, 9.5°, 14.5°, and 18.5° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 13; or by combinations thereof.
  • Rilpivirine L-malate Form 1 can be characterized by a powder XRD pattern having peaks at 5.4°, 9.2°, 9.5°, 14.5°, and 18.5° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 10.5°, 12.5°, 19.1°, 19.5° and 26.5° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine
  • the present invention provides a crystalline Rilpivirine
  • Rilpivirine benzenesulfonate Form 1 can be characterized by a powder XRD pattern with peaks at 4.3°, 18.4°, 19.2°, 20.2°, and 24.2° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 15; or by combinations thereof.
  • Rilpivirine benzenesulfonate Form 1 can be characterized a powder XRD pattern having peaks at 4.3°, 18.4°, 19.2°, 20.2°, and 24.2° ⁇ 0.2° 2 ⁇ , and also having any one, two, or three peaks selected from 12.1° ⁇ 0.2° 2 ⁇ , 14.5° ⁇ 0.3° 2 ⁇ , and 16.2° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine ethanesulfonate.
  • the present invention provides a crystalline Rilpivirine
  • Rilpivirine ethanesulfonate Form 1 can be characterized by a powder XRD pattern with peaks at 10.4°, 15.9°, 18.9°, 20.9°, and 26.0° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 16; or by combinations thereof.
  • Rilpivirine ethanesulfonate Form 1 can be characterized by a powder XRD pattern having peaks at 10.4°, 15.9°, 18.9°, 20.9°, and 26.0° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four, or five peaks selected from 14.7°, 17.9°, 19.5°, 19.9°, and 24.7° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine malonate.
  • the present invention provides a crystalline Rilpivirine malonate, designated Form 1.
  • Rilpivirine malonate Form 1 can be characterized by a powder XRD pattern with peaks at 10.7°, 14.2°, 21.8°, 23.8°, and 25.0° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 22; or by combinations thereof.
  • Rilpivirine malonate Form 1 can be characterized by a powder XRD pattern having peaks at 10.7°, 14.2°, 21.8°, 23.8°, and 25.0° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 9.8°, 14.8°, 19.2°, 20.8°, and 25.4° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ .
  • the present invention provides Rilpivirine L-tartrate.
  • the present invention provides an amorphous Rilpivirine L-tartrate.
  • the amorphous Rilpivirine L-tartrate can be characterized by a powder XRD pattern as shown in figure 23.
  • the present invention provides Rilpivirine citrate.
  • the present invention provides an amorphous Rilpivirine citrate.
  • the amorphous Rilpivirine citrate can be characterized by a powder XRD pattern as shown in figure 24.
  • the present invention also provides a crystalline Rilpivirine acetate, designated Form IV.
  • Form IV can be characterized by data selected from: a powder XRD pattern with peaks at 6.0°, 7.6°, 9.3°, 14.7°, and 15.2° 2 ⁇ ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figure 25; a solid-state 13 C NMR spectrum with signals at 103.0, 130.9 and 134.2 ⁇ 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 90 to 180 ppm of 10.6, 38.5 and 41.8 ⁇ 0.1 ppm; a solid-state 13 C NMR spectrum as shown in figures 37 or 38; and any combinations thereof.
  • the signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 180 ppm is typically at 92.4 ⁇ 1 ppm.
  • Form IV can be characterized by a powder XRD pattern having peaks at 6.0°, 7.6°, 9.3°, 14.7°, and 15.2° 2 ⁇ ⁇ 0.2 degrees 2 ⁇ , and also having any one, two, three, four or five peaks selected from 12.1°, 18.5°, 20.5°, 23.8° and 25.2° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the present invention provides Rilpivirine base DMSO solvate.
  • the present invention also provides a crystalline Rilpivirine base, designated Form V.
  • Rilpivirine base Form V can be characterized by a powder XRD pattern with peaks at 6.6°, 13.2°, 16.4°, 19.9°, and 25.0° ⁇ 0.2° 2 ⁇ ; or by a powder XRD pattern as shown in figure 26; or by combinations thereof.
  • Rilpivirine base Form V can be characterized by a powder XRD pattern having peaks at 6.6°, 13.2°, 16.4°, 19.9°, and 25.0° ⁇ 0.2° 2 ⁇ , and also having any one, two, three, four or five peaks selected from 18.2°, 19.6°, 22.5°, 24.2°, and 32.1° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the Rilpivirine base Form V can be a DMSO solvate.
  • Rilpivirine salts and crystalline forms of Rilpivirine salts can be used to prepare Rilpivirine base, for example by reacting any of the above mentioned Rilpivirine salts with a base.
  • the above described Rilpivirine salts and crystalline forms of Rilpivirine salts can be used also to prepare a different Rilpivirine salt, for example by reacting any of the above mentioned Rilpivirine salts with an acid; or, alternatively, by reacting any of the above mentioned Rilpivirine salt with a base, and further reacting the product of that reaction with another acid.
  • salts of Rilpivirine and polymorphs of Rilpivirine base, or of Rilpivirine salts can be used to prepare other salts of Rilpivirine and formulations thereof, or formulations of Rilpivirine base.
  • salts of Rilpivirine can be prepared from the crystalline forms of Rilpivirine base by reacting them with an acid.
  • the present invention encompasses a process for preparing other Rilpivirine salts.
  • the process comprising preparing any one of the Rilpivirine salts and solid state forms of Rilpivirine by the processes of the present invention, and converting that salt to said other Rilpivirine salt.
  • the conversion can be done, for example, by a process comprising basifying any one or a combination of the above described Rilpivirine salts and/or solid state forms thereof, and reacting the obtained Rilpivirine base with an appropriate acid, to obtain the corresponding salt.
  • the conversion can be done by salt switching, i.e., reacting a Rilpivirine salt, with an acid having a pKa which is lower than the pKa of the acid of the first Rilpivirine salt.
  • the present invention further encompasses 1) a pharmaceutical composition comprising any one or combination of solid state Forms, as described above, and at least one pharmaceutically acceptable excipient and 2) the use of any one or combination of the above-described solid state Forms, in the manufacture of a pharmaceutical composition.
  • the pharmaceutical composition can be useful for the treatment of HIV infection.
  • 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 Rilpivirine base or salts.
  • the present invention also provides solid state forms as described above for use as a medicament, preferably for the treatment of HIV infection.
  • X-Ray powder diffraction data was obtained by using methods known in the art using a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 A was used. A round sample holder with zero background 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
  • the peak positions are determined by using silicon powder as an internal standard in an admixture with the sample measured.
  • the position of the silicon (111) peak was corrected to be 28.45 degrees two theta.
  • the positions of the listed peaks were corrected accordingly. (No correction was performed on the diffractograms provided in the figures).
  • Spectral reference was set according to glycine as external standard (176.03 ppm for low field carboxyl signal)
  • Rilpivirine HC1 form A (0.15 g) was dissolved in 2,2,2-trifiuoroethanol at reflux (78°C) with stirring. To the resulting solution was added an antisolvent (see list below) (10V), leading to precipitation. The resulting mixture was stirred at the same temperature for 19 h, and then cooled to room temperature over a period of 1 h. The resulting solid precipitate was isolated by filtration to give Rilpivirine HC1 Form E. Drying of this material in a vacuum oven at 70° C for 20 h afforded the same polymorphic form as was identified prior to drying, as confirmed by XRD analysis.
  • Antisolvents dimethylcarbonate 1 ,2-dimethoxyethane, diisopropylether, acetonitrile, toluene.
  • Example Id Preparation of Rilpivirine hydrochloride Form E
  • Rilpivirine HC1 form Zl as an off-white solid.
  • Example 10 Preparation of Rilpivirine mesylate Form 1 [00205] Rilpivirine base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45°C. Methanesulfonic acid (87 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing Rilpivirine base at 45°C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. A precipitate formed and was isolated by filtration to give Rilpivirine mesylate Form 1 as indicated by XRD.
  • Rilpivirine mesylate Form 1 was dried in a vacuum oven at 50°C for 18 h to afford Rilpivirine mesylate Form 2.
  • Rilpivirine base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45°C.
  • Maleic acid (105 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing Rilpivirine base at 45°C with stirring.
  • the reaction mixture was removed from the heat source and precipitation was observed after stirring for about 20 min. The stirring was continued at room temperature for about 17 h.
  • the precipitate was isolated by filtration to give Rilpivirine maleate form 1. Drying of this material in a vacuum oven at 50°C for 17 h afforded the same polymorphic form as was identified prior to drying, as confirmed by XRD analysis.
  • Rilpivirine base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45°C.
  • Succinic acid (106 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing Rilpivirine base at 45°C with stirring.
  • the reaction mixture was removed from the heat source and stirred at room temperature for about 17 h. leading to precipitation.
  • the precipitate was isolated by filtration to give Rilpivirine succinate Form 1. Drying of this material in a vacuum oven at 50°C for 18 h afforded the same polymorphic form as was identified prior to drying.
  • Example 14 Preparation of Rilpivirine L-malate Form 1
  • Rilpivirine base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45°C.
  • L-Malic acid (121 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing Rilpivirine base at 45°C with stirring.
  • the reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h.
  • a precipitate formed and was isolated by filtration to give Rilpivirine L-malate Form 1. Drying of this material in a vacuum oven at 50°C for 18 h afforded the same polymorphic form as was identified prior to drying.
  • Ethanesulfonic acid 95% (104 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and was then added dropwise to a stirred solution of Rilpivirine base form II (0.30 g, 0.82 mmol) in THF (6 mL, 20V) at 45°C. Precipitation was observed. The reaction mixture was cooled to room temperature for 30 min and stirring was continued at the same temperature for 17 h. The reaction mixture was then filtered to give the title compound. The filter cake was dried in a vacuum oven at 50°C for 17 h. A white solid was obtained. XRD analysis of the solid indicated the same polymorphic form as was identified in the wet material.
  • Rilpivirine p-toluenesulfonate form 1 was dried in a vacuum oven at 50°C for 17 h to give amorphous Rilpivirine p-toluenesulfonate, as confirmed by XRD analysis.
  • Example 19 Preparation of Rilpivirine sulfate Form 2 [00213] H 2 SO 4 (0.5 mL of 98%) was dissolved in 9.5 mL of acetone at ambient temperature. Rilpivirine base Form II (0.30 g, 0.82 mmol) and acetone (9 mL, 30V) were mixed and the mixture was heated to reflux until a clear solution was observed (about 15 min). Then, the above described sulfuric acid solution in acetone (1.0 mL, 0.90 mmol, 1.1 mol eq) was added to the Rilpivirine base solution in one portion. Stirring of the reaction mixture was continued at reflux for 15 min.
  • Rilpivirine base form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45°C.
  • Malonic acid (94 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion-wise to the solution containing Rilpivirine base at 45°C with stirring.
  • the reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h.
  • the mixture was then cooled to - 18°C and maintained at that temperature over a period of 10 days.
  • a precipitate formed and was isolated by vacuum filtration at -15°C to room temperature to give Rilpivirine malonate Form 1 as a pale yellow solid. Drying of this material in a vacuum oven at 50°C for 17 h afforded Rilpivirine malonate Form 1.
  • Rilpivirine base form II (0.15 g, 0.41 mmol) was mixed with acetic acid (glacial) (3 mL, 20V) at 25°C affording a yellow suspension.
  • the suspension was heated with stirring to 56°C, followed by the addition of n-heptane (6 mL, 40V).
  • the mixture was then cooled to 25°C over a period of 1 h, and stirring was continued at the same temperature for another 22 h, leading to the formation of a white precipitate.
  • the precipitate was separated by vacuum filtration, washed with n-heptane (0.5 mL) and dried in a vacuum oven (10 mbar) at 50°C for 24 h to afford Rilpivirine acetate form IV.
  • Example 29 Preparation of Rilpivirine base Form V and Form I
  • Rilpivirine base form II (0.50 g, 1.36 mmol) was mixed with DMSO (7.5 mL, 15 V) and heated to 50°C. Stirring of the resulting yellow solution was continued at the same temperature for 1 h and then the mixture was cooled to room temperature. Stirring was continued at ambient temperature for 3 h and the reaction mixture was then transferred to a refrigerator where it was kept a 5°C for about 16 h leading to the formation of a precipitate. The precipitate was isolated by vacuum filtration to afford Rilpivirine base Form V. The material was dried in a vacuum oven (10 mbar) at 70°C for 20 h to afford Rilpivirine base form I.
  • Rilpivirine sulfate form 2 was stored in a glass vial for about 6 weeks at room temperature. It was then analyzed by XRPD and found to have transformed to Rilpivirine sulfate form 3.
  • Rilpivirine phosphate form 3 was exposed to 100% relative humidity at room temperature for 7 days. The sample was tested by XRPD and found to be Rilpivirine phosphate form 4, which was obtained as a white solid.
  • Rilpivirine phosphate form 3 was exposed to ethanol vapors in a closed vessel at room temperature for 3 days. The sample was tested by XRPD, and found to be Rilpivirine phosphate form 5, obtained as a white solid.
  • Rilpivirine sulfate form 2 was placed in a Petri dish in a desiccator in an atmosphere of water, 100% RH (determined by digital hygrometer), at room temperature. After 24 hours the sample was tested by powder XRD, and found to be Rilpivirine sulfate form 4.
  • Rilpivirine base form II (11.28 g, 30.78 mmol) was mixed with acetone (330 mL, 30V) at 25°C affording a yellow suspension.
  • the suspension was heated to reflux (56°C) to obtain a brownish solution, and stirring was continued at the same temperature for lh.
  • the resulting gentle slurry was filtered hot and the filtrate was returned to the reaction vessel and re-heated to 56°C.
  • HC1 (32%, 3.2 ml, 33.86 mmol, 1.1 eq based on starting quantities of Rilpivirine base) was added drop-wise, producing a suspension.
  • the suspension was stirred for 0.5h at the same temperature.
  • Rilpivirine base form II (16.0 g) was mixed with glacial acetic acid (80 mL, 5V) and heated to 50°C with stirring. The stirring was continued for about 30 min at 50°C and then for 10 min at 85°C, after which water (80 mL, 5V) was added drop-wise to the mixture. The resulting suspension was stirred at 85°C for 1 h and was then gradually cooled to room temperature over a period of 2 h. Stirring was continued at ambient temperature for 22 h and the reaction mixture was filtered. The isolated solid was dried in a vacuum oven at 50°C overnight to afford the Rilpivirine acetate.
  • Example 42 Preparation of Rilpivirine phosphate form 3
  • Phosphoric acid (85%, 3 mL, 45.03 mmol, 1.1 eq) was dissolved at ambient temperature in acetone (30 mL, 2V).
  • Rilpivirine base form II (15.0 g, 40.93 mmol) and acetone (450 mL, 30V) were mixed and the mixture was heated to reflux (56°C) for 30 min.
  • the resulting gentle slurry was filtered hot and the filtrate was charged back to the reaction vessel and re-heated to reflux.
  • the above described phosphoric acid solution in acetone was added to the Rilpivirine base solution in one portion at 56°C.
  • reaction mixture was then gradually cooled to room temperature over a period of 1 h and stirred at the same temperature for about 17 h.
  • a precipitate formed and was isolated by vacuum filtration and dried in a vacuum oven at 50°C for about 20 h to afford Rilpivirine phosphate Form 3.
  • Example 43 polymorphic stability test
  • Example 44 Polymorphic stability Rilpivirine maleate form 3 under relative humidity
  • Example 45 Polymorphic stability of Rilpivirine maleate form 3 under heating [00239] The thermal stability of Rilpivirine maleate form 3 was also studied by heating the sample to 100°C for 50 minutes. No change in the crystal form (monitored by XRPD) was observed.

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Abstract

La présente invention concerne des formes à l'état solide de base Rilpivirine, des sels de Rilpivirine, des formes à l'état solide de sels de Rilpivirine et des procédés de préparation des formes à l'état solide. L'invention concerne également des compositions pharmaceutiques associées.
PCT/US2012/029619 2011-03-17 2012-03-19 Formes à l'état solide de base rilpivirine et sels de rilpivirine WO2012125993A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013087794A1 (fr) * 2011-12-14 2013-06-20 Sandoz Ag Polymorphe de chlorhydrate de rilpivirine et son utilisation à titre d'antiviral
WO2013153161A3 (fr) * 2012-04-11 2013-12-05 Sandoz Ag Nouveau polymorphe de chlorhydrate de rilpivirine
EP2702044B1 (fr) * 2011-04-25 2017-03-22 Hetero Research Foundation Procédé de préparation de rilpivirine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2702044B1 (fr) * 2011-04-25 2017-03-22 Hetero Research Foundation Procédé de préparation de rilpivirine
WO2013087794A1 (fr) * 2011-12-14 2013-06-20 Sandoz Ag Polymorphe de chlorhydrate de rilpivirine et son utilisation à titre d'antiviral
WO2013153161A3 (fr) * 2012-04-11 2013-12-05 Sandoz Ag Nouveau polymorphe de chlorhydrate de rilpivirine

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