WO2013153161A2 - Novel polymorph of rilpivirine hydrochloride - Google Patents

Novel polymorph of rilpivirine hydrochloride Download PDF

Info

Publication number
WO2013153161A2
WO2013153161A2 PCT/EP2013/057596 EP2013057596W WO2013153161A2 WO 2013153161 A2 WO2013153161 A2 WO 2013153161A2 EP 2013057596 W EP2013057596 W EP 2013057596W WO 2013153161 A2 WO2013153161 A2 WO 2013153161A2
Authority
WO
WIPO (PCT)
Prior art keywords
rilpivirine hydrochloride
tablet
solvate
rilpivirine
crystalline
Prior art date
Application number
PCT/EP2013/057596
Other languages
French (fr)
Other versions
WO2013153161A3 (en
Inventor
Andreas Hotter
Arthur Pichler
Verena Adamer
Ulrich Griesser
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2013153161A2 publication Critical patent/WO2013153161A2/en
Publication of WO2013153161A3 publication Critical patent/WO2013153161A3/en

Links

Classifications

    • 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 present invention relates to a novel polymorph and to novel solvates of rilpivirine hydrochloride, as well as to their preparation.
  • the novel solvates are valuable intermediates for the preparation of the novel polymorph of rilpivirine hydrochloride of the present invention.
  • the present invention relates to the use of the novel polymorph for the preparation of a medicament.
  • the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph of rilpivirine hydrochloride and to methods of preparing the same.
  • pharmaceutical combinations comprising an effective amount of the novel polymorph 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
  • Rilpivirine hydrochloride is represented by the following general formula (I):
  • EP1419152 B1 discloses 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 discloses amongst others a solid pharmaceutical composition comprising crystalline forms A, B, C or D of rilpivirine hydrochloride.
  • said patent discloses 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 or bioavailability.
  • the preparation process of a crystalline form, especially on large scale plays an important role in the development of an active pharmaceutical ingredient. It is essential that the crystallization process is robust and reliably produces the desired crystalline form in polymorphically pure form, also on large scale.
  • the bioavailability of a compound intended to be administered orally is dependent on the compounds solubility in aqueous systems such as e.g. water, as well as the compounds permeability 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. This is particularly true for badly water soluble active pharmaceutical ingredients such as rilpivirine hydrochloride.
  • Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament, whereas the novel polymorph of the present invention is an anhydrous form and hence especially suitable for the preparation of an orally administered medicament.
  • the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner because these forms are obtained from the same solvent system.
  • the polymorphs A and C of rilpivirine hydrochloride are obtained from the same solvent system, namely acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtained in pure form in a quite narrow range of critical parameters, such as the crystallization temperature, as described in the concrete examples A.a) and A.c) of EP1632232 B1 .
  • novel polymorph of rilpivirine hydrochloride of the present invention is easily obtained in polymorphically pure form in a reliable manner by applying the novel solvates of rilpivirine hydrochloride of the present invention as intermediates in the production of the novel polymorph.
  • 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 require tremendous solvent volumina and hence the usage of tremendously large reaction vessels.
  • the novel polymorph of the present invention is obtained by applying higher initial concentrations of the novel solvates of rilpivirine hydrochloride of the present invention, which are employed as intermediates for the production of the novel polymorph of the present invention and is thus suitable for large scale production.
  • the 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 polymorph of rilpivirine hydrochloride, which is obtained in polymorphically pure form in an easy and reliable manner, also on large scale.
  • rilpivirine hydrochloride form F is an anhydrous and non-solvated crystalline form and shows certain advantages 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 polymorph of rilpivirine hydrochloride, in the following named rilpivirine hydrochloride form F.
  • Form F of rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 5.6 ⁇ 0.2°, 6.1 ⁇ 0.2°, 6.9 ⁇ 0.2°, 12.5 ⁇ 0.2° and 13.8 ⁇ 0.2°.
  • the present invention relates to processes of preparing form F of rilpivirine hydrochloride in which the novel crystalline solvates of rilpivirine hydrochloride of the present invention are employed as intermediates.
  • the present invention relates to novel solvates of rilpivirine hydrochloride.
  • the present invention relates to solvates of rilpivirine hydrochloride which are isomorphic and can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.9 ⁇ 0.2° and 23.8 ⁇ 0.2°.
  • the present invention relates to additional solvates of rilpivirine hydrochloride which are isomorphic and can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.5 ⁇ 0.2°.
  • the present invention relates to a dichloromethane solvate of rilpivirine hydrochloride which can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 21 .2 ⁇ 0.2° and 24.1 ⁇ 0.2°.
  • the present invention relates to a cyclohexanone solvate of rilpivirine hydrochloride which can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.8 ⁇ 0.2° and 23.3 ⁇ 0.2°.
  • the present invention also relates to a method of preparing the novel solvates of rilpivirine hydrochloride comprising the steps of:
  • the present invention relates to the use of the novel solvates of rilpivirine hydrochloride as intermediates for the preparation of rilpivirine hydrochloride form F.
  • the present invention relates to the use of the novel polymorph F of rilpivirine hydrochloride for the preparation of a medicament.
  • the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph F of rilpivirine hydrochloride and a pharmaceutically acceptable carrier and to processes of preparing the same.
  • the present invention relates to pharmaceutical combinations comprising an effective amount of the novel polymorph F of rilpivirine hydrochloride and additional therapeutic agents.
  • Figure 1 X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride form F
  • FIG. 2 Fourier transform infrared (FTIR) spectrum of rilpivirine hydrochloride form
  • Figure 3 Overlay X-ray powder diffractograms (XRPD) of rilpivirine hydrochloride 1 -propanol, 2-propanol, acetone, tetrahydrofuran and chloroform solvates
  • FIG. 4 Overlay X-ray powder diffractograms (XRPD) of rilpivirine hydrochloride 1 ,4- dioxane and 2-butanone solvates
  • Figure 5 X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride dichloromethane solvate
  • Figure 6 X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride cyclohexanone solvate
  • FIG. 7 Overlay Fourier transform infrared spectra (FTIR) of rilpivirine hydrochloride 1 - propanol, 2-propanol, acetone, tetrahydrofuran and chloroform solvates
  • FIG. 8 Overlay Fourier transform infrared spectra (FTIR) of rilpivirine hydrochloride 1 ,4- dioxane, 2-butanone, dichloromethane and cyclohexanone solvates
  • FIG. 1 Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride acetone solvate
  • 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 7.5, 1 .2 (2012)].
  • solvate as used herein describes a crystalline compound in which solvent molecules are incorporated into the crystal lattice of the compound in a stoichiometric or non- stoichiometric manner.
  • concentrated hydrochloric acid means aqueous hydrochloric acid having a concentration of about 37 %.
  • Rilpivirine hydrochloride exists in two stereoisomeric forms, namely an E-isomeric form and a Z-isomeric form.
  • the novel crystalline forms of rilpivirine hydrochloride of the present invention are 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 %.
  • the present invention relates to a novel polymorph of rilpivirine hydrochloride (hereinafter also referred to as rilpivirine hydrochloride form F).
  • Form F of rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 5.6 ⁇ 0.2°, 6.1 ⁇ 0.2°, 6.9 ⁇ 0.2°, 12.5 ⁇ 0.2° and 13.8 ⁇ 0.2°.
  • the X-ray powder diffractogram of form F of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 15.9 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.6 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21 .2 ⁇ 0.2°, 21 .8 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°, 23.8 ⁇ 0.2°, 24.2 ⁇ 0.2°, 24.6 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.6 ⁇ 0.2° and 27.4 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 1 .
  • F of rilpivirine hydrochloride can be characterized by showing an FTIR- spectrum comprising peaks at wavenumbers of 3223 ⁇ 2 cm “1 , 2222 ⁇ 2 cm “1 , 1652 ⁇ 2 cm “1 , 966 ⁇ 2 cm “1 and 81 1 ⁇ 2 cm “1 .
  • the FTIR-spectrum of form F of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3176 ⁇ 2 cm “1 , 3055 ⁇ 2 cm “1 , 2961 ⁇ 2 cm “1 , 2862 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1598 ⁇ 2 cm “1 , 1566 ⁇ 2 cm “1 , 1541 ⁇ 2 cm “1 , 1522 ⁇ 2 cm “1 , 1503 ⁇ 2 cm “1 , 1444 ⁇ 2 cm “1 , 1416 ⁇ 2 cm “1 , 1386 ⁇ 2 cm “1 , 1357 ⁇ 2 cm “1 , 1338 ⁇ 2 cm “1 , 1308 ⁇ 2 cm “1 , 1273 ⁇ 2 cm “1 , 1241 ⁇ 2 cm “1 , 1213 ⁇ 2 cm “1 , 1 178 ⁇ 2 cm “1 , 1 154 ⁇ 2 cm “1 , 1097 ⁇ 2 cm “1 ,
  • form F of rilpivirine hydrochloride can be characterized as being an anhydrous form containing less than about 1 .5 %, preferably less than about 1 .0 % water.
  • the present invention also relates to a process for the preparation of form F of rilpivirine hydrochloride comprising slurrying a novel solvate of rilpivirine hydrochloride of the present invention in water, collecting the obtained crystals and drying the crystals at about 80 to about 180 °C and/or below about 5 % relative humidity.
  • a suspension of a novel solvate of rilpivirine hydrochloride of the present invention in water is provided.
  • Any crystalline solvate of rilpivirine hydrochloride of the present invention may be applied e.g.
  • the initial rilpivirine hydrochloride concentration applied in the process may range from about 1 to 200 g/L, preferably from about 5 to 150 g/L, more preferably from about 10 to 100 g/L and most preferably from about 15 to 30 g/L.
  • the suspension is stirred, at a temperature preferably ranging from about 0 to 40 °C, more preferably from about 10 to 30 °C and most preferably the suspension is stirred at about room temperature, for a time preferably ranging from about 1 to 72 hours, more preferably from about 6 to 60 hours, and most preferably from about 12 to 48 hours.
  • the obtained crystals are then collected by any conventional methods such as filtration, centrifugation or evaporation of the solvent, preferably by filtration.
  • the crystals are dried preferably under vacuum at a temperature preferably ranging from about 80 3 ⁇ 4 to 180 °C, more preferably from about 90 °C to 140 °C and most preferably from about 100 °C to 1 10 °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 crystals can be dried at room temperature by storing them at an atmosphere having a relative humidity of ⁇ 5 % e.g. by storing the crystals in a closed containment over a desiccant such as e.g. P 2 0 5 or silica gel, whereat the storing time may range from about 1 to 72 hours, more preferably from about 6 to 48 hours and most preferably from about 12 to 24 hours.
  • the storing time may be decreased by storing the crystals at ⁇ 5 % relative humidity and applying elevated temperatures preferably ranging from about 30 to 180 °C, more preferably from about 40 to 140 °C and most preferably from about 50 to 110 °C.
  • the particle size of rilpivirine hydrochloride form F obtained according to the processes of the present invention typically ranges from about 10 to 150 ⁇ determined by optical light microscopy.
  • the particle size can be decreased by any conventional method such as e.g. milling or grinding.
  • the particle size can be homogenized by applying an additional sieving step. Preferably milling and sieving are performed in such a manner that rilpivirine hydrochloride form F having a particle size ranging from about 0.1 to 50 ⁇ , more preferably from about 0.1 to 25 ⁇ and most preferably from about 0.1 to 15 ⁇ is obtained.
  • the bioavailability of a compound intended to be administered orally is dependent on the compounds solubility in aqueous systems such as e.g. water, as well as the compounds permeability 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. This is particularly true for badly water soluble active pharmaceutical ingredients such as rilpivirine hydrochloride.
  • an anhydrous form is preferred over a hydrated form for the formulation of an orally administered medicament comprising rilpivirine hydrochloride.
  • Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament, whereas the novel polymorph F of the present invention is an anhydrous form and hence especially suitable for the preparation of an orally administered medicament.
  • the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner because these forms are obtained from the same solvent system.
  • the polymorphs A and C of rilpivirine hydrochloride are obtained from the same solvent system, namely acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtained in pure form in a quite narrow range of critical parameters, such as the crystallization temperature, as described in the concrete examples A.a) and A.c) of EP1632232 B1 .
  • novel polymorph F of rilpivirine hydrochloride of the present invention is easily obtained in polymorphically pure form in a reliable manner by applying the novel solvates of rilpivirine hydrochloride of the present invention as intermediates in the process for the production of the novel polymorph F.
  • the novel solvates are slurried in water and dried at ⁇ 80 °C and or at ⁇ 5 % relative humidity to obtain polymorphically pure form F of rilpivirine hydrochloride.
  • 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 require tremendous solvent volumina and hence the usage of tremendously large reaction vessels.
  • the novel polymorph F of the present invention is obtained by applying higher initial concentrations of the novel solvates of rilpivirine hydrochloride of the present invention, which are employed as intermediates for form F production, such as e.g. 20 mg/mL (see example 1 ) and is thus suitable for large scale production.
  • novel polymorph F 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 an anhydrous form obtained in polymorphically pure form in an easy and reliable manner according to the processes of the present invention, also on large scale.
  • polymorph F of rilpivirine hydrochloride is the most favored form to be used in an oral antiviral 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 pharmaceutical compositions comprising rilpivirine hydrochloride form F as described above and a pharmaceutically acceptable carrier.
  • the present invention relates to pharmaceutical compositions, wherein more than 95 % of rilpivirine hydrochloride are stably present as rilpivirine hydrochloride form F, more preferably wherein rilpivirine hydrochloride form F is the only detectable crystalline form of rilpivirine hydrochloride.
  • rilpivirine hydrochloride form F is the only detectable crystalline form of rilpivirine hydrochloride.
  • forms A, B, C and D of EP1632232 B1 can be tested by comparing an XRPD taken of any crystalline rilpivirine hydrochloride with the XRPD of form F as obtained from example 1 and shown in figure 1 , which for this comparison is to be taken as an XRPD of 100 % form F.
  • rilpivirine hydrochloride form F is still present as rilpivirine hydrochloride form F after storage for the indicated period.
  • compositions of the present invention comprising rilpivirine hydrochloride form F 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 discloses examples of wetting agents for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • EP1632232 B1 disclose examples of binders for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • 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
  • EP1632232 B1 discloses examples of suitable diluents for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • 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 silicified microcrystalline cellulose, starch, modified starch, dibasic calcium phosphate and dibasic calcium cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fruct
  • EP1632232 B1 discloses examples of glidants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • 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 F.
  • 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,
  • EP1632232 B1 discloses examples of lubricants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • 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.
  • the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F may comprise other optional excipients such as, for example, flavors, sweeteners and colors.
  • EP1632232 B1 discloses examples of film coatings for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F.
  • 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, optionally a plasticizer, optionally a pigment or an opacifier and/or optionally a filler of the coating layer.
  • a suitable film-forming polymer is hydroxypropyl methylcellulose e.g. hypromellose 2910 mPa.s
  • an example for a suitable plasticizer is polyethyleneglycol e.g.
  • a suitable commercially available ready to use film coating powder which can be applied for the preparation of the pharmaceutical composition of the present invention is e.g. Opadry ® II White.
  • the pharmaceutical composition of the present invention comprising rilpivirine hydrochloride form F preferably is an oral dosage form, in particular a capsule or tablet.
  • a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30) and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • Another preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), dibasic calcium phosphate (dihydrate or anhydrate e.g. Emcompress ® or anhydrous Emcompress ® ), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, lactose monohydrate, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • a further preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, modified starch, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30) and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • step c) spraying the binder solution of step b) on the mixture obtained in step a),
  • Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2- propanol, propyl acetate and tetrahydrofuran.
  • water acetic acid, acetone, anisole, 1 -butanol,
  • a particular tablet of the present invention may be prepared by wet granulation comprising the steps of: a) dry blending rilpivirine hydrochloride form F of the present invention and lactose monohydrate,
  • step c) spraying the binder solution of step b) on the mixture obtained in step a),
  • Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2- propanol, propyl acetate and tetrahydrofuran.
  • water acetic acid, acetone, anisole, 1 -butanol,
  • a further preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • Another preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, dibasic calcium phosphate (dihydrate or anhydrate e.g. Emcompress ® or anhydrous Emcompress ® ), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, lactose monohydrate, magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, modified starch and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
  • a particular tablet of the present invention may be prepared by direct compression comprising the steps of:
  • Formulations of the present invention typically comprise about 100 mg, preferably about 75 mg, more preferably about 50 mg and most preferably about 25 mg rilpivirine hydrochloride form F (calculated as rilpivirine free base).
  • compositions of the present invention comprising crystalline form F of rilpivirine hydrochloride are preferably packaged or filled into containers.
  • Containers are typically used for stable storage of the pharmaceutical compositions of the present invention for example at a temperature of about 20 °C to 30 °C e.g. at about 25 °C for a prolonged time e.g. for at least 6 months, preferably at least about 24 months, for up to at least 24 months e.g. for up to at least about 30 months, such as for up to about 60 months.
  • the container used for the stable storage of the pharmaceutical compositions of the present invention comprising crystalline form F of rilpivirine hydrochloride ensures an environment having a relative humidity of about 0 to 70 %, more preferably of about 0 to 50 % and most preferably of about 0 to 30 %.
  • a preferred container is a bottle, in particular a polyethylene bottle e.g. a HDPE bottle or a glass bottle, having e.g. a screw closure with an aluminum induction seal liner, or is a blister, e.g. an aluminum blister or strip, e.g. a blister consisting of two aluminum foils or strips, or may be any other suitable container. More preferably said container is a gas-tight container, such as an air-tight container.
  • the present invention relates to a pharmaceutical combination comprising an effective amount of rilpivirine hydrochloride form F and one or more additional therapeutic agents such as e.g. anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections.
  • 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 anti-viral agent for the pharmaceutical combination with rilpivirine hydrochloride form F of the present invention is preferably chosen from the class of nucleoside analog HIV-1 reverse transcriptase inhibitors, whereat emtricitabine and tenofovir are most preferred.
  • a preferred pharmaceutical combination of the present invention comprises 25 mg rilpivirine hydrochloride form F (calculated as free base), 200 mg emtricitabine and 245 mg tenofovir disoproxil fumarate (calculated as free base) and one or more pharmaceutically acceptable excipients.
  • the present invention relates to novel crystalline solvates of rilpivirine hydrochloride.
  • solvates of rilpivirine hydrochloride produce very similar X-ray powder diffractograms indicating that these solvates are isomorphic.
  • Isomorphic solvates means that even though the solvates contain different solvents, they exhibit essentially the same molecular packing resulting in very similar corresponding unit cell parameters. Thus these solvates can be identified by some common characteristic reflections as described below.
  • the present invention relates to crystalline isomorphic solvates of rilpivirine hydrochloride, which are characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.9 ⁇ 0.2° and 23.8 ⁇ 0.2°. Representative diffractograms are displayed in figure 3.
  • the isomorphic solvates of rilpivirine hydrochloride are characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride, wherein the solvent incorporated into the crystal lattice is selected from 1 - propanol, 2-propanol, acetone, tetrahydrofuran or chloroform.
  • isomorphic solvates of rilpivirine hydrochloride are surprisingly stable as the desolvation occurs only at about > 150 °C, more preferably at about > 200 °C as indicated by thermogravimetric analysis.
  • the present invention relates to additional crystalline isomorphic solvates of rilpivirine hydrochloride, which are characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.5 ⁇ 0.2°. Representative diffractograms are displayed in figure 4.
  • the isomorphic solvates of rilpivirine hydrochloride are characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride, wherein the solvent incorporated into the crystal lattice is selected from 1 ,4- dioxane or 2-butanone.
  • isomorphic solvates of rilpivirine hydrochloride are surprisingly stable as the desolvation occurs only at about > 150 °C, more preferably at about > 200 °C as indicated by thermogravimetric analysis.
  • the present invention relates to a dichloromethane solvate which is characterized by an X-ray powder diffraction pattern comprising peaks at 2- theta angles of 8.2 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 21.2 ⁇ 0.2° and 24.1 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 5.
  • the dichloromethane solvate of rilpivirine hydrochloride is characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol dichloromethane per mol rilpivirine hydrochloride.
  • the dichloromethane solvate of rilpivirine hydrochloride is surprisingly stable as the desolvation occurs only at about > 150 °C indicated by thermogravimetric analysis.
  • the present invention relates to a cyclohexanone solvate characterized by an X-ray powder diffraction pattern showing peaks at 2-theta angles of 8.1 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.8 ⁇ 0.2° and 23.3 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 6.
  • the cyclohexanone solvate of rilpivirine hydrochloride is characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol cyclohexanone per mol rilpivirine hydrochloride.
  • cyclohexanone solvate of rilpivirine hydrochloride is surprisingly stable as the desolvation occurs only at about > 200 °C as indicated by thermogravimetric analysis.
  • the FTIR- spectra of the novel solvates of rilpivirine hydrochloride of the present invention can be distinguished from these of non-solvated crystalline forms of rilpivirine hydrochloride such as e.g. forms A, B and C of EP1632232 B1 or form F of the present invention and from hydrated forms of rilpivirine hydrochloride such as form D of EP1632232 B1 .
  • the present invention relates to novel crystalline solvates of rilpivirine hydrochloride characterized by an infrared spectrum displaying peaks at wavenumbers of 3057 ⁇ 2 cm “1 , 2228 ⁇ 2 cm “1 , 2218 ⁇ 2 cm “1 , 1656 ⁇ 2 cm “1 and 1542 ⁇ 2 cm “1 .
  • Representative infrared spectra are displayed in figures 7 and 8.
  • Suitable alcohols which can be used for the present process are e.g. 1 -propanol or 2- propanol
  • suitable ketones are e.g. acetone, 2-butanone or cyclohexanone
  • suitable chlorinated hydrocarbons are e.g. dichloromethane or chloroform
  • suitable ethers are e.g. tetrahydrofuran or 1 ,4-dioxane.
  • the initial rilpivirine concentration applied in the process may range from about 1 to 200 g/L, preferably from about 1 to 200 g/L, more preferably from about 1 to 150 g/L and most preferably from about 1 to 100 g/L.
  • Rilpivirine free base may either be suspended or dissolved in the applied solvent prior to the hydrochloric acid addition.
  • a possible dissolution step may be performed at elevated temperatures ranging from about room temperature to about the reflux temperature of the applied solvent.
  • Hydrochloric acid may be applied in the process in any suitable concentration e.g gaseous hydrochloric acid or aqueous hydrochloric acid, whereat the applied aqueous hydrochloric acid preferably has a concentration between about 9 % and about 37 %, more preferably between about 18 % and about 37 % and most preferably concentrated hydrochloric acid is used having a concentration of about 37 %.
  • aqueous hydrochloric acid preferably has a concentration between about 9 % and about 37 %, more preferably between about 18 % and about 37 % and most preferably concentrated hydrochloric acid is used having a concentration of about 37 %.
  • the amount of hydrochloric acid used in the process of the present invention preferably ranges from about 1.0 to 10.0 mol equivalents, more preferably from about 1 .0 to 8.0 mol equivalents and most preferably from about 1 .0 to 5.0 mol equivalents.
  • the mixture is stirred at a temperature preferably ranging from about 0 to 40 °C, more preferably from about 10 to 30 °C and most preferably at about room temperature, for a time ranging from about 1 to 72 hours, preferably from about 1 to 48 hours, more preferably from about 1 to 24 hours and most preferably from about 1 to 18 hours.
  • the obtained crystals are collected by any conventional methods such as filtration, centrifugation or evaporation of the solvent, most preferably by filtration.
  • the crystals are dried preferably under vacuum at a temperature preferably ranging from about 25 3 ⁇ 4 to 150 °C, more preferably from about 30 °C to 100 °C and most preferably from about 40 °C to 80 °C for a time preferably ranging from about 2 to 72 hours, more preferably from about 12 to 48 hours and most preferably from about 24 to 36 hours.
  • crystalline solvates such as a 1 -propanol solvate, a 2-propanol solvate, an acetone solvate, a 2- butanone solvate, a tetrahydrofuran solvate, a 1 ,4-dioxane solvate, a dichloromethane solvate, a chloroform solvate or a cyclohexanone solvate of rilpivirine hydrochloride are obtained.
  • the present invention also relates to a novel 1 -propanol solvate of rilpivirine hydrochloride.
  • the novel crystalline 1 -propanol solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.9 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline 1 - propanol solvate comprises additional characteristic peaks at 2-theta angles of 10.6 ⁇ 0.2°,
  • novel crystalline 1 -propanol solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3059 ⁇ 2 cm “1 , 2230 ⁇ 2 cm “1 , 2220 ⁇ 2 cm “1 , 1657 ⁇ 2 cm “1 and 1543 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline 1 -propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ⁇ 2 cm “1 , 3242 ⁇ 2 cm “1 , 3182 ⁇ 2 cm “1 , 2968 ⁇ 2 cm “1 , 2875 ⁇ 2 cm “1 , 1637 ⁇ 2 cm “1 , 1603 ⁇ 2 cm “1 , 1567 ⁇ 2 cm “1 , 1506 ⁇ 2 cm “1 , 1450 ⁇ 2 cm “1 , 1419 ⁇ 2 cm “1 , 1387 ⁇ 2 cm “1 , 1345 ⁇ 2 cm “1 , 1273 ⁇ 2 cm “1 , 1245 ⁇ 2 cm “1 , 1217 ⁇ 2 cm “1 , 1 181 ⁇ 2 cm “1 , 1 156 ⁇ 2 cm “1 , 1074 ⁇ 2 cm “1 , 1055 ⁇ 2 cm “1 , 970 ⁇ 2 cm “1
  • the 1 -propanol solvate of rilpivirine hydrochloride of the present invention preferably contains from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 1 - propanol per mol rilpivirine hydrochloride.
  • the 1 -propanol solvate contains about 0.5 mol 1 -propanol per mol rilpivirine hydrochloride as detected by single X-ray diffraction and can thus be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline 2-propanol solvate of rilpivirine hydrochloride.
  • novel crystalline 2-propanol solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.9 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline 2- propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 10.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, , 19.0 ⁇ 0.2°, 19.7 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.5 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.7 ⁇ 0.2°, 24.1 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.1 ⁇ 0.2°, 26.3 ⁇ 0.2°, 26.6 ⁇ 0.2°, 27.5 ⁇ 0.2°, 27.8 ⁇ 0.2°, 28.8 ⁇ 0.2°, 29.1 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.4 ⁇ 0.2° and 33.4 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 3.
  • novel crystalline 2-propanol solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3057 ⁇ 2 cm “1 , 2228 ⁇ 2 cm “1 , 2218 ⁇ 2 cm “1 , 1656 ⁇ 2 cm “1 and 1541 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline 2-propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ⁇ 2 cm “1 , 3230 ⁇ 2 cm “1 , 3178 ⁇ 2 cm “1 , 2968 ⁇ 2cm “ 1,2872 ⁇ 2cm “1 , 1634 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1563 ⁇ 2 cm “1 , 1499 ⁇ 2 cm “1 , 1448 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1384 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1315 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1244 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1179 ⁇ 2 cm “1 , 1155 ⁇ 2 cm “1 , 1129 ⁇ 2 cm “1 , 1098 ⁇ 2 cm “1 , 1073
  • the 2-propanol solvate of rilpivirine hydrochloride of the present invention preferably contains from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 2- propanol per mol rilpivirine hydrochloride.
  • the 2-propanol solvate contains about 0.5 mol 2-propanol per mol rilpivirine hydrochloride as detected by single X-ray diffraction and can thus be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline acetone solvate of rilpivirine hydrochloride.
  • the novel crystalline acetone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ⁇ 0.2°, 8.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.9 ⁇ 0.2° and 23.8 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline acetone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 9.4 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.8 ⁇ 0.2°,
  • novel crystalline acetone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2218 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1542 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline acetone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3276 ⁇ 2 cm “1 , 3239 ⁇ 2 cm “1 , 3178 ⁇ 2 cm “1 , 2963 ⁇ 2 cm “1 , 2873 ⁇ 2 cm “1 , 1716 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1564 ⁇ 2 cm “1 , 1503 ⁇ 2 cm “1 , 1448 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1383 ⁇ 2 cm “1 , 1343 ⁇ 2 cm “1 , 1314 ⁇ 2 cm “1 , 1270 ⁇ 2 cm “1 , 1242 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1 179 ⁇ 2 cm “1 , 1 154 ⁇ 2 cm “1 , 1 100 ⁇ 2 cm “1 , 1072
  • the acetone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol acetone per mol rilpivirine hydrochloride.
  • the acetone solvate comprises about 0.4 mol acetone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention also relates to a novel crystalline 2-butanone solvate of rilpivirine hydrochloride.
  • novel crystalline 2-butanone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.9 ⁇ 0.2° and 23.4 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline 2- butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 10.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.3 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.3 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.9 ⁇ 0.2°, 21 .2 ⁇ 0.2°, 21 .4 ⁇ 0.2°, 21 .9 ⁇ 0.2°, 22.5 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.2 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.2 ⁇ 0.2°, 27.5 ⁇ 0.2°, 27.8 ⁇ 0.2°, 29.2 ⁇ 0.2° and
  • novel crystalline 2-butanone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2219 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1542 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline 2-butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ⁇ 2 cm “1 , 3241 ⁇ 2 cm “1 , 3173 ⁇ 2 cm “1 , 2968 ⁇ 2 cm “1 , 2873 ⁇ 2 cm “1 , 1711 ⁇ 2 cm “1 , 1636 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1563 ⁇ 2 cm “1 , 1520 ⁇ 2 cm “1 , 1498 ⁇ 2 cm “1 , 1447 ⁇ 2 cm “1 , 1418 ⁇ 2 cm “1 , 1382 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1314 ⁇ 2 cm “1 , 1270 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1214 ⁇ 2 cm “1 , 1180 ⁇ 2 cm “1 , 1155 ⁇ 2 cm “1 , 1099
  • the 2-butanone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 2- butanone per mol rilpivirine hydrochloride.
  • the 2-butanone solvate comprises about 0.5 mol 2-butanone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride.
  • novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.9 ⁇ 0.2° and 23.7 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 10.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.6 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.2 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.6 ⁇ 0.2°, 29.2 ⁇ 0.2° and 29.5 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 3.
  • novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2219 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1542 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline 2-butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ⁇ 2 cm “1 , 3240 ⁇ 2 cm “1 , 3174 ⁇ 2 cm “1 , 2969 ⁇ 2 cm “1 , 2872 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1563 ⁇ 2 cm “1 , 1521 ⁇ 2 cm “1 , 1499 ⁇ 2 cm “1 , 1448 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1384 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1311 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1179 ⁇ 2 cm “1 , 1154 ⁇ 2 cm “1 , 1099 ⁇ 2 cm “1 , 1071
  • the tetrahydrofuran solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol tetrahydrofuran per mol rilpivirine hydrochloride.
  • the tetrahydrofuran solvate comprises about 0.5 mol tetrahydrofuran per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline 1 ,4-dioxane solvate of rilpivirine hydrochloride.
  • novel crystalline 1 ,4-dioxane solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.5 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline 1,4- dioxane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 14.0 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.8 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.0 ⁇ 0.2°, 26.3 ⁇ 0.2°, 27.6 ⁇ 0.2°, 29.2 ⁇ 0.2°, 29.5 ⁇ 0.2°, 32.2 ⁇ 0.2 and 32.4 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 4.
  • novel crystalline 1,4-dioxane solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2220 ⁇ 2 cm “1 , 1654 ⁇ 2 cm “1 and 1541 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline 1,4-dioxane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3274 ⁇ 2 cm “1 , 3237 ⁇ 2 cm “1 , 3179 ⁇ 2 cm “1 , 2962 ⁇ 2 cm “1 , 2874 ⁇ 2 cm “1 , 2852 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1563 ⁇ 2 cm “1 , 1520 ⁇ 2 cm “1 , 1498 ⁇ 2 cm “1 , 1447 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1384 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1314 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1244 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1179 ⁇ 2 cm “1 , 1154 ⁇ 2 cm “1
  • 1,4-dioxane solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 1,4-dioxane per mol rilpivirine hydrochloride.
  • the 1,4-dioxane solvate comprises about 0.6 mol 1 ,4-dioxane per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention also relates to a novel crystalline dichloromethane solvate of rilpivirine hydrochloride.
  • novel crystalline dichloromethane solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 21.2 ⁇ 0.2° and 24.1 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline dichloromethane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 8.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 18.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21 .5 ⁇ 0.2°, 21 .7 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.6 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.6 ⁇ 0.2°, 26.8 ⁇ 0.2°, 27.6 ⁇ 0.2, 28.0 ⁇ 0.2°, 29.1 ⁇ 0.2°, 29.5 ⁇ 0.2°, 32.5
  • novel crystalline dichloromethane solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3058 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2218 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1541 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline dichloromethane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3280 ⁇ 2 cm “1 , 3242 ⁇ 2 cm “1 , 3177 ⁇ 2 cm “1 , 2968 ⁇ 2 cm “1 , 2873 ⁇ 2 cm “1 , 1635 ⁇ 2 cm “1 , 1601 ⁇ 2 cm “1 , 1563 ⁇ 2 cm “1 , 1521 ⁇ 2 cm “1 , 1504 ⁇ 2 cm “1 , 1448 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1385 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1315 ⁇ 2 cm “1 , 1270 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1 179 ⁇ 2 cm “1 , 1 154 ⁇ 2 cm “1 , 1 122 ⁇ 2 cm “1
  • the dichloromethane solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol dichloromethane per mol rilpivirine hydrochloride.
  • the dichloromethane solvate comprises about 0.5 mol dichloromethane per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline chloroform solvate of rilpivirine hydrochloride.
  • the novel crystalline chloroform solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ⁇ 0.2°, 8.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.8 ⁇ 0.2° and 23.7 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline chloroform solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 9.4 ⁇ 0.2°, 9.8 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.3 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.6 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.2 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.6 ⁇ 0.2°, 29.2 ⁇ 0.2°, 29.5 ⁇
  • novel crystalline chloroform solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3057 ⁇ 2 cm “1 , 2229 ⁇ 2 cm “1 , 2219 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1541 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline chloroform solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ⁇ 2 cm “1 , 3236 ⁇ 2 cm “1 , 3179 ⁇ 2 cm “1 , 2966 ⁇ 2 cm “1 , 2872 ⁇ 2 cm “1 , 1634 ⁇ 2 cm “1 , 1600 ⁇ 2 cm “1 , 1562 ⁇ 2 cm “1 , 1520 ⁇ 2 cm “1 , 1499 ⁇ 2 cm “1 , 1447 ⁇ 2 cm “1 , 1417 ⁇ 2 cm “1 , 1384 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1215 ⁇ 2 cm “1 , 1 179 ⁇ 2 cm “1 , 1 154 ⁇ 2 cm “1 , 1072 ⁇ 2 cm “1 , 1035 ⁇ 2 cm “1 , 969
  • the chloroform solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol chloroform per mol rilpivirine hydrochloride.
  • the chloroform solvate comprises about 0.4 mol chloroform per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the present invention relates to a novel crystalline cyclohexanone solvate of rilpivirine hydrochloride.
  • novel crystalline cyclohexanone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.8 ⁇ 0.2° and 23.3 ⁇ 0.2°.
  • the X-ray powder diffractogram of the novel crystalline cyclohexanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 8.6 ⁇ 0.2°, 14.4 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21 .1 ⁇ 0.2°, 21 .3 ⁇ 0.2°, 21 .8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.6 ⁇ 0.2°, 26.0 ⁇ 0.2°, 28.1 ⁇ 0.2°, 29.0 ⁇ 0.2 and 31.9 ⁇ 0.2°.
  • a representative diffractogram is displayed in figure 6.
  • novel crystalline cyclohexanone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ⁇ 2 cm “1 , 2228 ⁇ 2 cm “1 , 2219 ⁇ 2 cm “1 , 1655 ⁇ 2 cm “1 and 1541 ⁇ 2 cm “1 .
  • the FTIR-spectrum of the novel crystalline cyclohexanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ⁇ 2 cm “1 , 3240 ⁇ 2 cm “1 , 3173 ⁇ 2 cm “1 , 2961 ⁇ 2 cm “1 , 2869 ⁇ 2 cm “1 , 1709 ⁇ 2 cm “1 , 1634 ⁇ 2 cm “1 , 1600 ⁇ 2 cm “1 , 1562 ⁇ 2 cm “1 , 1520 ⁇ 2 cm “1 , 1498 ⁇ 2 cm “1 , 1447 ⁇ 2 cm “1 , 1418 ⁇ 2 cm “1 , 1384 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1312 ⁇ 2 cm “1 , 1271 ⁇ 2 cm “1 , 1243 ⁇ 2 cm “1 , 1214 ⁇ 2 cm “1 , 1 179 ⁇ 2 cm “1 , 1 155 ⁇ 2 cm “1
  • cyclohexanone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol cyclohexanone per mol rilpivirine hydrochloride.
  • the cyclohexanone solvate comprises about 0.5 mol cyclohexanone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
  • the novel solvates of rilpivirine hydrochloride of the present invention are valuable intermediates for the preparation of rilpivirine hydrochloride form F of the present invention.
  • the solvates of the present invention may be transformed to form F according to the process disclosed for form F production.
  • the solvates of rilpivirine hydrochloride of the present invention are applied as starting materials and slurried in water, followed by drying the isolated crystals at increased temperatures ranging from about 80 °C to 180 °C, more preferably from about 90 °C to 140 °C and most preferably from about 100 °C to 120 °C and/or at decreased relative humidities such as ⁇ 5 % relative humidity.
  • the present invention relates to the use of the crystalline 1 -propanol solvate, the crystalline 2-propanol solvate, the crystalline acetone solvate, the crystalline 2-butanone solvate and/or the crystalline tetrahydrofuran solvate of rilpivirine hydrochloride of the present invention for the preparation of a medicament.
  • the X-ray powder diffractograms were 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) and a solid state PIX'cel detector.
  • the diffractograms were recorded at a tube voltage of 40 kV, tube current of 40 mA.
  • a typical precision of the 2-theta values is in the range of about ⁇ 0.2° 2-theta. Thus 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.
  • FTIR Fourier transform infrared
  • TGA Thermogravimetric analysis
  • Example 1 Preparation of polymorph F of rilpivirine hydrochloride A novel solvate of rilpivirine hydrochloride of the present invention (see table 1 ) was suspended in water at a concentration of 20 mg/mL and stirred for 40 hours at room temperature. The obtained crystals were collected by filtration and dried at 105 °C under vacuum for 16 hours to obtain polymorph F of rilpivirine hydrochloride.
  • Table 8 XRPD angles 2-theta and relative intensities of the acetone solvate of rilpivirine hydrochloride
  • Example 1 1 Preparation of the dichloromethane solvate of rilpivirine hydrochloride
  • Example 12 Preparation of the dichloromethane solvate of rilpivirine hydrochloride To a suspension of 25 mg rilpivirine base in 2 ml_ dichloromethane 50 ⁇ _ (8.8 mol equivalents) concentrated hydrochloric acid were added at room temperature. The suspension was stirred for 4 hours at room temperature before the crystals were isolated by filtration and dried at 80 under vacuum for 5 hours.
  • Table 20 XRPD angles 2-theta and relative intensities of the cyclohexanone solvate of rilpivirine hydrochloride [2-theta] [%] [2-theta] [%]
  • Example 17 Tablet formulation comprising rilpivirine hydrochloride form F rilpivirine hydrochloride form F 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
  • Example 18 Tablet formulation comprising rilpivirine hydrochloride form F
  • Example 19 Tablet formulation comorisina. rilpivirine hydrochloride 1 -Drooanol solvate
  • Example 20 Tablet formulation comprising rilpivirine hydrochloride 1 -propanol solvate tablet core
  • Example 21 Tablet formulation comprising rilpivirine hydrochloride 2-propanol solvate
  • Example 22 Tablet formulation comorisino. rilpivirine hydrochloride 2-prooanol solvate
  • Example 23 Tablet formulation comorisino. rilpivirine hydrochloride acetone solvate rilpivirine hydrochloride acetone solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
  • Example 24 Tablet formulation comprising rilpivirine hydrochloride acetone solvate
  • Example 25 Tablet formulation comorisina. rilpivirine hydrochloride 2-butanone solvate
  • Example 26 Tablet formulation comprising rilpivirine hydrochloride 2-butanone solvate tablet core
  • Example 27 Tablet formulation comprising rilpivirine hydrochloride tetrahydrofuran solvate
  • Examole 28 Tablet formulation comorisina riloivirine hydrochloride tetrahydrofuran solvate

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a novel polymorph and to novel solvates of rilpivirine hydrochloride, as well as to their preparation. The novel solvates are valuable intermediates for the preparation of the novel polymorph of rilpivirine hydrochloride of the present invention. Moreover the present invention relates to the use of the novel polymorph for the preparation of a medicament. In addition the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph of rilpivirine hydrochloride and to methods of preparing the same. Finally the present invention relates to pharmaceutical combinations comprising an effective amount of the novel polymorph of rilpivirine hydrochloride and additional therapeutic agents.

Description

Novel polymorph of rilpivirine hydrochloride
FIELD OF THE INVENTION
The present invention relates to a novel polymorph and to novel solvates of rilpivirine hydrochloride, as well as to their preparation. The novel solvates are valuable intermediates for the preparation of the novel polymorph of rilpivirine hydrochloride of the present invention. Moreover the present invention relates to the use of the novel polymorph for the preparation of a medicament. In addition the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph of rilpivirine hydrochloride and to methods of preparing the same. Finally the present invention relates to pharmaceutical combinations comprising an effective amount of the novel polymorph of rilpivirine hydrochloride and additional therapeutic agents.
BACKGROUND OF THE INVENTION
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. Rilpivirine hydrochloride was launched as film coated tablets in Europe and the US (brand name Edurant). In addition rilpivirine hydrochloride was launched as a combination product with nucleoside analog HIV-1 reverse transcriptase inhibitors in the EU (brand name Eviplera) and the US (brand name Complera). Rilpivirine hydrochloride is represented by the following general formula (I):
Figure imgf000002_0001
EP1419152 B1 discloses 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 discloses amongst others a solid pharmaceutical composition comprising crystalline forms A, B, C or D of rilpivirine hydrochloride. In addition said patent discloses 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 or bioavailability. In addition the preparation process of a crystalline form, especially on large scale, plays an important role in the development of an active pharmaceutical ingredient. It is essential that the crystallization process is robust and reliably produces the desired crystalline form in polymorphically pure form, also on large scale.
The bioavailability of a compound intended to be administered orally, is dependent on the compounds solubility in aqueous systems such as e.g. water, as well as the compounds permeability 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. This is particularly true for badly water soluble active pharmaceutical ingredients such as rilpivirine hydrochloride. Hence an anhydrous form is preferred over a hydrated form for the formulation of an orally administered medicament comprising rilpivirine hydrochloride. Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament, whereas the novel polymorph of the present invention is an anhydrous form and hence especially suitable for the preparation of an orally administered medicament.
In addition the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner because these forms are obtained from the same solvent system. As the polymorphs A and C of rilpivirine hydrochloride are obtained from the same solvent system, namely acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtained in pure form in a quite narrow range of critical parameters, such as the crystallization temperature, as described in the concrete examples A.a) and A.c) of EP1632232 B1 . In contrast the novel polymorph of rilpivirine hydrochloride of the present invention is easily obtained in polymorphically pure form in a reliable manner by applying the novel solvates of rilpivirine hydrochloride of the present invention as intermediates in the production of the novel polymorph.
According to example A.b) of EP1632232 B1 form B is obtained by recrystallizing rilpivirine hydrochloride from propanone using an initial rilpivirine hydrochloride concentration of 0.3 g/L. However, this concentration is not suitable for up-scaling as larger amounts of rilpivirine hydrochloride would require tremendous solvent volumina and hence the usage of tremendously large reaction vessels. In contrast the novel polymorph of the present invention is obtained by applying higher initial concentrations of the novel solvates of rilpivirine hydrochloride of the present invention, which are employed as intermediates for the production of the novel polymorph of the present invention and is thus suitable for large scale production.
Hence the 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 polymorph of rilpivirine hydrochloride, which is obtained in polymorphically pure form in an easy and reliable manner, also on large scale.
SUMMARY OF THE INVENTION
The inventors of the present invention have found a novel polymorph of rilpivirine hydrochloride, in the following named rilpivirine hydrochloride form F. Polymorph F is an anhydrous and non-solvated crystalline form and shows certain advantages 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.
Hence in a preferred embodiment the present invention relates to a novel polymorph of rilpivirine hydrochloride, in the following named rilpivirine hydrochloride form F. Form F of rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 5.6 ± 0.2°, 6.1 ± 0.2°, 6.9 ± 0.2°, 12.5 ± 0.2° and 13.8 ± 0.2°.
In a further preferred embodiment, the present invention relates to processes of preparing form F of rilpivirine hydrochloride in which the novel crystalline solvates of rilpivirine hydrochloride of the present invention are employed as intermediates. Thus in an additional preferred embodiment, the present invention relates to novel solvates of rilpivirine hydrochloride.
In one embodiment the present invention relates to solvates of rilpivirine hydrochloride which are isomorphic and can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.9 ± 0.2° and 23.8 ± 0.2°.
In a further embodiment the present invention relates to additional solvates of rilpivirine hydrochloride which are isomorphic and can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 16.1 ± 0.2°, 18.8 ± 0.2° and 23.5 ± 0.2°.
In still another embodiment the present invention relates to a dichloromethane solvate of rilpivirine hydrochloride which can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ± 0.2°, 16.5 ± 0.2°, 17.8 ± 0.2°, 21 .2 ± 0.2° and 24.1 ± 0.2°.
Moreover in another embodiment the present invention relates to a cyclohexanone solvate of rilpivirine hydrochloride which can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 8.2 ± 0.2°, 17.3 ± 0.2°, 18.8 ± 0.2°, 20.8 ± 0.2° and 23.3 ± 0.2°.
The present invention also relates to a method of preparing the novel solvates of rilpivirine hydrochloride comprising the steps of:
a) providing a suspension or solution of rilpivirine free base in a solvent selected from alcohols, ketones, ethers, or chlorinated hydrocarbons,
b) adding hydrochloric acid to the suspension or solution and
c) recovering the novel solvate of rilpivirine hydrochloride.
Furthermore the present invention relates to the use of the novel solvates of rilpivirine hydrochloride as intermediates for the preparation of rilpivirine hydrochloride form F.
In addition the present invention relates to the use of the novel polymorph F of rilpivirine hydrochloride for the preparation of a medicament. In another embodiment the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph F of rilpivirine hydrochloride and a pharmaceutically acceptable carrier and to processes of preparing the same.
Finally the present invention relates to pharmaceutical combinations comprising an effective amount of the novel polymorph F of rilpivirine hydrochloride and additional therapeutic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride form F
Figure 2: Fourier transform infrared (FTIR) spectrum of rilpivirine hydrochloride form F Figure 3: Overlay X-ray powder diffractograms (XRPD) of rilpivirine hydrochloride 1 -propanol, 2-propanol, acetone, tetrahydrofuran and chloroform solvates
Figure 4: Overlay X-ray powder diffractograms (XRPD) of rilpivirine hydrochloride 1 ,4- dioxane and 2-butanone solvates
Figure 5: X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride dichloromethane solvate
Figure 6: X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride cyclohexanone solvate
Figure 7: Overlay Fourier transform infrared spectra (FTIR) of rilpivirine hydrochloride 1 - propanol, 2-propanol, acetone, tetrahydrofuran and chloroform solvates
Figure 8: Overlay Fourier transform infrared spectra (FTIR) of rilpivirine hydrochloride 1 ,4- dioxane, 2-butanone, dichloromethane and cyclohexanone solvates
Figure 9: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride 1 -propanol solvate
Figure 10: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride 2-propanol solvate
Figure 1 1 : Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride acetone solvate
Figure 12: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride 2-butanone solvate
Figure 13: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride tetrahydrofuran solvate
Figure 14: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride 1 ,4-dioxane solvate
Figure 15: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride dichloromethane solvate Figure 16: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride chloroform solvate
Figure 17: Thermogravimetric analysis (TGA) curve of rilpivirine hydrochloride cyclohexanone solvate
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "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 7.5, 1 .2 (2012)].
The term "solvate" as used herein describes a crystalline compound in which solvent molecules are incorporated into the crystal lattice of the compound in a stoichiometric or non- stoichiometric manner.
The term "concentrated hydrochloric acid" as used herein means aqueous hydrochloric acid having a concentration of about 37 %.
Rilpivirine hydrochloride exists in two stereoisomeric forms, namely an E-isomeric form and a Z-isomeric form. The novel crystalline forms of rilpivirine hydrochloride of the present invention are 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 %.
The chemical structure of the E-isomeric form of rilpivirine hydrochloride is represented by the followin general formula (II):
Figure imgf000007_0001
The chemical structure of the Z-isomeric form of rilpivirine hydrochloride is represented by the following general formula (III):
Figure imgf000008_0001
In a first aspect, the present invention relates to a novel polymorph of rilpivirine hydrochloride (hereinafter also referred to as rilpivirine hydrochloride form F).
Form F of rilpivirine hydrochloride can be characterized by showing an X-ray powder diffractogram comprising characteristic peaks at 2-theta angles of 5.6 ± 0.2°, 6.1 ± 0.2°, 6.9 ± 0.2°, 12.5 ± 0.2° and 13.8 ± 0.2°. The X-ray powder diffractogram of form F of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 15.9 ± 0.2°, 16.6 ± 0.2°, 17.6 ± 0.2°, 17.9 ± 0.2°, 18.5 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 21 .2 ± 0.2°, 21 .8 ± 0.2°, 22.0 ± 0.2°, 22.8 ± 0.2°, 23.5 ± 0.2°, 23.8 ± 0.2°, 24.2 ± 0.2°, 24.6 ± 0.2°, 24.9 ± 0.2°, 25.5 ± 0.2°, 26.6 ± 0.2° and 27.4 ± 0.2°. A representative diffractogram is displayed in figure 1 .
In addition form F of rilpivirine hydrochloride can be characterized by showing an FTIR- spectrum comprising peaks at wavenumbers of 3223 ± 2 cm"1 , 2222 ± 2 cm"1 , 1652 ± 2 cm"1 , 966 ± 2 cm"1 and 81 1 ± 2 cm"1. The FTIR-spectrum of form F of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3176 ± 2 cm"1 , 3055 ± 2 cm"1 , 2961 ± 2 cm"1 , 2862 ± 2 cm"1 , 1635 ± 2 cm"1 , 1598 ± 2 cm"1 , 1566 ± 2 cm"1 , 1541 ± 2 cm"1 , 1522 ± 2 cm"1 , 1503 ± 2 cm"1 , 1444 ± 2 cm"1 , 1416 ± 2 cm"1 , 1386 ± 2 cm"1 , 1357 ± 2 cm"1 , 1338 ± 2 cm"1 , 1308 ± 2 cm"1 , 1273 ± 2 cm"1 , 1241 ± 2 cm"1 , 1213 ± 2 cm"1 , 1 178 ± 2 cm"1 , 1 154 ± 2 cm"1 , 1097 ± 2 cm"1 , 1072 ± 2 cm"1 , 1031 ± 2 cm"1 , 1018 ± 2 cm"1 , 985 ± 2 cm"1 , 869 ± 2 cm"1 , 851 ± 2 cm"1 , 794 ± 2 cm"1 , 713 ± 2 cm"1 , 680 ± 2 cm"1 , 666 ± 2 cm"1 and 623 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 2.
Furthermore form F of rilpivirine hydrochloride can be characterized as being an anhydrous form containing less than about 1 .5 %, preferably less than about 1 .0 % water.
The present invention also relates to a process for the preparation of form F of rilpivirine hydrochloride comprising slurrying a novel solvate of rilpivirine hydrochloride of the present invention in water, collecting the obtained crystals and drying the crystals at about 80 to about 180 °C and/or below about 5 % relative humidity.
In a first step a suspension of a novel solvate of rilpivirine hydrochloride of the present invention in water is provided. Any crystalline solvate of rilpivirine hydrochloride of the present invention may be applied e.g. crystalline rilpivirine hydrochloride 1 -propanol solvate, crystalline rilpivirine hydrochloride 2-propanol solvate, crystalline rilpivirine hydrochloride acetone solvate, crystalline rilpivirine hydrochloride 2-butanone solvate, crystalline rilpivirine hydrochloride cyclohexanone solvate, crystalline rilpivirine hydrochloride tetrahydrofuran solvate, crystalline rilpivirine hydrochloride 1 ,4-dioxane solvate, crystalline rilpivirine hydrochloride dichloromethane solvate, crystalline rilpivirine hydrochloride chloroform solvate or mixtures thereof.
The initial rilpivirine hydrochloride concentration applied in the process may range from about 1 to 200 g/L, preferably from about 5 to 150 g/L, more preferably from about 10 to 100 g/L and most preferably from about 15 to 30 g/L.
The suspension is stirred, at a temperature preferably ranging from about 0 to 40 °C, more preferably from about 10 to 30 °C and most preferably the suspension is stirred at about room temperature, for a time preferably ranging from about 1 to 72 hours, more preferably from about 6 to 60 hours, and most preferably from about 12 to 48 hours.
The obtained crystals are then collected by any conventional methods such as filtration, centrifugation or evaporation of the solvent, preferably by filtration.
Thereafter the crystals are dried preferably under vacuum at a temperature preferably ranging from about 80 ¾ to 180 °C, more preferably from about 90 °C to 140 °C and most preferably from about 100 °C to 1 10 °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.
Alternatively the crystals can be dried at room temperature by storing them at an atmosphere having a relative humidity of < 5 % e.g. by storing the crystals in a closed containment over a desiccant such as e.g. P205 or silica gel, whereat the storing time may range from about 1 to 72 hours, more preferably from about 6 to 48 hours and most preferably from about 12 to 24 hours. The storing time may be decreased by storing the crystals at < 5 % relative humidity and applying elevated temperatures preferably ranging from about 30 to 180 °C, more preferably from about 40 to 140 °C and most preferably from about 50 to 110 °C.
The particle size of rilpivirine hydrochloride form F obtained according to the processes of the present invention typically ranges from about 10 to 150 μιη 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. Preferably milling and sieving are performed in such a manner that rilpivirine hydrochloride form F having a particle size ranging from about 0.1 to 50 μιη, more preferably from about 0.1 to 25 μιη and most preferably from about 0.1 to 15 μιη is obtained.
The bioavailability of a compound intended to be administered orally, is dependent on the compounds solubility in aqueous systems such as e.g. water, as well as the compounds permeability 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. This is particularly true for badly water soluble active pharmaceutical ingredients such as rilpivirine hydrochloride. Hence, an anhydrous form is preferred over a hydrated form for the formulation of an orally administered medicament comprising rilpivirine hydrochloride. Rilpivirine hydrochloride form D of EP1632232 B1 is a hydrate and thus not preferred for the preparation of an orally administered medicament, whereas the novel polymorph F of the present invention is an anhydrous form and hence especially suitable for the preparation of an orally administered medicament.
In addition, the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner because these forms are obtained from the same solvent system. As the polymorphs A and C of rilpivirine hydrochloride are obtained from the same solvent system, namely acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtained in pure form in a quite narrow range of critical parameters, such as the crystallization temperature, as described in the concrete examples A.a) and A.c) of EP1632232 B1 . In contrast, the novel polymorph F of rilpivirine hydrochloride of the present invention is easily obtained in polymorphically pure form in a reliable manner by applying the novel solvates of rilpivirine hydrochloride of the present invention as intermediates in the process for the production of the novel polymorph F. The novel solvates are slurried in water and dried at≥ 80 °C and or at < 5 % relative humidity to obtain polymorphically pure form F of rilpivirine hydrochloride.
According to example A.b) of EP1632232 B1 form B is obtained by recrystallizing rilpivirine hydrochloride from propanone using an initial rilpivirine hydrochloride concentration of 0.3 g/L. However, this concentration is not suitable for up-scaling as larger amounts of rilpivirine hydrochloride would require tremendous solvent volumina and hence the usage of tremendously large reaction vessels. In contrast the novel polymorph F of the present invention is obtained by applying higher initial concentrations of the novel solvates of rilpivirine hydrochloride of the present invention, which are employed as intermediates for form F production, such as e.g. 20 mg/mL (see example 1 ) and is thus suitable for large scale production.
The novel polymorph F 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 an anhydrous form obtained in polymorphically pure form in an easy and reliable manner according to the processes of the present invention, also on large scale.
Thus polymorph F of rilpivirine hydrochloride is the most favored form to be used in an oral antiviral 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 pharmaceutical compositions comprising rilpivirine hydrochloride form F as described above and a pharmaceutically acceptable carrier.
Preferably, the present invention relates to pharmaceutical compositions, wherein more than 95 % of rilpivirine hydrochloride are stably present as rilpivirine hydrochloride form F, more preferably wherein rilpivirine hydrochloride form F is the only detectable crystalline form of rilpivirine hydrochloride. The absence of other crystalline forms of rilpivirine hydrochloride, such as forms A, B, C and D of EP1632232 B1 can be tested by comparing an XRPD taken of any crystalline rilpivirine hydrochloride with the XRPD of form F as obtained from example 1 and shown in figure 1 , which for this comparison is to be taken as an XRPD of 100 % form F.
"Stably present" as defined herein means that even after storage of the pharmaceutical composition for 180 days and preferably even after storage for 3 years, the crystalline form of rilpivirine hydrochloride designated as rilpivirine hydrochloride form F initially comprised in the pharmaceutical composition is still present as rilpivirine hydrochloride form F after storage for the indicated period.
The pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F may further comprise one or more pharmaceutically acceptable excipients. Such 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. Furthermore, the pharmaceutical composition may comprise a combination of two or more excipients also within one of the members of the above mentioned group.
Examples of suitable excipients for pharmaceutical compositions of the invention comprising rilpivirine hydrochloride form F are given e.g. in EP1632232 B1 , which is herein incorporated by reference in paragraphs [0063] to [0080].
Paragraph [0063] of EP1632232 B1 discloses examples of wetting agents for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. The preferred wetting agents, which can also be used for the pharmaceutical compositions of the present invention, comprise sodium lauryl sulphate, sodium dioctyl sulfosuccinate or wetting agents belonging to the group of the polyethylene glycol sorbitan fatty acid esters, such as wetting agents known as Tween, e.g. Tween 20, 60 and 80, whereat Tween 20 (= polysorbate 20) is most preferred.
Paragraphs [0065] to [0072] of EP1632232 B1 disclose examples of binders for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. 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 and xanthan gum, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g. poloxamers and poloxamines, copovidone, whereat starch, polyvinylpyrrolidone or a cellulose ether e.g PVP K29-32, PVP K90, methyl cellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose or hydroxypropyl methylcellulose (HPMC) are preferred. Paragraph [0075] of EP1632232 B1 discloses examples of suitable diluents for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. The preferred diluents, which can also be used for the pharmaceutical compositions of the present invention, comprise e.g. calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulphate, 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 silicified microcrystalline cellulose, starch, modified starch, dibasic calcium phosphate and dibasic calcium phosphate dihydrate are preferred.
Paragraph [0076] of EP1632232 B1 discloses examples of glidants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. 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.
Paragraph [0078] of EP1632232 B1 discloses examples of disintegrants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. 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.
Paragraph [0079] of EP1632232 B1 discloses examples of lubricants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F. 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. In addition the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form F 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 F. 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, optionally a plasticizer, optionally a pigment or an opacifier and/or optionally a filler of the coating layer. An example for a suitable film-forming polymer is hydroxypropyl methylcellulose e.g. hypromellose 2910 mPa.s, an example for a suitable plasticizer is polyethyleneglycol e.g. macrogol 3000 or 6000 and/or triacetin, an example for a suitable pigment respectively opacifier is titanium dioxide and an example for a suitable filler is lactose monohydrate. A suitable commercially available ready to use film coating powder which can be applied for the preparation of the pharmaceutical composition of the present invention is e.g. Opadry® II White.
Examples of suitable processes for the preparation of the pharmaceutical compositions of the present invention, which are preferably film coated tablets, are given e.g. in EP1632232 B1 , which is herein incorporated by reference in paragraphs [0084] to [0086], wherein it is to be understood that whenever the term compound of formula (I), (la) or (l-b) or active ingredient is used in EP1632232 B1 an equivalent amount of rilpivirine hydrochloride form F of the present invention is to be used.
Concrete examples for the production of formulations of the present invention are given e.g. in EP1632232 B1 , paragraphs [0120] to [0137]. These examples can be repeated by substituting the compound of formula (1 -a) against rilpivirine hydrochloride form F of the present invention.
The pharmaceutical composition of the present invention comprising rilpivirine hydrochloride form F preferably is an oral dosage form, in particular a capsule or tablet.
A preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30) and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide. Another preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), dibasic calcium phosphate (dihydrate or anhydrate e.g. Emcompress® or anhydrous Emcompress®), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
In addition a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, lactose monohydrate, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
A further preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, modified starch, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30) and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
In one embodiment a tablet of the present invention may be prepared by wet granulation comprising the steps of:
a) dry blending rilpivirine hydrochloride form F of the present invention and a part of the diluent,
b) preparing a binder solution by dissolving a binder and a wetting agent in a suitable solvent,
c) spraying the binder solution of step b) on the mixture obtained in step a),
d) drying the obtained granulate and sieving the same,
e) mixing the obtained granulate with the remaining part of diluent and a disintegrant, f) adding an optional glidant and/or an optional lubricant to the mixture,
g) compressing the obtained mixture into a tablet and
h) optionally film-coating the obtained tablet.
Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2- propanol, propyl acetate and tetrahydrofuran.
A particular tablet of the present invention may be prepared by wet granulation comprising the steps of: a) dry blending rilpivirine hydrochloride form F of the present invention and lactose monohydrate,
b) preparing a binder solution by dissolving polyvinylpyrrolidone K30 (PVP K30) and polysorbate 20 (Tween 20) in a suitable solvent,
c) spraying the binder solution of step b) on the mixture obtained in step a),
d) drying the obtained granulate and sieving the same,
e) mixing the obtained granulate with silicified microcrystalline cellulose and croscarmellose sodium,
f) adding magnesium stearate to the mixture,
g) compressing the obtained mixture into a tablet and
h) optionally film-coating the obtained tablet.
Suitable solvents in step b) of the herein disclosed wet granulation process are e.g. water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2- propanol, propyl acetate and tetrahydrofuran.
A further preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
Another preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, dibasic calcium phosphate (dihydrate or anhydrate e.g. Emcompress® or anhydrous Emcompress®), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide. Moreover, a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, lactose monohydrate, magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
In addition a preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form F of the present invention, microcrystalline cellulose, modified starch and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
In another embodiment a tablet of the present invention may be prepared by direct compression comprising the steps of:
a) dry blending rilpivirine hydrochloride form F of the present invention, a disintegrant, an optional glidant and an optional lubricant with at least one diluent,
b) compressing the obtained mixture in the dry state into a tablet and
c) optionally film-coating the obtained tablet.
A particular tablet of the present invention may be prepared by direct compression comprising the steps of:
a) dry blending rilpivirine hydrochloride form F of the present invention, croscarmellose sodium and magnesium stearate with lactose monohydrate and silicified microcrystalline cellulose,
b) compressing the obtained mixture in the dry state into a tablet and
c) optionally film-coating the obtained tablet.
Formulations of the present invention typically comprise about 100 mg, preferably about 75 mg, more preferably about 50 mg and most preferably about 25 mg rilpivirine hydrochloride form F (calculated as rilpivirine free base).
The pharmaceutical compositions of the present invention comprising crystalline form F of rilpivirine hydrochloride are preferably packaged or filled into containers. Containers are typically used for stable storage of the pharmaceutical compositions of the present invention for example at a temperature of about 20 °C to 30 °C e.g. at about 25 °C for a prolonged time e.g. for at least 6 months, preferably at least about 24 months, for up to at least 24 months e.g. for up to at least about 30 months, such as for up to about 60 months. The container used for the stable storage of the pharmaceutical compositions of the present invention comprising crystalline form F of rilpivirine hydrochloride ensures an environment having a relative humidity of about 0 to 70 %, more preferably of about 0 to 50 % and most preferably of about 0 to 30 %.
A preferred container is a bottle, in particular a polyethylene bottle e.g. a HDPE bottle or a glass bottle, having e.g. a screw closure with an aluminum induction seal liner, or is a blister, e.g. an aluminum blister or strip, e.g. a blister consisting of two aluminum foils or strips, or may be any other suitable container. More preferably said container is a gas-tight container, such as an air-tight container.
In a further embodiment the present invention relates to a pharmaceutical combination comprising an effective amount of rilpivirine hydrochloride form F and one or more additional therapeutic agents such as e.g. anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections. Preferably 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 anti-viral agent for the pharmaceutical combination with rilpivirine hydrochloride form F of the present invention is preferably chosen from the class of nucleoside analog HIV-1 reverse transcriptase inhibitors, whereat emtricitabine and tenofovir are most preferred.
A preferred pharmaceutical combination of the present invention comprises 25 mg rilpivirine hydrochloride form F (calculated as free base), 200 mg emtricitabine and 245 mg tenofovir disoproxil fumarate (calculated as free base) and one or more pharmaceutically acceptable excipients.
In a second aspect the present invention relates to novel crystalline solvates of rilpivirine hydrochloride.
Some of the solvates of rilpivirine hydrochloride produce very similar X-ray powder diffractograms indicating that these solvates are isomorphic. Isomorphic solvates means that even though the solvates contain different solvents, they exhibit essentially the same molecular packing resulting in very similar corresponding unit cell parameters. Thus these solvates can be identified by some common characteristic reflections as described below. Hence in one embodiment the present invention relates to crystalline isomorphic solvates of rilpivirine hydrochloride, which are characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.9 ± 0.2° and 23.8 ± 0.2°. Representative diffractograms are displayed in figure 3.
The isomorphic solvates of rilpivirine hydrochloride are characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride, wherein the solvent incorporated into the crystal lattice is selected from 1 - propanol, 2-propanol, acetone, tetrahydrofuran or chloroform.
In addition the isomorphic solvates of rilpivirine hydrochloride are surprisingly stable as the desolvation occurs only at about > 150 °C, more preferably at about > 200 °C as indicated by thermogravimetric analysis.
In another embodiment the present invention relates to additional crystalline isomorphic solvates of rilpivirine hydrochloride, which are characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 16.1 ± 0.2°, 18.8 ± 0.2° and 23.5 ± 0.2°. Representative diffractograms are displayed in figure 4.
The isomorphic solvates of rilpivirine hydrochloride are characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride, wherein the solvent incorporated into the crystal lattice is selected from 1 ,4- dioxane or 2-butanone.
In addition the isomorphic solvates of rilpivirine hydrochloride are surprisingly stable as the desolvation occurs only at about > 150 °C, more preferably at about > 200 °C as indicated by thermogravimetric analysis.
In still another embodiment the present invention relates to a dichloromethane solvate which is characterized by an X-ray powder diffraction pattern comprising peaks at 2- theta angles of 8.2 ± 0.2°, 16.5 ± 0.2°, 17.8 ± 0.2°, 21.2 ± 0.2° and 24.1 ± 0.2°. A representative diffractogram is displayed in figure 5.
The dichloromethane solvate of rilpivirine hydrochloride is characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol dichloromethane per mol rilpivirine hydrochloride. In addition the dichloromethane solvate of rilpivirine hydrochloride is surprisingly stable as the desolvation occurs only at about > 150 °C indicated by thermogravimetric analysis.
In a further embodiment the present invention relates to a cyclohexanone solvate characterized by an X-ray powder diffraction pattern showing peaks at 2-theta angles of 8.1 ± 0.2°, 17.3 ± 0.2°, 18.8 ± 0.2°, 20.8 ± 0.2° and 23.3 ± 0.2°. A representative diffractogram is displayed in figure 6.
The cyclohexanone solvate of rilpivirine hydrochloride is characterized by a solvent content of about 0.3 to 0.7 mol, more preferably about 0.4 to 0.6 mol cyclohexanone per mol rilpivirine hydrochloride.
In addition the cyclohexanone solvate of rilpivirine hydrochloride is surprisingly stable as the desolvation occurs only at about > 200 °C as indicated by thermogravimetric analysis.
The novel crystalline solvates of the present invention cannot be distinguished unambiguously by means of FTIR-spectroscopy as they all show very similar FTIR-spectra. Differences are only detectable at some peak positions, which can directly be related to the incorporated solvent. Acetone, 2-butanone and cyclohexanone e.g. display a peak between 1710 - 1717 cm"1 which can directly be related to the C=0 stretching vibration of these solvents. But apart from these differences no significant differences are detectable, thus again indicating that the solvates crystallize in similar crystal structures. However, the FTIR- spectra of the novel solvates of rilpivirine hydrochloride of the present invention can be distinguished from these of non-solvated crystalline forms of rilpivirine hydrochloride such as e.g. forms A, B and C of EP1632232 B1 or form F of the present invention and from hydrated forms of rilpivirine hydrochloride such as form D of EP1632232 B1 .
Hence, the present invention relates to novel crystalline solvates of rilpivirine hydrochloride characterized by an infrared spectrum displaying peaks at wavenumbers of 3057 ± 2 cm"1 , 2228 ± 2 cm"1 , 2218 ± 2 cm"1 , 1656 ± 2 cm"1 and 1542 ± 2 cm"1. Representative infrared spectra are displayed in figures 7 and 8.
In a further embodiment the present invention relates to a process for the preparation of the novel solvates comprising the steps of:
a) providing a suspension or solution of rilpivirine free base in a solvent selected from alcohols, ketones, ethers or chlorinated hydrocarbons,
b) adding hydrochloric acid to the suspension or solution and c) recovering the novel solvate of rilpivirine hydrochloride.
Suitable alcohols, which can be used for the present process are e.g. 1 -propanol or 2- propanol, suitable ketones are e.g. acetone, 2-butanone or cyclohexanone, suitable chlorinated hydrocarbons are e.g. dichloromethane or chloroform and suitable ethers are e.g. tetrahydrofuran or 1 ,4-dioxane.
The initial rilpivirine concentration applied in the process may range from about 1 to 200 g/L, preferably from about 1 to 200 g/L, more preferably from about 1 to 150 g/L and most preferably from about 1 to 100 g/L.
Rilpivirine free base may either be suspended or dissolved in the applied solvent prior to the hydrochloric acid addition. A possible dissolution step may be performed at elevated temperatures ranging from about room temperature to about the reflux temperature of the applied solvent.
Hydrochloric acid may be applied in the process in any suitable concentration e.g gaseous hydrochloric acid or aqueous hydrochloric acid, whereat the applied aqueous hydrochloric acid preferably has a concentration between about 9 % and about 37 %, more preferably between about 18 % and about 37 % and most preferably concentrated hydrochloric acid is used having a concentration of about 37 %.
The amount of hydrochloric acid used in the process of the present invention preferably ranges from about 1.0 to 10.0 mol equivalents, more preferably from about 1 .0 to 8.0 mol equivalents and most preferably from about 1 .0 to 5.0 mol equivalents.
After the hydrochloric acid addition the mixture is stirred at a temperature preferably ranging from about 0 to 40 °C, more preferably from about 10 to 30 °C and most preferably at about room temperature, for a time ranging from about 1 to 72 hours, preferably from about 1 to 48 hours, more preferably from about 1 to 24 hours and most preferably from about 1 to 18 hours.
The obtained crystals are collected by any conventional methods such as filtration, centrifugation or evaporation of the solvent, most preferably by filtration.
Thereafter the crystals are dried preferably under vacuum at a temperature preferably ranging from about 25 ¾ to 150 °C, more preferably from about 30 °C to 100 °C and most preferably from about 40 °C to 80 °C for a time preferably ranging from about 2 to 72 hours, more preferably from about 12 to 48 hours and most preferably from about 24 to 36 hours.
Depending on the solvent applied in the above described process different crystalline solvates such as a 1 -propanol solvate, a 2-propanol solvate, an acetone solvate, a 2- butanone solvate, a tetrahydrofuran solvate, a 1 ,4-dioxane solvate, a dichloromethane solvate, a chloroform solvate or a cyclohexanone solvate of rilpivirine hydrochloride are obtained.
Therefore the present invention also relates to a novel 1 -propanol solvate of rilpivirine hydrochloride.
The novel crystalline 1 -propanol solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.8 ± 0.2° and 23.9 ± 0.2°. The X-ray powder diffractogram of the novel crystalline 1 - propanol solvate comprises additional characteristic peaks at 2-theta angles of 10.6 ± 0.2°,
14.5 ± 0.2°, 15.2 ± 0.2°, 15.6 ± 0.2°, 16.4 ± 0.2°, 18.3 ± 0.2°, 18.5 ± 0.2°, 19.0 ± 0.2°, 19.7 ± 0.2°, 21 .2 ± 0.2°, 21 .6 ± 0.2°, 21.9 ± 0.2°, 22.7 ± 0.2°, 24.2 ± 0.2°, 25.1 ± 0.2°, 26.4 ± 0.2°,
26.6 ± 0.2°, 27.8 ± 0.2°, 29.4 ± 0.2° and 32.4 ± 0.2°. A representative diffractogram is displayed in figure 3.
In addition the novel crystalline 1 -propanol solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3059 ± 2 cm"1 , 2230 ± 2 cm"1 , 2220 ± 2 cm"1 , 1657 ± 2 cm"1 and 1543 ± 2 cm"1. The FTIR-spectrum of the novel crystalline 1 -propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ± 2 cm"1 , 3242 ± 2 cm"1 , 3182 ± 2 cm"1 , 2968 ± 2 cm"1 , 2875 ± 2 cm"1 , 1637 ± 2 cm"1 , 1603 ± 2 cm"1 , 1567 ± 2 cm"1 , 1506 ± 2 cm"1 , 1450 ± 2 cm"1 , 1419 ± 2 cm"1 , 1387 ± 2 cm"1 , 1345 ± 2 cm"1 , 1273 ± 2 cm"1 , 1245 ± 2 cm"1 , 1217 ± 2 cm"1 , 1 181 ± 2 cm"1 , 1 156 ± 2 cm"1 , 1074 ± 2 cm"1 , 1055 ± 2 cm"1 , 970 ± 2 cm"1 , 872 ± 2 cm"1 , 825 ± 2 cm"1 and 797 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 7.
Furthermore the 1 -propanol solvate of rilpivirine hydrochloride of the present invention preferably contains from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 1 - propanol per mol rilpivirine hydrochloride. E.g. the 1 -propanol solvate contains about 0.5 mol 1 -propanol per mol rilpivirine hydrochloride as detected by single X-ray diffraction and can thus be characterized as being a hemisolvate. In addition the present invention relates to a novel crystalline 2-propanol solvate of rilpivirine hydrochloride.
The novel crystalline 2-propanol solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.8 ± 0.2° and 23.9 ± 0.2°. The X-ray powder diffractogram of the novel crystalline 2- propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 10.6 ±0.2°, 14.5 ±0.2°, 15.2 ±0.2°, 15.6 ±0.2°, 16.4 ±0.2°, 18.2 ±0.2°, 18.5 ±0.2°, , 19.0 ±0.2°, 19.7 ±0.2°, 21.2 ±0.2°, 21.5 ±0.2°, 21.9 ±0.2°, 22.7 ±0.2°, 24.1 ±0.2°, 24.5 ± 0.2°, 25.1 ± 0.2°, 26.3 ± 0.2°, 26.6 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°, 28.8 ± 0.2°, 29.1 ± 0.2°, 29.4 ± 0.2°, 32.4 ± 0.2° and 33.4 ± 0.2°. A representative diffractogram is displayed in figure 3.
In addition the novel crystalline 2-propanol solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3057 ± 2 cm"1, 2228 ± 2 cm"1, 2218 ± 2 cm"1, 1656 ± 2 cm"1 and 1541 ±2 cm"1. The FTIR-spectrum of the novel crystalline 2-propanol solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ± 2 cm"1, 3230 ± 2 cm"1, 3178 ± 2 cm"1, 2968 ± 2cm"1,2872 ±2cm"1, 1634 ±2 cm"1, 1601 ±2 cm"1, 1563 ±2 cm"1, 1499 ±2 cm"1, 1448 ±2 cm"1, 1417 ± 2 cm"1, 1384 ± 2 cm"1, 1344 ± 2 cm"1, 1315 ± 2 cm"1, 1271 ± 2 cm"1, 1244 ± 2 cm"1, 1215 ± 2 cm"1, 1179 ± 2 cm"1, 1155 ± 2 cm"1, 1129 ± 2 cm"1, 1098 ± 2 cm"1, 1073 ± 2 cm"1 , 1033 ± 2 cm"1 , 969 ± 2 cm"1 ,951 ±2 cm"1 , 870 ± 2 cm"1 , 844 ± 2 cm"1 , 822 ± 2 cm"1 and 795 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 7.
Furthermore the 2-propanol solvate of rilpivirine hydrochloride of the present invention preferably contains from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 2- propanol per mol rilpivirine hydrochloride. E.g. the 2-propanol solvate contains about 0.5 mol 2-propanol per mol rilpivirine hydrochloride as detected by single X-ray diffraction and can thus be characterized as being a hemisolvate.
Moreover the present invention relates to a novel crystalline acetone solvate of rilpivirine hydrochloride.
The novel crystalline acetone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.9 ± 0.2° and 23.8 ± 0.2°. The X-ray powder diffractogram of the novel crystalline acetone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 9.4 ± 0.2°, 9.9 ± 0.2°, 10.6 ± 0.2°, 14.5 ± 0.2°, 15.2 ± 0.2°, 15.6 ± 0.2°, 16.4 ± 0.2°, 17.8 ± 0.2°,
18.5 ± 0.2°, 19.8 ± 0.2°, 21 .2 ± 0.2°, 21 .6 ± 0.2°, 21 .9 ± 0.2°, 22.7 ± 0.2°, 24.1 ± 0.2°, 24.6 ± 0.2°, 25.2 ± 0.2°, 26.3 ± 0.2°, 26.5 ± 0.2°, 27.7 ± 0.2°, 29.2 ± 0.2°, 29.6 ± 0.2° and 32.5 ± 0.2°. A representative diffractogram is displayed in figure 3.
In addition the novel crystalline acetone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ± 2 cm"1 , 2229 ± 2 cm"1 , 2218 ± 2 cm"1 , 1655 ± 2 cm"1 and 1542 ± 2 cm"1. The FTIR-spectrum of the novel crystalline acetone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3276 ± 2 cm"1 , 3239 ± 2 cm"1 , 3178 ± 2 cm"1 , 2963 ± 2 cm"1 , 2873 ± 2 cm"1 , 1716 ± 2 cm"1 , 1635 ± 2 cm"1 , 1601 ± 2 cm"1 , 1564 ± 2 cm"1 , 1503 ± 2 cm"1 , 1448 ± 2 cm"1 , 1417 ± 2 cm"1 , 1383 ± 2 cm"1 , 1343 ± 2 cm"1 , 1314 ± 2 cm"1 , 1270 ± 2 cm"1 , 1242 ± 2 cm"1 , 1215 ± 2 cm"1 , 1 179 ± 2 cm"1 , 1 154 ± 2 cm"1 , 1 100 ± 2 cm"1 , 1072 ± 2 cm"1 , 1030 ± 2 cm"1 , 969 ± 2 cm"1 , 870 ± 2 cm"1 , 850 ± 2 cm"1 , 823 ± 2 cm"1 , 794 ± 2 cm"1 and 717 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 7.
Furthermore the acetone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol acetone per mol rilpivirine hydrochloride. E.g. the acetone solvate comprises about 0.4 mol acetone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
The present invention also relates to a novel crystalline 2-butanone solvate of rilpivirine hydrochloride.
The novel crystalline 2-butanone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 16.1 ± 0.2°, 18.9 ± 0.2° and 23.4 ± 0.2°. The X-ray powder diffractogram of the novel crystalline 2- butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 10.6 ± 0.2°, 14.5 ± 0.2°, 15.1 ± 0.2°, 15.3 ± 0.2°, 17.4 ± 0.2°, 17.7 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, 19.9 ± 0.2°, 21 .2 ± 0.2°, 21 .4 ± 0.2°, 21 .9 ± 0.2°, 22.5 ± 0.2°, 24.0 ± 0.2°, 24.4 ± 0.2°, 25.2 ± 0.2°, 25.9 ± 0.2°, 26.2 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°, 29.2 ± 0.2° and
29.6 ± 0.2°. A representative diffractogram is displayed in figure 4.
In addition the novel crystalline 2-butanone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ± 2 cm"1 , 2229 ± 2 cm"1 , 2219 ± 2 cm"1 , 1655 ± 2 cm"1 and 1542 ± 2 cm"1. The FTIR-spectrum of the novel crystalline 2-butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3277 ± 2 cm"1, 3241 ± 2 cm"1, 3173 ± 2 cm"1, 2968 ± 2 cm"1, 2873 ±2 cm"1, 1711 ±2 cm"1, 1636 ± 2 cm"1, 1601 ± 2 cm"1, 1563 ±2 cm"1, 1520 ±2 cm"1, 1498 ± 2 cm"1, 1447 ± 2 cm"1, 1418 ± 2 cm"1, 1382 ± 2 cm"1, 1344 ± 2 cm"1, 1314 ± 2 cm"1, 1270 ± 2 cm"1, 1243 ± 2 cm"1, 1214 ± 2 cm"1, 1180 ± 2 cm"1, 1155 ± 2 cm"1, 1099 ± 2 cm"1, 1073 ± 2 cm"1, 1037 ± 2 cm"1, 988 ± 2 cm"1, 970 ± 2 cm"1, 884 ± 2 cm"1, 870 ± 2 cm"1, 849 ± 2 cm"1, 823 ± 2 cm"1 and 794 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 8.
Furthermore the 2-butanone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 2- butanone per mol rilpivirine hydrochloride. E.g. the 2-butanone solvate comprises about 0.5 mol 2-butanone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
In addition the present invention relates to a novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride.
The novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 17.5 ± 0.2°, 18.9 ± 0.2° and 23.7 ± 0.2°. The X-ray powder diffractogram of the novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 10.6 ± 0.2°, 14.5 ± 0.2°, 15.2 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 17.8 ± 0.2°, 18.3 ± 0.2°, 19.8 ± 0.2°, 21.2 ± 0.2°, 21.5 ± 0.2°, 22.0 ± 0.2°, 22.6 ± 0.2°, 24.0 ± 0.2°, 24.5 ± 0.2°, 25.2 ± 0.2°, 26.2 ± 0.2°, 26.4 ± 0.2°, 27.6 ± 0.2°, 29.2 ± 0.2° and 29.5 ± 0.2°. A representative diffractogram is displayed in figure 3.
In addition the novel crystalline tetrahydrofuran solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ± 2 cm"1, 2229 ±2 cm"1, 2219 ±2 cm"1, 1655 ±2 cm"1 and 1542 ±2 cm"1. The FTIR-spectrum of the novel crystalline 2-butanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ± 2 cm"1, 3240 ± 2 cm"1, 3174 ± 2 cm"1, 2969 ± 2 cm"1, 2872 ± 2 cm"1, 1635 ± 2 cm"1, 1601 ± 2 cm"1, 1563 ± 2 cm"1, 1521 ±2 cm"1, 1499 ± 2 cm"1, 1448 ± 2 cm"1, 1417 ± 2 cm"1, 1384 ± 2 cm"1, 1344 ± 2 cm"1, 1311 ±2 cm"1, 1271 ± 2 cm"1, 1243 ± 2 cm"1, 1215 ± 2 cm"1, 1179 ± 2 cm"1, 1154 ± 2 cm"1, 1099 ± 2 cm"1, 1071 ± 2 cm"1 , 1038 ± 2 cm"1 , 988 ± 2 cm"1 , 969 ± 2 cm"1 , 884 ± 2 cm"1 , 870 ± 2 cm"1 , 850 ± 2 cm"1 , 824 ± 2 cm"1, 793 ± 2 cm"1 and 716 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 7.
Furthermore the tetrahydrofuran solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol tetrahydrofuran per mol rilpivirine hydrochloride. E.g. the tetrahydrofuran solvate comprises about 0.5 mol tetrahydrofuran per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
Moreover the present invention relates to a novel crystalline 1 ,4-dioxane solvate of rilpivirine hydrochloride.
The novel crystalline 1 ,4-dioxane solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 16.2 ± 0.2°, 18.8 ± 0.2° and 23.5 ± 0.2°. The X-ray powder diffractogram of the novel crystalline 1,4- dioxane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 14.0 ±0.2°, 14.5 ±0.2°, 15.1 ±0.2°, 15.4 ±0.2°, 16.5 ±0.2°, 17.4 ±0.2°, 17.7 ± 0.2°, 18.3 ± 0.2°, 19.8 ± 0.2°, 21.1 ± 0.2°, 21.4 ± 0.2°, 21.9 ± 0.2°, 22.5 ± 0.2°, 23.8 ± 0.2°, 24.4 ± 0.2°, 25.2 ± 0.2°, 26.0 ± 0.2°, 26.3 ± 0.2°, 27.6 ± 0.2°, 29.2 ± 0.2°, 29.5 ± 0.2°, 32.2 ± 0.2 and 32.4 ± 0.2°. A representative diffractogram is displayed in figure 4.
In addition the novel crystalline 1,4-dioxane solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ± 2 cm"1, 2229 ± 2 cm"1, 2220 ± 2 cm"1, 1654 ± 2 cm"1 and 1541 ±2 cm"1. The FTIR-spectrum of the novel crystalline 1,4-dioxane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3274 ± 2 cm"1, 3237 ± 2 cm"1, 3179 ± 2 cm"1, 2962 ± 2 cm"1, 2874 ±2 cm"1, 2852 ±2 cm"1, 1635 ±2 cm"1, 1601 ±2 cm"1, 1563 ±2 cm"1, 1520 ±2 cm"1, 1498 ± 2 cm"1, 1447 ± 2 cm"1, 1417 ± 2 cm"1, 1384 ± 2 cm"1, 1344 ± 2 cm"1, 1314 ± 2 cm"1, 1271 ± 2 cm"1, 1244 ± 2 cm"1, 1215 ± 2 cm"1, 1179 ± 2 cm"1, 1154 ± 2 cm"1, 1122 ± 2 cm"1, 1073 ± 2 cm"1, 1031 ±2 cm"1, 987 ± 2 cm"1, 968 ± 2 cm"1, 873 ± 2 cm"1, 849 ± 2 cm"1, 825 ± 2 cm"1, 792 ± 2 cm"1, 727 ± cm"1 and 716 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 8.
Furthermore the 1,4-dioxane solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol 1,4-dioxane per mol rilpivirine hydrochloride. E.g. the 1,4-dioxane solvate comprises about 0.6 mol 1 ,4-dioxane per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
The present invention also relates to a novel crystalline dichloromethane solvate of rilpivirine hydrochloride.
The novel crystalline dichloromethane solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 16.5 ± 0.2°, 17.8 ± 0.2°, 21.2 ± 0.2° and 24.1 ± 0.2°. The X-ray powder diffractogram of the novel crystalline dichloromethane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 8.9 ± 0.2°, 14.6 ± 0.2°, 15.3 ± 0.2°, 15.8 ± 0.2°, 16.2 ± 0.2°, 18.4 ± 0.2°, 18.6 ± 0.2°, 18.8 ± 0.2°, 19.1 ± 0.2°, 19.8 ± 0.2°, 21 .5 ± 0.2°, 21 .7 ± 0.2°, 22.0 ± 0.2°, 22.8 ± 0.2°, 23.7 ± 0.2°, 24.4 ± 0.2°, 24.6 ± 0.2°, 24.9 ± 0.2°, 25.2 ± 0.2°, 26.6 ± 0.2°, 26.8 ± 0.2°, 27.6 ± 0.2, 28.0 ± 0.2°, 29.1 ± 0.2°, 29.5 ± 0.2°, 32.5 ± 0.2°, 32.9 ± 0.2 and 33.7 ± 0.2°. A representative diffractogram is displayed in figure 5.
In addition the novel crystalline dichloromethane solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3058 ± 2 cm"1 , 2229 ± 2 cm"1 , 2218 ± 2 cm"1 , 1655 ± 2 cm"1 and 1541 ± 2 cm"1. The FTIR-spectrum of the novel crystalline dichloromethane solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3280 ± 2 cm"1 , 3242 ± 2 cm"1 , 3177 ± 2 cm"1 , 2968 ± 2 cm"1 , 2873 ± 2 cm"1 , 1635 ± 2 cm"1 , 1601 ± 2 cm"1 , 1563 ± 2 cm"1 , 1521 ± 2 cm"1 , 1504 ± 2 cm"1 , 1448 ± 2 cm"1 , 1417 ± 2 cm"1 , 1385 ± 2 cm"1 , 1344 ± 2 cm"1 , 1315 ± 2 cm"1 , 1270 ± 2 cm"1 , 1243 ± 2 cm"1 , 1215 ± 2 cm"1 , 1 179 ± 2 cm"1 , 1 154 ± 2 cm"1 , 1 122 ± 2 cm"1 , 1099 ± 2 cm"1 , 1073 ± 2 cm"1 , 1031 ± 2 cm"1 , 987 ± 2 cm"1 , 969 ± 2 cm"1 , 871 ± 2 cm"1 , 849 ± 2 cm"1 , 823 ± 2 cm"1 , 795 ± 2 cm"1 , 761 ± cm"1 and 740 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 8.
Furthermore the dichloromethane solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol dichloromethane per mol rilpivirine hydrochloride. E.g. the dichloromethane solvate comprises about 0.5 mol dichloromethane per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
In addition the present invention relates to a novel crystalline chloroform solvate of rilpivirine hydrochloride. The novel crystalline chloroform solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 17.5 ± 0.2°, 18.8 ± 0.2° and 23.7 ± 0.2°. The X-ray powder diffractogram of the novel crystalline chloroform solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2- theta angles of 9.4 ± 0.2°, 9.8 ± 0.2°, 10.6 ± 0.2°, 14.0 ± 0.2°, 14.5 ± 0.2°, 15.2 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 16.6 ± 0.2°, 18.3 ± 0.2°, 19.8 ± 0.2°, 21.1 ± 0.2°, 21.5 ± 0.2°, 22.0 ± 0.2°, 22.6 ± 0.2°, 24.5 ± 0.2°, 25.2 ± 0.2°, 26.2 ± 0.2°, 26.4 ± 0.2°, 27.6 ± 0.2°, 29.2 ± 0.2°, 29.5 ±
0.2, 31 .3 ± 0.2°, 32.4 ± 0.2°, 33.2 ± 0.2° and 33.6 ± 0.2°. A representative diffractogram is displayed in figure 3.
In addition the novel crystalline chloroform solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3057 ± 2 cm"1 , 2229 ± 2 cm"1 , 2219 ± 2 cm"1 , 1655 ± 2 cm"1 and 1541 ± 2 cm"1. The FTIR-spectrum of the novel crystalline chloroform solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ± 2 cm"1 , 3236 ± 2 cm"1 , 3179 ± 2 cm"1 , 2966 ± 2 cm"1 , 2872 ± 2 cm"1 , 1634 ± 2 cm"1 , 1600 ± 2 cm"1 , 1562 ± 2 cm"1 , 1520 ± 2 cm"1 , 1499 ± 2 cm"1 , 1447 ± 2 cm"1 , 1417 ± 2 cm"1 , 1384 ± 2 cm"1 , 1344 ± 2 cm"1 , 1271 ± 2 cm"1 , 1243 ± 2 cm"1 , 1215 ± 2 cm"1 , 1 179 ± 2 cm"1 , 1 154 ± 2 cm"1 , 1072 ± 2 cm"1 , 1035 ± 2 cm"1 , 969 ± 2 cm"
1 , 870 ± 2 cm"1 , 942 ± 2 cm"1 , 823 ± 2 cm"1 , 795 ± 2 cm"1 , 758 ± 2 cm"1 and 729 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 7.
Furthermore the chloroform solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol chloroform per mol rilpivirine hydrochloride. E.g. the chloroform solvate comprises about 0.4 mol chloroform per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
Moreover the present invention relates to a novel crystalline cyclohexanone solvate of rilpivirine hydrochloride.
The novel crystalline cyclohexanone solvate of rilpivirine hydrochloride can be characterized by an XRPD pattern comprising peaks at 2-theta angles of 8.1 ± 0.2°, 17.3 ± 0.2°, 18.8 ± 0.2°, 20.8 ± 0.2° and 23.3 ± 0.2°. The X-ray powder diffractogram of the novel crystalline cyclohexanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at 2-theta angles of 8.6 ± 0.2°, 14.4 ± 0.2°, 14.8 ± 0.2°, 15.2 ± 0.2°, 15.9 ± 0.2°, 16.1 ± 0.2°, 16.5 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 20.0 ± 0.2°, 21 .1 ± 0.2°, 21 .3 ± 0.2°, 21 .8 ± 0.2°, 22.4 ± 0.2°, 24.0 ± 0.2°, 24.8 ± 0.2°, 25.6 ± 0.2°, 26.0 ± 0.2°, 28.1 ± 0.2°, 29.0 ± 0.2 and 31.9 ± 0.2°. A representative diffractogram is displayed in figure 6.
In addition the novel crystalline cyclohexanone solvate of rilpivirine hydrochloride can be characterized by showing an FTIR-spectrum comprising peaks at wavenumbers of 3056 ± 2 cm"1 , 2228 ± 2 cm"1 , 2219 ± 2 cm"1 , 1655 ± 2 cm"1 and 1541 ± 2 cm"1. The FTIR-spectrum of the novel crystalline cyclohexanone solvate of rilpivirine hydrochloride comprises additional characteristic peaks at wavenumbers of 3278 ± 2 cm"1 , 3240 ± 2 cm"1 , 3173 ± 2 cm"1 , 2961 ± 2 cm"1 , 2869 ± 2 cm"1 , 1709 ± 2 cm"1 , 1634 ± 2 cm"1 , 1600 ± 2 cm"1 , 1562 ± 2 cm"1 , 1520 ± 2 cm"1 , 1498 ± 2 cm"1 , 1447 ± 2 cm"1 , 1418 ± 2 cm"1 , 1384 ± 2 cm"1 , 1344 ± 2 cm"1 , 1312 ± 2 cm"1 , 1271 ± 2 cm"1 , 1243 ± 2 cm"1 , 1214 ± 2 cm"1 , 1 179 ± 2 cm"1 , 1 155 ± 2 cm"1 , 1 1 17 ± 2 cm"1 , 1097 ± 2 cm"1 , 1072 ± 2 cm"1 , 1032 ± 2 cm"1 , 1018 ± 2 cm"1 , 987 ± 2 cm"1 , 970 ± 2 cm"1 , 886 ± 2 cm"1 , 870 ± 2 cm"1 , 848 ± cm"1 , 824 ± 2 cm"1 , 793 ± 2 cm"1 , 728 ± cm"1 and 694 ± 2 cm"1. A representative FTIR spectrum is displayed in figure 8.
Furthermore the cyclohexanone solvate of rilpivirine hydrochloride of the present invention preferably comprises from about 0.3 to 0.7 mol, more preferably from about 0.4 to 0.6 mol cyclohexanone per mol rilpivirine hydrochloride. E.g. the cyclohexanone solvate comprises about 0.5 mol cyclohexanone per mol rilpivirine hydrochloride as detected by NMR and can be characterized as being a hemisolvate.
The novel solvates of rilpivirine hydrochloride of the present invention are valuable intermediates for the preparation of rilpivirine hydrochloride form F of the present invention. The solvates of the present invention may be transformed to form F according to the process disclosed for form F production. The solvates of rilpivirine hydrochloride of the present invention are applied as starting materials and slurried in water, followed by drying the isolated crystals at increased temperatures ranging from about 80 °C to 180 °C, more preferably from about 90 °C to 140 °C and most preferably from about 100 °C to 120 °C and/or at decreased relative humidities such as < 5 % relative humidity.
In addition the present invention relates to the use of the crystalline 1 -propanol solvate, the crystalline 2-propanol solvate, the crystalline acetone solvate, the crystalline 2-butanone solvate and/or the crystalline tetrahydrofuran solvate of rilpivirine hydrochloride of the present invention for the preparation of a medicament.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the description and the following specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the description and the other parts of the present disclosure.
EXAMPLES
The X-ray powder diffractograms (XRPD) were 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) and a solid state PIX'cel detector. The diffractograms were recorded at a tube voltage of 40 kV, tube current of 40 mA. A typical precision of the 2-theta values is in the range of about ± 0.2° 2-theta. Thus 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) spectra were recorded with a Bruker IFS 25 spectrometer (Bruker GmbH, Karlsruhe, D) in the spectral range from 4000 to 600 cm"1. The samples were 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 "1. Thus, an infrared peak that appears at 1716 cm"1 can appear between 1714 and 1718 cm"1.
Intensity data for the crystal structures were collected with Mo (λ = 0.71073 A) radiation on an Oxford Diffraction Gemini-R Ultra diffractometer at 173 K. The structures were solved using the direct methods procedure in SHELXS97 and refined by full-matrix least squares on F2 using SHELXL97.
Thermogravimetric analysis (TGA) were performed with a TGA 7 thermogravimetric system (Perkin-Elmer). The samples were placed into a 50 μΙ_ platinum pan and heated at a heating rate of 10 °C/min. The determinations were performed under nitrogen purge (balance purge: 40 mL/min, sample purge: 20 mL/min).
1 HNMR spectra were measured on a Bruker Avance DPX 300 at a frequency of 300 MHz. DMSO-d6 was used as solvent.
Example 1 : Preparation of polymorph F of rilpivirine hydrochloride A novel solvate of rilpivirine hydrochloride of the present invention (see table 1 ) was suspended in water at a concentration of 20 mg/mL and stirred for 40 hours at room temperature. The obtained crystals were collected by filtration and dried at 105 °C under vacuum for 16 hours to obtain polymorph F of rilpivirine hydrochloride.
Table 1 : Applied starting materials
Figure imgf000031_0001
Table 2: XRPD angles 2-theta and relative intensities of polymorph F of rilpivirine hydrochloride
Figure imgf000031_0002
Table 3: FTIR peaks of polymorph F of rilpivirine hydrochloride
wavenumber
[cm 1]
3223 1444 1031
3176 1416 1018 3055 1386 985
2961 1357 966
2862 1338 869
2222 1308 851
1652 1273 81 1
1635 1241 794
1598 1213 713
1566 1178 680
1541 1154 666
1522 1097 623
1503 1072
Example 2: Preparation of the 1 -propanol solvate of rilpivirine hydrochloride
100 mg rilpivirine base were dissolved in 16 ml_ 1 -propanol upon heating to reflux temperature. To the hot solution 100 μΙ_ (4.4 mol equivalents) concentrated hydrochloric acid were added and the mixture was cooled to room temperature. The obtained suspension was further stirred at room temperature for 15 hours before the crystals were collected by filtration and dried at 80 °C under vacuum for 5 hours.
Yield: 100 mg
Table 4: XRPD angles 2-theta and relative intensities of the 1 -propanol solvate of rilpivirine hydrochloride
angle relative intensity angle relative intensity
[2-theta] [%] [2-theta] [%]
8.1 39 21 .2 33
8.8 31 21 .6 36
10.6 6 21 .9 21
14.5 16 22.7 27
15.2 12 23.9 100
15.6 14 24.2 12
16.4 67 25.1 47
17.6 39 26.4 11
18.3 16 26.6 10
18.5 10 27.8 11
18.8 25 29.4 21
19.0 18 32.4 18
Figure imgf000033_0001
Table 5: FTIR peaks of the 1 -propanol solvate of rilpivirine hydrochloride
Figure imgf000033_0002
Example 3: Preparation of the 2-propanol solvate of rilpivirine hydrochloride
100 mg rilpivirine base were dissolved in 18 ml_ 2-propanol upon heating to reflux temperature. To the hot solution 100 μΙ_ (4.4 mol equivalents) concentrated hydrochloric acid were added and the mixture was cooled to room temperature. The obtained suspension was further stirred at room temperature for 15 hours before the crystals were collected by filtration and dried at 80 °C under vacuum for 5 hours.
Yield: 100 mg
Table 6: XRPD angles 2-theta and relative intensities of the 2-propanol solvate of rilpivirine hydrochloride
angle relative intensity angle relative intensity
[2-theta] [%] [2-theta] [%]
8.1 92 21 .9 55
8.8 51 22.7 41
10.6 10 23.9 100
14.5 21 24.1 28
15.2 25 24.5 18
15.6 35 25.1 54
16.4 47 26.3 12
17.6 70 26.6 25 18.2 26 27.5 22
18.5 18 27.8 11
18.8 68 28.8 12
19.0 33 29.1 14
19.7 38 29.4 14
21 .2 69 32.4 16
21 .5 51 33.4 31
Table 7: FTIR peaks of the 2-propanol solvate of rilpivirine hydrochloride
Example 4: Preparation of the acetone solvate of rilpivirine hydrochloride
To a suspension of 270 mg rilpivirine base in 7 mL acetone 200 μΙ_ (3.3 mol equivalents) concentrated hydrochloric acid were added at room temperature. The suspension was stirred for additional 10 minutes at room temperature before the crystals were isolated by filtration and dried at 60 °C under vacuum for 5 hours.
Yield: 255 mg
Example 5: Preparation of the acetone solvate of rilpivirine hydrochloride
250 mg rilpivirine base were dissolved in 6 mL acetone upon heating to reflux temperature. To the hot solution 200 μί (3.3 mol equivalents) concentrated hydrochloric acid were added, whereat crystallization occurred within about 5 minutes. The suspension was cooled to room temperature before the crystals were collected by filtration and dried at 60 °C under vacuum for 5 hours. Yield: 270 mg
Table 8: XRPD angles 2-theta and relative intensities of the acetone solvate of rilpivirine hydrochloride
Figure imgf000035_0001
Table 9: FTIR peaks of the acetone solvate of rilpivirine hydrochloride
wavenumber
[cm 1]
3276 1564 1154
3239 1542 1100
3178 1503 1072
3056 1448 1030
2963 1417 969
2873 1383 870
2229 1343 850
2218 1314 823
1716 1270 794
1655 1242 717
1635 1215
1601 1179 Example 6: Preparation of the 2-butanone solvate of rilpivirine hydrochloride
To a suspension of 100 mg rilpivirine base in 3 ml_ 2-butanone 100 μΙ_ (4.4 mol equivalents) concentrated hydrochloric acid were added at room temperature, whereat a clear solution was obtained. Within about 5 minutes crystallization was observed and the obtained suspension was further stirred for 15 hours before the crystals were isolated and dried at 80
°C under vacuum for 5 hours.
Yield: 92 mg
Table 10: XRPD angles 2-theta and relative intensities of the 2-butanone solvate of rilpivirine hydrochloride
Figure imgf000036_0001
Table 11 : FTIR peaks of the 2-butanone solvate of rilpivirine hydrochloride
wavenumber
[cm 1]
3277 1563 1180
3241 1542 1155
3173 1520 1099
3056 1498 1073
2968 1447 1037
2873 1418 988 2229 1382 970
2219 1344 884
171 1 1314 870
1655 1270 849
1636 1243 823
1601 1214 794
Example 7: Preparation of the tetrahydrofuran solvate of rilpivirine hydrochloride
To a solution of 250 mg rilpivirine base in 3 mL tetrahydrofuran 200 μΙ_ (3.5 mol equivalents) concentrated hydrochloric acid were added at room temperature, whereat a suspension was obtained. The mixture was further stirred for about 10 minutes before the crystals were isolated by filtration and dried at 80 °C under vacuum for 5 hours.
Yield: 271 mg
Example 8: Preparation of the tetrahydrofuran solvate of rilpivirine hydrochloride
A solution of 250 mg rilpivirine base in 3 mL tetrahydrofuran was heated to reflux temperature. To the hot solution 200 μί (3.5 mol equivalents) concentrated hydrochloric acid were added and the resulting suspension was cooled to room temperature. Thereafter the crystals were isolated by filtration and dried at 80 °C under vacuum for 5 hours.
Yield: 268 mg
Table 12: XRPD angles 2-theta and relative intensities of the tetrahydrofuran solvate of rilpivirine hydrochloride
angle relative intensity angle relative intensity
[2-theta] [%] [2-theta] [%]
8.2 83 21 .5 39
8.7 32 22.0 41
10.6 6 22.6 41
14.5 32 23.7 100
15.2 31 24.0 13
15.5 29 24.5 15
16.3 54 25.2 37
17.5 70 26.2 13
17.8 14 26.4 25
18.3 28 27.6 25
18.9 85 29.2 14
19.8 33 29.5 13 21 .2 89
Table 13: FTIR peaks of the tetrahydrofuran solvate of rilpivirine hydrochloride
Figure imgf000038_0001
Example 9: Preparation of the 1 ,4-dioxane solvate of rilpivirine hydrochloride
To a solution of 100 mg rilpivirine base in 4 mL 1 ,4-dioxane 100 μΙ_ (4.4 mol equivalents) concentrated hydrochloric acid were added at room temperature. The solution was cooled to about 4 °C and stored at the same for 15 hours, whereat crystallization was observed. The crystals were filtered off and dried at 80 °C under vacuum.
Yield: 150 mg
Example 10: Preparation of the 1 ,4-dioxane solvate of rilpivirine hydrochloride
25 mg rilpivirine base were dissolved in 2 mL 1 ,4-dioxane upon heating to reflux temperature. To the hot solution 50 μί (8.8 mol equivalents) concentrated hydrochloric acid were added and the solution was cooled to room temperature, whereat crystallization was observed. The crystals were isolated by filtration and dried at 80 °C under vacuum.
Table 14: XRPD angles 2-theta and relative intensities of the 1 ,4-dioxane solvate of rilpivirine hydrochloride
angle relative intensity angle relative intensity
[2-theta] [%] [2-theta] [%]
8.2 43 21 .4 42
8.7 25 21 .9 40
14.0 7 22.5 41 14.5 32 23.5 93
15.1 33 23.8 13
15.4 20 24.4 13
16.2 50 25.2 43
16.5 10 26.0 12
17.4 70 26.3 24
17.7 10 27.6 17
18.3 38 29.2 17
18.8 97 29.5 14
19.8 32 32.2 10
21 .1 100 32.4 19
Table 15: FTIR peaks of the 1 ,4-dioxane solvate of rilpivirine hydrochloride
Figure imgf000039_0001
Example 1 1 : Preparation of the dichloromethane solvate of rilpivirine hydrochloride
A mixture of 108 mg rilpivirine base in 45 mL dichloromethane was dissolved upon heating to 45 °C. To the hot solution 100 μΙ (4.1 mol equivalents) concentrated hydrochloric acid were added and the solution was cooled to about 4 °C and stored at the same temperature for 65 hours. The obtained crystals were isolated by filtration and dried at 80 °C under vacuum. Yield: 1 10 mg
Example 12: Preparation of the dichloromethane solvate of rilpivirine hydrochloride To a suspension of 25 mg rilpivirine base in 2 ml_ dichloromethane 50 μΙ_ (8.8 mol equivalents) concentrated hydrochloric acid were added at room temperature. The suspension was stirred for 4 hours at room temperature before the crystals were isolated by filtration and dried at 80 under vacuum for 5 hours.
Table 16: XRPD angles 2-theta and relative intensities of the dichloromethane solvate of rilpivirine hydrochloride
Figure imgf000040_0001
Table 17: FTIR peaks of the dichloromethane solvate of rilpivirine hydrochloride
wavenumber
[cm 1]
3280 1521 1099
3242 1504 1073
3177 1448 1031
3058 1417 987
2968 1385 969
2873 1344 871 2229 1315 849
2218 1270 823
1655 1243 795
1635 1215 761
1601 1179 740
1563 1154
1541 1122
Example 13: Preparation of the chloroform solvate of rilpivirine hydrochloride
To a suspension of 120 mg rilpivirine base in 3 mL chloroform 100 μΙ_ (3.7 mol equivalents) concentrated hydrochloric acid were added at room temperature and the suspension was stirred for 65 hours. Thereafter the obtained crystals were isolated by filtration and dried at
100 °C under vacuum for 5 hours.
Yield: 130 mg
Example 14: Preparation of the chloroform solvate of rilpivirine hydrochloride
32 mg of rilpivirine base were dissolved in 15 mL chloroform upon heating to 40 °C. To the hot solution 50 μί (6.9 mol equivalents) concentrated hydrochloric acid were added, whereat crystallization occurred. The obtained suspension was cooled to room temperature before the crystals were collected by filtration and dried at 80 °C under vacuum for 5 hours.
Table 18: XRPD angles 2-theta and relative intensities of the chloroform solvate of rilpivirine hydrochloride
angle relative intensity angle relative intensity
[2-theta] [%] [2-theta] [%]
8.2 45 21 .5 45
8.7 21 22.0 36
9.4 5 22.6 44
9.8 5 23.7 100
10.6 9 24.5 21
14.0 8 25.2 40
14.5 34 26.2 17
15.2 27 26.4 32
15.5 28 27.6 24
16.3 40 29.2 20
16.6 16 29.5 18
17.5 77 31 .3 10 18.3 34 32.4 22
18.8 95 33.2 11
19.8 38 33.6 11
21 .1 75
Table 19: FTIR peaks of the chloroform solvate of rilpivirine hydrochloride
Figure imgf000042_0002
Example 15: Preparation of the cyclohexanone solvate of rilpivirine hydrochloride
To a solution of 34 mg rilpivirine base in 1 ml_ cyclohexanone 50 μΙ_ (6.5 mol equivalents) concentrated hydrochloric acid were added at room temperature, whereat crystallization occurred within about 5 minutes. The obtained suspension was further stirred at room temperature for 4 hours before the crystals were isolated by filtration and dried at 80 °C for 5 hours.
Example 16: Preparation of the cyclohexanone solvate of rilpivirine hydrochloride
A solution of 34 mg rilpivirine base in 2 ml_ cyclohexanone was heated to reflux temperature. To the hot solution 50 μΙ_ (6.5 mol equivalents) concentrated hydrochloric acid were added, whereat crystallization occurred within about 10 minutes. The obtained suspension was cooled to room temperature before the crystals were isolated by filtration and dried at 80 °C under vacuum for 5 hours.
Table 20: XRPD angles 2-theta and relative intensities of the cyclohexanone solvate of rilpivirine hydrochloride
Figure imgf000042_0001
[2-theta] [%] [2-theta] [%]
8.1 44 20.0 36
8.6 18 20.8 36
14.4 39 21 .1 28
14.8 14 21 .3 23
15.2 44 21 .8 39
15.9 18 22.4 44
16.1 16 23.3 98
16.5 10 24.0 12
17.3 75 24.8 13
17.7 15 25.6 11
18.0 14 26.0 28
18.2 22 28.1 10
18.6 36 29.0 23
18.8 100 31 .9 11
Table 21 : FTIR peaks of the cyclohexanone solvate of rilpivirine hydrochloride
Figure imgf000043_0002
Example 17: Tablet formulation comprising rilpivirine hydrochloride form F
Figure imgf000043_0001
rilpivirine hydrochloride form F 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 18: Tablet formulation comprising rilpivirine hydrochloride form F
tablet core
rilpivirine hydrochloride form F 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 19: Tablet formulation comorisina. rilpivirine hydrochloride 1 -Drooanol solvate
tablet core
rilpivirine hydrochloride 1 -propanol solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 20: Tablet formulation comprising rilpivirine hydrochloride 1 -propanol solvate tablet core
rilpivirine hydrochloride 1 -propanol solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 21 : Tablet formulation comprising rilpivirine hydrochloride 2-propanol solvate
tablet core
rilpivirine hydrochloride 2-propanol solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 22: Tablet formulation comorisino. rilpivirine hydrochloride 2-prooanol solvate
tablet core
rilpivirine hydrochloride 2-propanol solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 23: Tablet formulation comorisino. rilpivirine hydrochloride acetone solvate
Figure imgf000045_0001
rilpivirine hydrochloride acetone solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 24: Tablet formulation comprising rilpivirine hydrochloride acetone solvate
tablet core
rilpivirine hydrochloride acetone solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 25: Tablet formulation comorisina. rilpivirine hydrochloride 2-butanone solvate
tablet core
rilpivirine hydrochloride 2-butanone solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 26: Tablet formulation comprising rilpivirine hydrochloride 2-butanone solvate tablet core
rilpivirine hydrochloride 2-butanone solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Example 27: Tablet formulation comprising rilpivirine hydrochloride tetrahydrofuran solvate
tablet core
rilpivirine hydrochloride THF solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
polyvinylpyrrolidone K30 (PVP K30) 3.25 mg
polysorbate 20 (Tween 20) 0.35 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.
Examole 28: Tablet formulation comorisina riloivirine hydrochloride tetrahydrofuran solvate
tablet core
rilpivirine hydrochloride THF solvate 25.0 mg (calculated as free base) lactose monohydrate 55.145 mg
silicified microcrystalline cellulose 16.605 mg
croscarmellose sodium 6.05 mg
magnesium stearate 1.10 mg
tablet film coat
coating powder Opadry® II White 4.4 mg
purified water (not present in final tablet) q.s.

Claims

Claims
1 ) Crystalline form of rilpivirine hydrochloride having an X-ray powder diffraction pattern comprising peaks at 2- theta angles of 5.6 ± 0.2°, 6.1 ± 0.2°, 6.9 ± 0.2°, 12.5 ± 0.2° and 13.8 ± 0.2°, preferably characterized by an X-ray powder diffraction pattern essentially in accordance with figure 1 .
2) The crystalline form of rilpivirine hydrochloride according to claim 1 characterized by an infrared spectrum comprising peaks at wavenumbers of 3223 ± 2 cm"1 , 2222 ± 2 cm"1 , 1652 ± 2 cm"1 , 965 ± 2 cm"1 and 81 1 ± 2 cm"1 , preferably characterized by an infrared spectrum essentially in accordance with figure 2.
3) The crystalline form of rilpivirine hydrochloride according to any of claims 1 to 2 having a water content of < 1 .5 %.
4) A pharmaceutical composition comprising the crystalline form of rilpivirine hydrochloride according to any one of claims 1 to 3, further comprising at least one pharmaceutically acceptable excipient.
5) The pharmaceutical composition according to claim 4, which is an oral dosage form, in particular a capsule or tablet.
6) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet, comprising a tablet core comprising the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3, croscarmellose sodium, magnesium stearate, lactose monohydrate, polyvinylpyrrolidone K30, polysorbate 20 and silicified microcrystalline cellulose and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, polyethylene glycol 3000, titanium dioxide and triacetin.
7) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), dibasic calcium phosphate (dihydrate or anhydrate), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide. 8) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, lactose monohydrate, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
9) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, modified starch, polysorbate 20 (Tween 20), polyvinylpyrrolidone K30 (PVP K30) and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
10) A pharmaceutical composition according to any of claims 4 to 5, which is a tablet, comprising a tablet core comprising the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3, croscarmellose sodium, magnesium stearate, lactose monohydrate and silicified microcrystalline cellulose and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, polyethylene glycol 3000, titanium dioxide and triacetin.
1 1 ) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, dibasic calcium phosphate (dihydrate or anhydrate), magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
12) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, lactose monohydrate, magnesium stearate and starch and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
13) A pharmaceutical composition according to any of the claims 4 to 5, which is a tablet comprising a tablet core comprising rilpivirine hydrochloride according to any of the claims 1 to 3, microcrystalline cellulose, modified starch and magnesium stearate and a tablet coating comprising hypromellose 2910 mPa.s, lactose monohydrate, macrogol 3000, triacetin and titanium dioxide.
14) A wet granulation process for preparing a tablet according to any of the claims 6 to 9 comprising the steps of:
a) dry blending the crystalline form of rilpivirine hydrochloride according to any of the claims 1 to 3 and a part of the diluent,
b) preparing a binder solution by dissolving a binder and a wetting agent in a suitable solvent,
c) spraying the binder solution of step b) on the mixture obtained in step a), d) drying the obtained granulate and sieving the same,
e) mixing the obtained granulate with the remaining part of diluent and a disintegrant,
f) adding an optional glidant and/or an optional lubricant to the mixture, g) compressing the obtained mixture into a tablet and
h) optionally film-coating the obtained tablet.
15) The wet granulation process according to claim 14, wherein the solvent in step b) is selected from water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 - propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and tetrahydrofuran.
16) A tablet according to any of the claims 6 to 9 prepared by the wet granulation process according to any of claims 14 to 15.
17) A wet granulation process for preparing a tablet according to claim 6 comprising the steps of:
a) dry blending the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3 and lactose monohydrate,
b) preparing a binder solution by dissolving polyvinylpyrrolidone K30 and
polysorbate 20 in a solvent,
c) spraying the binder solution of step b) on the mixture obtained in step a), d) drying the obtained granulate and sieving the same, e) mixing the obtained granulate with silicified microcrystalline cellulose and croscarmellose sodium,
f) adding magnesium stearate to the mixture,
g) compressing the obtained mixture into a tablet and
h) optionally film-coating the obtained tablet.
18) The wet granulation process according to claim 17, wherein the solvent in step b) is selected from water, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1 - propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate and tetrahydrofuran.
19) A tablet according to claim 6 prepared by the wet granulation process according to any of the claims 17 to 18.
20) A process for preparing a tablet according to any of the claims 10 to 13 comprising the steps of:
a) dry blending the crystalline form of rilpivirine hydrochloride according to any of the claims 1 to 3, a disintegrant, an optional glidant and an optional lubricant with at least one diluent,
b) compressing the obtained mixture in the dry state into a tablet and
c) optionally film-coating the obtained tablet.
21 ) A tablet according to any of the claims 10 to 13 prepared by the direct compression process according to claim 20.
22) A process for preparing a tablet according to claim 10 comprising the steps of:
a) dry blending the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3, croscarmellose sodium and magnesium stearate with lactose monohydrate and silicified microcrystalline cellulose,
b) compressing the obtained mixture in the dry state into a tablet and
c) optionally film-coating the obtained tablet.
23) A tablet according to claim 10 prepared by the direct compression process according to claim 22. 24) Use of the crystalline form of rilpivirine hydrochloride according to any one of claims 1 to 3 for the production of a pharmaceutical composition.
25) The pharmaceutical compositions as defined in any of the claims 4 to 13 or as obtained by the use according to claim 24 for use in the treatment of HIV-1 infections.
26) The tablet according to any of the claims 16, 19, 21 or 23 for use in the treatment of HIV-1 infections.
27) Crystalline isomorphic solvates of rilpivirine hydrochloride having an X-ray powder diffraction pattern with peaks at 2- theta angles of 8.2 ± 0.2°, 8.8 ± 0.2°, 17.6 ± 0.2°, 18.9 ± 0.2° and 23.8 ± 0.2°.
28) The crystalline isomorphic solvates of rilpivirine hydrochloride according to claim 27 with 0.3 to 0.7 mol, preferably 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride.
29) The crystalline isomorphic solvates of rilpivirine hydrochloride according to any of claims 27 to 28, wherein the solvent is selected from 1 -propanol, 2-propanol, acetone, tetrahydrofuran or chloroform.
30) Crystalline isomorphic solvates of rilpivirine hydrochloride having an X-ray powder diffraction pattern with peaks at 2- theta angles of 8.2 ± 0.2°, 8.7 ± 0.2°, 16.1 ± 0.2°, 18.8 ± 0.2° and 23.5 ± 0.2°.
31 ) The crystalline isomorphic solvates of rilpivirine hydrochloride according to claim 30 with 0.3 to 0.7 mol, preferably 0.4 to 0.6 mol solvent per mol rilpivirine hydrochloride.
32) The crystalline isomorphic solvates of rilpivirine hydrochloride according to any of claims 30 to 31 , wherein the solvent is selected from 1 ,4-dioxane or 2-butanone.
33) Crystalline dichloromethane solvate of rilpivirine hydrochloride having an X-ray powder diffraction pattern comprising peaks at 2- theta angles of 8.2 ± 0.2°, 16.5 ± 0.2°, 17.8 ± 0.2°, 21 .2 ± 0.2° and 24.1 ± 0.2°.
34) The crystalline dichloromethane solvate of rilpivirine hydrochloride according to claim 33 comprising 0.3 to 0.7 mol, preferably 0.4 to 0.6 mol dichloromethane per mol rilpivirine hydrochloride. 35) Crystalline cyclohexanone solvate of rilpivirine hydrochloride having an X-ray powder diffraction pattern with peaks at 2- theta angles of 8.1 ± 0.2°, 17.3 ± 0.2°, 18.8 ± 0.2°, 20.8 ± 0.2° and 23.3 ± 0.2°.
36) The crystalline cyclohexanone solvate of rilpivirine hydrochloride according to claim 35 comprising 0.3 to 0.7 mol, preferably 0.4 to 0.6 mol cyclohexanone per mol rilpivirine hydrochloride.
37) A crystalline solvate of rilpivirine hydrochloride characterized by an infrared spectrum displaying peaks at wavenumbers of 3057 ± 2 cm"1 , 2228 ± 2 cm"1 , 2218 ± 2 cm"1 , 1656 ± 2 cm"1 and 1542 ± 2 cm"1 , preferably characterized by an infrared spectrum essentially in accordance with one of the infrared spectra of figure 7 or figure 8.
38) A method for the preparation of the crystalline solvates according to any of claims 27 to 37 comprising the steps of:
a) providing a suspension or solution of rilpivirine free base in a solvent selected from alcohols, ketones, chlorinated hydrocarbons or ethers,
b) adding hydrochloric acid to the suspension or solution and
c) recovering the novel solvate of rilpivirine hydrochloride.
39) A method according to claim 38, wherein the alcohol is selected from 1 -propanol or 2- propanol the ketone is selected from acetone, 2-butanone or cyclohexanone, the chlorinated hydrocarbon is selected from dichloromethane or chloroform and the ether is selected from tetrahydrofuran or 1 ,4-dioxane.
40) Use of the crystalline solvates of rilpivirine hydrochloride as defined in any of the claims 27 to 37 as intermediates in a process for the production of the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3.
41 ) A method for the preparation of the crystalline form of rilpivirine hydrochloride according to any one of claims 1 to 3 comprising the steps of slurrying the crystalline solvates of rilpivirine hydrochloride as defined in any of the claims 27 to 37 in water and drying the obtained crystals above 80 °C and/or below 5 % relative humidity.
42) A pharmaceutical composition comprising a crystalline solvate of rilpivirine hydrochloride according to any one of claims 27 to 37, wherein the solvate is selected from a 1 -propanol solvate, a 2-propanol solvate, an acetone solvate, a 2-butanone solvate or a tetrahydrofuran solvate. 43) The pharmaceutical composition according to claim 42, which is an oral dosage form, in particular a capsule or tablet.
44) A pharmaceutical combination comprising an effective amount of the crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3 and additional therapeutic agents selected from anti-viral agents, antibiotics, immunomodulators or vaccines for the treatment of viral infections.
45) A pharmaceutical combination according to claim 44, wherein the additional therapeutic agents are anti-viral agents.
46) The pharmaceutical combination according to claim 45, wherein the anti-viral agents are selected from nucleoside analog HIV-1 reverse transcriptase inhibitors.
47) The pharmaceutical combination according to claim 46, wherein the analog HIV-1 reverse transcriptase inhibitors are selected from emtricitabine and tenofovir.
48) The pharmaceutical composition according to any of the claims 5 to 13, having an equilibrium relative humidity ranging from 0 to 70 % determined according to the equilibrium relative humidity method.
49) The pharmaceutical composition of any of the claims 4 to 13, comprised in a container, preferably in a container containing means for keeping the equilibrium relative humidity of the pharmaceutical composition in a range from 0 to 70 % determined according to the equilibrium relative humidity method, preferably for an extended period of time, more preferably for at least 180 days, more preferably for at least 2 years.
50) A container comprising a pharmaceutical composition according to any of the claims 4 to 13, the container containing means for keeping the equilibrium relative humidity of the pharmaceutical composition in a range of from 0 to 70 % determined according to the equilibrium relative humidity method, preferably for an extended period of time, more preferably for at least 180 days, more preferably for at least 2 years.
51 ) The crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3 having a particle size of less than 50 μιη.
52) The crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3 having a particle size of less than 25 μιη. 53) The crystalline form of rilpivirine hydrochloride according to any of claims 1 to 3 having a particle size of less than 15 μιη.
PCT/EP2013/057596 2012-04-11 2013-04-11 Novel polymorph of rilpivirine hydrochloride WO2013153161A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12163720.1 2012-04-11
EP12163720 2012-04-11

Publications (2)

Publication Number Publication Date
WO2013153161A2 true WO2013153161A2 (en) 2013-10-17
WO2013153161A3 WO2013153161A3 (en) 2013-12-05

Family

ID=48050762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/057596 WO2013153161A2 (en) 2012-04-11 2013-04-11 Novel polymorph of rilpivirine hydrochloride

Country Status (1)

Country Link
WO (1) WO2013153161A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015136294A1 (en) * 2014-03-13 2015-09-17 Cipla Limited Pharmaceutical composittion comprising rilpivirine
US11166952B2 (en) 2019-11-29 2021-11-09 Aptorum Therapeutics Limited Composition including rilpivirine and method for treating tumors or cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1632232B1 (en) 2004-09-02 2011-05-11 Janssen Pharmaceutica NV Salt of 4[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
EP1419152B1 (en) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Hiv inhibiting pyrimidines derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125993A1 (en) * 2011-03-17 2012-09-20 Teva Pharmaceutical Industries Ltd. Solid state forms of rilpivirine base, and rilipivirine salts
KR101879468B1 (en) * 2011-04-15 2018-07-17 엠큐어 파마슈티컬즈 리미티드 Process for preparation of rilpivirine intermediate
WO2012147091A2 (en) * 2011-04-25 2012-11-01 Hetero Research Foundation Process for rilpivirine
CA2848631C (en) * 2011-09-16 2019-10-01 Hetero Research Foundation Rilpivirine hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1419152B1 (en) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Hiv inhibiting pyrimidines derivatives
EP1632232B1 (en) 2004-09-02 2011-05-11 Janssen Pharmaceutica NV Salt of 4[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015136294A1 (en) * 2014-03-13 2015-09-17 Cipla Limited Pharmaceutical composittion comprising rilpivirine
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

Also Published As

Publication number Publication date
WO2013153161A3 (en) 2013-12-05

Similar Documents

Publication Publication Date Title
CA2885266C (en) Novel crystalline form of vortioxetine hydrobromide
US20200148644A1 (en) Crystalline forms of pitavastatin calcium
JP6770035B2 (en) Amorphous letermovir and its solid pharmaceutical formulation for oral administration
EP3177629B1 (en) Novel hydrates of dolutegravir sodium
US9624236B2 (en) Amorphous darunavir
US10525059B2 (en) Pharmaceutical compositions comprising Afatinib
EP3333167A1 (en) Solid forms of venetoclax
WO2014076712A2 (en) Lurasidone hydrochloride solid dispersion
WO2016097314A1 (en) Amorphous and crystalline forms of idelalisib and process for forming the same
AU2014286308B2 (en) 1-[2-(2,4-dimethylphenylsulfanyl) phenyl]piperazine acetate in crystalline form
WO2013153161A2 (en) Novel polymorph of rilpivirine hydrochloride
WO2013153162A1 (en) Polymorph of rilpivirine hydrochloride
EP2604593A1 (en) Polymorph of Rilpivirine hydrochloride and its use as antiviral
EP2628732A1 (en) Novel crystalline form of rilpivirine hydrochloride
WO2013087794A1 (en) Polymorph of rilpivirine hydrochloride and its use as antiviral
EP3048104A1 (en) Amorphous and crystalline forms of idelalisib and process for forming the same
WO2013171766A2 (en) Saxagliptin solid dispersion
US20170369475A1 (en) Flibanserin Hydrate
WO2014174529A2 (en) Polymorphs of avanafil
US20190248788A1 (en) Abt-199 addition salt and crystal form thereof, preparation method thereof, and pharmaceutical composition thereof
WO2014108921A2 (en) Carvedilol phosphate solid dispersion
WO2014102832A2 (en) Saxagliptin hydrochloride solid dispersion
EA043692B1 (en) AMORPHOUS LETERMOVIR AND SOLID PHARMACEUTICAL PREPARATIONS CONTAINING IT, INTENDED FOR ORAL ADMINISTRATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13714974

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 13714974

Country of ref document: EP

Kind code of ref document: A2