WO2013087794A1 - Polymorphe de chlorhydrate de rilpivirine et son utilisation à titre d'antiviral - Google Patents

Polymorphe de chlorhydrate de rilpivirine et son utilisation à titre d'antiviral Download PDF

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Publication number
WO2013087794A1
WO2013087794A1 PCT/EP2012/075455 EP2012075455W WO2013087794A1 WO 2013087794 A1 WO2013087794 A1 WO 2013087794A1 EP 2012075455 W EP2012075455 W EP 2012075455W WO 2013087794 A1 WO2013087794 A1 WO 2013087794A1
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Prior art keywords
rilpivirine hydrochloride
crystalline form
rilpivirine
hydrochloride according
present
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PCT/EP2012/075455
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English (en)
Inventor
Andreas Hotter
Verena Adamer
Ulrich Griesser
Original Assignee
Sandoz Ag
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Priority claimed from EP11193438.6A external-priority patent/EP2604593A1/fr
Priority claimed from EP12156160.9A external-priority patent/EP2628732A1/fr
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2013087794A1 publication Critical patent/WO2013087794A1/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

Definitions

  • the present invention relates to a novel crystalline form/polymorph of Rilpivirine hydrochloride and to methods for its preparation. Furthermore the present invention relates to the use of the novel crystalline form for the preparation of a medicament. In addition the present invention relates to pharmaceutical compositions comprising an effective amount of the novel crystalline form of Rilpivirine hydrochloride and to methods of preparing the same. Finally the present invention relates to pharmaceutical combinations comprising the novel crystalline form of Rilpivirine hydrochloride and additional therapeutic agents.
  • Rilpivirine hydrochloride 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile monohydrochloride, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1 ) and indicated for the treatment of HIV-1 infection in treatment-naive adult patients in combination with other antiretroviral agents.
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • EP1419152 B1 claims amongst others Rilpivirine base and Rilpivirine hydrochloride per se as well as pharmaceutical compositions comprising the same. However, only concrete examples for preparing Rilpivirine base are given in said patent but no concrete examples describing the production of the hydrochloride salt are provided.
  • EP1632232 B1 claims amongst others a solid pharmaceutical composition comprising crystalline forms A, B, C or D of Rilpivirine hydrochloride.
  • said patent claims a process for the production of Rilpivirine hydrochloride by reacting Rilpivirine base with hydrochloric acid in the presence of a suitable acid, such as acetic acid.
  • Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD pattern and FTIR spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct advantageous physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, bioavailability, etc.
  • the bioavailability of a compound intended to be administered orally is dependent on the solubility of the compound in aqueous systems, such as water, as well as the permeability of the compound as mentioned in EP1632232 B1. It is known to the person skilled in the art that the solubility of a crystalline solvate form in the solvent, which is incorporated in this form, is smaller than the solubility of a non-solvated form of the same compound. This means that the solubility of a hydrate - wherein water is the incorporated solvent - in water is thus smaller than that of a corresponding non-hydrated form. For example, hydrates are known to be less soluble in aqueous systems than anhydrous forms of the same compound.
  • Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament
  • form E of the present invention is an anhydrate, in particular a non-hydrated form, and hence especially suitable for the preparation of an orally administered medicament.
  • novel crystalline form/polymorph E of Rilpivirine hydrochloride of the present invention shows high solubility in aqueous systems e.g. a higher solubility than forms A and C of EP1632232 B1 and is thus especially suitable for the preparation of an orally administered medicament.
  • EP1632232 B1 form B is obtained by recrystallizing Rilpivirine hydrochloride from propanone using an initial Rilpivirine hydrochloride concentration of 0.3 g/L.
  • this concentration is not suitable for up-scaling as larger amounts of Rilpivirine hydrochloride would ask for tremendous solvent volumina and hence the usage of tremendously large reaction vessels.
  • form E of the present invention is also obtained by applying higher initial Rilpivirine hydrochloride concentrations such as e.g. ⁇ 10 g/L and is thus suitable for large scale production.
  • aim of the present invention is to circumvent the drawbacks of the known forms A, B, C and D of EP1632232 B1 by providing an anhydrous, in particular a non-hydrated crystalline form of Rilpivirine hydrochloride, which is obtainable in an easy and reliable manner also in large scale.
  • novel crystalline form shows high solubility in aqueous systems making it especially suitable for the preparation of an orally administered medicament.
  • Rilpivirine hydrochloride form E is an anhydrous, in particular a non-hydrated/non-solvated crystalline form and shows advantageous physical properties compared to the known forms A, B, C and D of Rilpivirine hydrochloride of EP1632232 B1 making it especially suitable for the preparation of an orally administered medicament.
  • the present invention relates to a novel crystalline form of Rilpivirine hydrochloride, in the following named Rilpivirine hydrochloride form E.
  • Form E of Rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 9.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.8 ⁇ 0.2° and 24.4 ⁇ 0.2°.
  • the present invention relates to a process of preparing form E of Rilpivirine hydrochloride comprising recrystallizing Rilpivirine hydrochloride from ethanol.
  • the present invention relates to the use of the novel crystalline form E of Rilpivirine hydrochloride for the preparation of a medicament.
  • the present invention relates to pharmaceutical compositions comprising an effective amount of the novel crystalline form E of Rilpivirine hydrochloride and a pharmaceutically acceptable carrier and to processes of preparing the same.
  • pharmaceutical combinations comprising the novel crystalline form E of Rilpivirine hydrochloride and additional therapeutic agents.
  • room temperature indicates that the applied temperature is not critical and that no exact temperature value has to be kept. Usually, “room temperature” is understood to mean temperatures of about 15°C to about 25°C [see e.g. EU Pharmacopoeia 7.2, 1.2 (2011 )].
  • the present invention relates to a novel crystalline form of Rilpivirine hydrochloride (hereinafter also referred to as Rilpivirine hydrochloride form E).
  • Rilpivirine hydrochloride exists in two stereoisomeric forms, namely an E-isomeric form and a Z-isomeric form.
  • Crystalline form E of Rilpivirine hydrochloride of the present invention is preferably present as the pure E-isomer, whereat pure in this context refers to an E-isomer content of at least about 95 %, more preferably of at least about 98 % and most preferably of at least about 99 %.
  • Form E of Rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 9.0 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.4 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.7 ⁇ 0.2°, 21.3 ⁇ 0.2°, 21.6 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 27.1 ⁇ 0.2°, 27.6 ⁇ 0.2°, 29.2 ⁇ 0.2° and 32.7 ⁇ 0.2°.
  • An illustrative diffractogram is displayed in figure 1.
  • E of Rilpivirine hydrochloride can be characterized by showing an FTIR- spectrum comprising peaks at wavelengths of 3280 ⁇ 2 cm “1 , 3243 ⁇ 2 cm “1 , 3175 ⁇ 2 cm “1 , 3057 ⁇ 2 cm “1 , 2968 ⁇ 2 cm “1 , 2872 ⁇ 2 cm “1 , 2228 ⁇ 2 cm “1 , 2218 ⁇ 2 cm “1 , 1656 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1562 ⁇ 2 cm “1 , 1541 ⁇ 2 cm “1 , 1504 ⁇ 2 cm “1 , 1448 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1386 ⁇ 2 cm “1 , 1343 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1179 ⁇ 2 cm “1 , 11
  • form E can be characterized as being an anhydrate, in particular a non-hydrated form, containing about 0 % water at a relative humidity of about 0 % and about 0.8 % water at a relative humidity of about 90 %.
  • the present invention also relates to a process for the preparation of form E of Rilpivirine hydrochloride comprising recrystallizing Rilpivirine hydrochloride from ethanol.
  • a mixture of Rilpivirine hydrochloride in ethanol is provided.
  • Any form of Rilpivirine hydrochloride may be applied e.g. amorphous Rilpivirine hydrochloride, crystalline Rilpivirine hydrochloride or a mixture of amorphous and crystalline Rilpivirine hydrochloride.
  • Suitable crystalline forms of Rilpivirine hydrochloride are e.g. forms A, B, C and D of EP1632232 B1 or mixtures thereof.
  • the initial Rilpivirine hydrochloride concentration applied in the process may range from about 0.1 to 50.0 g/L, preferably from about 0.5 to 30.0 g/L, more preferably from about 1.0 to 20.0 g/L and most preferably from about 5.0 to 10.0 g/L.
  • the starting material is preferably dissolved upon heating the mixture to about 30 °C to reflux temperature, preferably to about 45 °C to reflux temperature, more preferably to about 60 °C to reflux temperature and most preferably to about 75 °C to reflux temperature, whereat the reflux temperature is about 78 °C.
  • the obtained solution may optionally be filtered in order to remove any undissolved particles.
  • the crystallization of form E is initiated by cooling the solution to a temperature ranging from about -25 to 60 °C, preferably from about -20 to 50 °C, more preferably from about -15 to 20 °C and most preferably from about -10 to about 10 °C.
  • a cooling rate preferably ranging from about -0.1 to -20 °C/min, more preferably from about -0.5 to -10 °C/min and most preferably from about -1 to -5 °C/min is applied.
  • an antisolvent may be added to the obtained suspension.
  • Suitable antisolvents in the process of the present invention are e.g. but not limited to aliphatic C 5 -C 8 hydrocarbons such as e.g. n-pentane, n-hexane, n-heptane and isooctane, mixtures of aliphatic hydrocarbons such as e.g. petroleum ether, cyclic hydrocarbons such as e.g. cyclohexane and ethers such as e.g. diethyl ether, tert-butylmethyl ether and isopropyl ether.
  • a preferred ethanol/antisolvent ratio (volume : volume) for the process of the present invention ranges from about 1 : 0.25 to 5, more preferably from about 1 : 0.5 to 3 and most preferably from about 1 : 1 to 2.
  • the antisolvent is preferably added at a temperature ranging from about -25 to 78 °C, more preferably from about -10 to 50 °C and most preferably from about 0 to 25 °C at an addition rate preferably ranging from about 1 to 500 mL/min, more preferably from about 10 to 250 mL/min and most preferably from about 20 to 100 mL/min.
  • the obtained crystals are then collected by any conventional methods such as filtration or centrifugation, preferably by filtration.
  • a washing step may also be applied by rinsing the crystals with ethanol, antisolvent or a mixture of ethanol and antisolvent and/or slurrying the crystals in ethanol, antisolvent or a mixture of ethanol and antisolvent, whereat the ratio of ethanol and antisolvent is preferably the same as the ethanol/antisolvent ratio of the mother liquor.
  • the crystals are dried preferably under vacuum at a temperature preferably ranging from about 25 °C to 100 °C, more preferably from about 30 °C to 80 °C and most preferably from about 40 °C to 60 °C for a time preferably ranging from about 1 to 72 hours, more preferably from about 6 to 48 hours and most preferably from about 12 to 24 hours.
  • the particle size of Rilpivirine hydrochloride form E obtained according to the process of the present invention typically ranges from about 10 to 100 pm determined by optical light microscopy. However, the particle size can be decreased by any conventional method such as e.g. milling or grinding. In addition the particle size can be homogenized by applying an additional sieving step. Hence, a preferred particle size of the crystalline form E of the present invention ranges from about 0.1 to 50 pm, more preferably from about 0.1 to 20 pm and most preferably from about 0.1 to 10 pm.
  • the bioavailability of a compound intended to be administered orally is dependent on the solubility of the compound in aqueous systems, such as water, as well as the permeability of the compound as mentioned in EP1632232 B1. It is known to the person skilled in the art that the solubility of a crystalline solvate form in the solvent, which is incorporated in this form, is smaller than the solubility of a non-solvated form of the same compound. This means that the solubility of a hydrate - wherein water is the incorporated solvent - in water is thus smaller than that of a corresponding non-hydrated form. For example hydrates are known to be less soluble in aqueous systems than anhydrous forms of the same compound.
  • Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament
  • form E of the present invention is an anhydrate, in particular a non-hydrated form, and hence especially suitable for the preparation of an orally administered medicament.
  • the novel crystalline form E of the present invention shows high solubility in aqueous systems e.g. a higher solubility than forms A and C of EP1632232 B1 in 0.01 N aqueous HCI and is thus especially suitable for the preparation of an orally administered medicament.
  • the solubility data of form E of the present invention and forms A and C of EP1632232 B1 in 0.01 N aqueous HCI at 25 ⁇ 0.1 °C are presented in table 1.
  • Table 1 Solubility data in 0.01 N aqueous HCI at 25 ⁇ 0.1 °C
  • EP1632232 B1 form B is obtained by recrystallizing Rilpivirine hydrochloride from propanone using an initial Rilpivirine hydrochloride concentration of 0.3 g/L.
  • this concentration is not suitable for up-scaling as larger amounts of Rilpivirine hydrochloride would ask for tremendous solvent volumina and hence the usage of tremendously large reaction vessels.
  • form E of the present invention is obtained by applying higher initial Rilpivirine hydrochloride concentrations such as e.g. >10 g/L and is thus suitable for large scale production.
  • the novel crystalline form E of Rilpivirine hydrochloride of the present invention circumvents the drawbacks of the known forms A, B, C and D of EP1632232 B1 as it is obtainable in an easy and reliable manner also in large scale.
  • the novel crystalline form shows high solubility in aqueous systems e.g. higher solubility in 0.01 N aqueous HCI compared to forms A and C of EP1632232 B1 making it especially suitable for the preparation of an orally administered medicament.
  • form E of Rilpivirine hydrochloride is the most favored form to be used in an antiretroviral pharmaceutical composition and may advantageously be employed in various pharmaceutical formulations for use in the treatment of HIV-1 infection.
  • the present invention therefore also relates to a pharmaceutical composition which comprises Rilpivirine hydrochloride form E as described above and a pharmaceutically acceptable carrier.
  • the present invention relates to pharmaceutical compositions, wherein more than 95 % of Rilpivirine hydrochloride is stably present as Rilpivirine hydrochloride form E, more preferably wherein Rilpivirine hydrochloride form E is the only detectable crystalline form of Rilpivirine hydrochloride.
  • Rilpivirine hydrochloride form E initially comprised in the pharmaceutical composition is still present as Rilpivirine hydrochloride form E after storage for the indicated period.
  • the pharmaceutical compositions of the invention comprising Rilpivirine hydrochloride form E may further comprise one or more pharmaceutically acceptable excipients.
  • excipients are preferably selected from the group consisting of fillers, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners.
  • Other excipients known in the field of pharmaceutical compositions may also be used.
  • the pharmaceutical composition may comprise a combination of two or more excipients also within one of the members of the above mentioned group.
  • EP1632232 B1 disclose examples of binders for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the preferred binders which can also be used for the pharmaceutical compositions of the present invention, comprise e.g.
  • alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluoses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches such as starch 1551 , pectins such as sodium carboxymethylamylopectin, chitin derivatives such as chitosan, heparin and heparinoids, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum
  • poloxamers and poloxamines are preferred.
  • copovidone whereat starch, polyvinylpyrrolidone, a cellulose ether such as PVP K29-32, PVP K90, methyl cellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose or hydroxypropyl methylcellulose (HPMC) are preferred.
  • EP1632232 B1 discloses examples of suitable diluents for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the preferred diluents, which can also be used for the pharmaceutical compositions of the present invention comprise e.g.
  • microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac®, a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), commercially available as Prosolv®, whereat lactose monohydrate, microcrystalline cellulose or silicified microcrystalline cellulose are preferred.
  • microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lacto
  • EP1632232 B1 discloses examples of glidants for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the preferred glidants, which can also be used for the pharmaceutical compositions of the present invention comprise talc, colloidal silicon dioxide, starch and magnesium stearate, whereat magnesium stearate is preferred.
  • EP1632232 B1 discloses examples of disintegrants for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the preferred disintegrants which can also be used for the pharmaceutical compositions of the present invention, comprise starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate and powdered cellulose, whereat croscarmellose sodium is preferred.
  • ion exchange resins e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium
  • EP1632232 B1 discloses examples of lubricants for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the preferred lubricants which can also be used for the pharmaceutical compositions of the present invention, are e.g. magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate, whereat magnesium stearate is preferred.
  • compositions of the present invention comprising Rilpivirine hydrochloride form E may comprise other optional excipients such as, for example, flavors, sweeteners and colors.
  • Paragraph [0083] of EP1632232 B1 discloses examples of film coatings for the pharmaceutical compositions of the present invention comprising Rilpivirine hydrochloride form E.
  • the film coatings which can also be used for the pharmaceutical compositions of the present invention, are preferably immediate release film coatings comprising a film-forming polymer and optionally a plasticizer or a pigment.
  • An example for a suitable film-forming polymer is hydroxypropyl methylcellulose
  • an example for a suitable plasticizer is polyethyleneglycol, e.g. macrogol 3000 or 6000, or triacetin and an example for a suitable pigment is titanium dioxide.
  • a preferred pharmaceutical composition of the present invention comprises a tablet core comprising Rilpivirine hydrochloride form E of the present invention, croscarmellose sodium, magnesium stearate, lactose monohydrate, povidone K30, polysorbate 20, and silicified microcrystalline cellulose and a tablet coating comprising hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin. Examples of suitable processes for the preparation of the pharmaceutical compositions of the present invention are given e.g.
  • Formulations of the present invention typically comprise 1 to 250 mg of Rilpivirine hydrochloride form E, whereat the preferred dosage is 25 mg (calculated as Rilpivirine base).
  • the present invention relates to a pharmaceutical combination comprising an effective amount of Rilpivirine hydrochloride form E of the present invention and additional therapeutic agents such as e.g. anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections.
  • additional therapeutic agents such as e.g. anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections.
  • the additional therapeutic agents are chosen from e.g.
  • emtricitabine tenofovir, abacavir, lamivudine, efavirenz, ritonavir, atazanavir, raltegravir, darunavir, fosamprenavir, lopinavir, telaprevir, boceprevir and/or zidovudine, most preferably emtricitabine, tenofovir, abacavir and/or lamivudine are used for the pharmaceutical combinations.
  • the X-ray powder diffractogram (XRPD) was obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Ka1 ,2 radiation source (wavelength 0.15419 nm) with a focussing mirror, a 0.5° divergence slit, a 0.02° soller slit collimator and a 1 °anti-scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° soller slit collimator and a Nickel filter on the diffracted beam side and a solid state PIX'cel detector.
  • XRPD X-ray powder diffractogram
  • the pattern was recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40 s per step in the angular range of 2° to 40° 2-theta.
  • a typical precision of the 2-theta values is in the range of about ⁇ 0.2° 2-theta.
  • a diffraction peak that appears at 5.0° 2-theta can appear between 4.8 and 5.2° 2-theta on most X-ray diffractometers under standard conditions.
  • the Fourier transform infrared (FTIR) spectrum was recorded with a Bruker IFS 25 spectrometer (Bruker GmbH, Düsseldorf, D) in the spectral range from 4000 to 600 cm “1 with a resolution of 2 cm “1 (64 scans).
  • the sample was prepared on a ZnSe disk using the Bruker IR microscope I, with 15x-Cassegrain-objectives.
  • a typical precision of the wavenumber values is in the range of about ⁇ 2 cm ⁇
  • an infrared peak that appears at 1716 cm -1 can appear between 1714 and 1718 cm “1 .
  • a suspension of 500 mg Rilpivirine hydrochloride in 50 ml_ ethanol was heated to reflux, whereat a clear solution was obtained.
  • the hot solution was filtered and cooled in an ice bath, whereat crystallization was observed during cooling.
  • the obtained suspension was further stirred for 15 hours at room temperature before the crystals were collected by filtration and dried at 80 °C under vacuum for 15 hours. 320 mg of crystalline form E of Rilpivirine hydrochloride were received.
  • Suspensions of forms A, C and E in 0.01 N aqueous HCI were stirred in closed vessels with a diameter of 25 mm in a thermostatic water bath at 25 ⁇ 0.1 °C. Before the solute was added the solvent was equilibrated to the temperature. Three samples of each modification were taken with Swinnex filter holders attached to volumetric pipettes (2 ml_) via a small glass tube after 30 min. They were sucked through Millipore membrane filters (0.45 ⁇ ) and

Abstract

Cette invention concerne une nouvelle forme cristalline de chlorhydrate de rilpivirine et des procédés pour la préparer. Cette invention concerne en outre l'utilisation de la nouvelle forme cristalline pour la préparation d'un médicament. Des compositions pharmaceutiques comprenant une quantité efficace de la nouvelle forme cristalline de chlorhydrate de rilpivirine et des procédés pour les préparer sont également décrits. Pour finir, cette invention concerne des associations pharmaceutiques comprenant la nouvelle forme cristalline de chlorhydrate de rilpivirine et d'autres agents thérapeutiques.
PCT/EP2012/075455 2011-12-14 2012-12-13 Polymorphe de chlorhydrate de rilpivirine et son utilisation à titre d'antiviral WO2013087794A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP11193438.6A EP2604593A1 (fr) 2011-12-14 2011-12-14 Polymorphe du chlorhydrate de rilpivirine et son utilisation comme antiviral
EP11193438.6 2011-12-14
EP12156160.9 2012-02-20
EP12156160.9A EP2628732A1 (fr) 2012-02-20 2012-02-20 Nouvelle forme cristalline d'hydrochlorure de rilpivirine

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US11166952B2 (en) 2019-11-29 2021-11-09 Aptorum Therapeutics Limited Composition including rilpivirine and method for treating tumors or cancer

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WO2009007441A2 (fr) * 2007-07-12 2009-01-15 Tibotec Pharmaceuticals Ltd. Forme cristalline de 4-[[4-[[4-(2-cyanoéthényl)-2,6-diméthylphényl]amino]-2-pyrimidinyl]amino]benzonitrile
EP1632232B1 (fr) 2004-09-02 2011-05-11 Janssen Pharmaceutica NV Sel de 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
EP1419152B1 (fr) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Derives de pyrimidines inhibiteurs de vih
WO2012125993A1 (fr) * 2011-03-17 2012-09-20 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de base rilpivirine et sels de rilpivirine

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EP1419152B1 (fr) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Derives de pyrimidines inhibiteurs de vih
WO2006024668A1 (fr) * 2004-09-02 2006-03-09 Janssen Pharmaceutica N.V. Chlorhydrate de 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile
EP1632232B1 (fr) 2004-09-02 2011-05-11 Janssen Pharmaceutica NV Sel de 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
WO2009007441A2 (fr) * 2007-07-12 2009-01-15 Tibotec Pharmaceuticals Ltd. Forme cristalline de 4-[[4-[[4-(2-cyanoéthényl)-2,6-diméthylphényl]amino]-2-pyrimidinyl]amino]benzonitrile
WO2012125993A1 (fr) * 2011-03-17 2012-09-20 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de base rilpivirine et sels de rilpivirine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11166952B2 (en) 2019-11-29 2021-11-09 Aptorum Therapeutics Limited Composition including rilpivirine and method for treating tumors or cancer
US11571422B2 (en) 2019-11-29 2023-02-07 Scipio Life Sciences Limited Composition including rilpivirine and method for treating tumors or cancer

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