WO2013153162A1 - Polymorphe de chlorhydrate de rilpivirine - Google Patents

Polymorphe de chlorhydrate de rilpivirine Download PDF

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Publication number
WO2013153162A1
WO2013153162A1 PCT/EP2013/057597 EP2013057597W WO2013153162A1 WO 2013153162 A1 WO2013153162 A1 WO 2013153162A1 EP 2013057597 W EP2013057597 W EP 2013057597W WO 2013153162 A1 WO2013153162 A1 WO 2013153162A1
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WO
WIPO (PCT)
Prior art keywords
tablet
rilpivirine hydrochloride
rilpivirine
pharmaceutical composition
crystalline form
Prior art date
Application number
PCT/EP2013/057597
Other languages
English (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 WO2013153162A1 publication Critical patent/WO2013153162A1/fr

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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

  • Rilpivirine hydrochloride is represented by the following general formula (I):
  • 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 methanol solvate of the present invention as an intermediate in the process for the production of the novel polymorph.
  • the methanol solvate is the only form obtained via crystallization from methanol and can be transformed to the novel polymorph of rilpivirine hydrochloride in a straight forward manner.
  • Figure 1 X-ray powder diffractogram (XRPD) of rilpivirine hydrochloride form G
  • 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.
  • the present invention also relates to a process for the preparation of form G of rilpivirine hydrochloride comprising heating the novel methanol solvate of rilpivirine hydrochloride of the present invention and recovering polymorph G.
  • 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.
  • example 3 if rilpivirine hydrochloride is recrystallized from methanol in order to obtain the novel methanol solvate of rilpivirine hydrochloride as an intermediate for polymorph G production.
  • the applied concentration used in the process of preparing the methanol solvate is suitable for large scale production. Once the methanol solvate is obtained it can be easily transformed to polymorph G of rilpivirine hydrochloride according to the herein disclosed processes for form G production, also on large scale.
  • compositions of the present invention comprising rilpivirine hydrochloride form G 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 suitable diluents for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form G.
  • suitable diluents which can also be used for the pharmaceutical compositions of the present invention, comprise e.g.
  • EP1632232 B1 discloses examples of glidants for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form G.
  • 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 G.
  • the preferred disintegrants, which can also be used for the pharmaceutical compositions of the present invention comprise starch, ion exchange resins, e.g.
  • EP1632232 B1 discloses examples of film coatings for the pharmaceutical compositions of the present invention comprising rilpivirine hydrochloride form G.
  • 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.
  • Another preferred tablet of the present invention comprises a tablet core comprising rilpivirine hydrochloride form G 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 particular tablet of the present invention may be prepared by direct compression comprising the steps of: d) dry blending rilpivirine hydrochloride form G of the present invention, croscarmellose sodium and magnesium stearate with lactose monohydrate and silicified microcrystalline cellulose,
  • a preferred pharmaceutical combination of the present invention comprises 25 mg rilpivirine hydrochloride form G (calculated as free base), 200 mg emtricitabine and 245 mg tenofovir disoproxil fumarate (calculated as free base) and one or more pharmaceutically acceptable excipients.
  • novel methanol solvate of rilpivirine hydrochloride can be characterized by showing an X-ray powder diffraction pattern comprising peaks at 2- theta angles of 8.2 ⁇ 0.2°, 8.4 ⁇ 0.2°, 13.0 ⁇ 0.2°, 15.1 ⁇ 0.2° and 23.7 ⁇ 0.2°.
  • the crystalline methanol solvate of rilpivirine hydrochloride can be characterized by showing an infrared spectrum comprising peaks at wavenumbers of 3347 ⁇ 2 cm “1 , 2221 ⁇ 2 cm “1 , 1661 ⁇ 2 cm “1 , 1595 ⁇ 2 cm “1 and 1362 ⁇ 2 cm “1 .
  • an optional filtration step may be applied, whereat the solution may be treated with charcoal prior to the filtration step. Thereafter the solution is cooled to room temperature at a cooling rate preferably ranging from about 0.1 °C/min to 10.0 °C/min, more preferably from about 0.3 °C/min to 5.0 °C/min and most preferably from about 0.5 °C/min to 2.0 °C/min.
  • crystals are dried at a temperature preferably ranging from about 25 °C to 80 ⁇ €, more preferably from about 30 °C to 60 °C and most preferably from about 40 °C to 50 °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.
  • the present invention also relates to the use of the crystalline methanol solvate of rilpivirine hydrochloride as an intermediate for the preparation of rilpivirine hydrochloride form G of the present invention.
  • 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.
  • Thermogravimetric analysis was performed with a TGA 7 thermogravimetric system (Perkin-Elmer). The sample was placed into a 50 ⁇ _ platinum pan and heated at a heating rate of 10 °C/min. The determination was performed under nitrogen purge (balance purge: 40 mLVmin, sample purge: 20 mLVmin).
  • rilpivirine hydrochloride methanol solvate e.g. prepared according to example 3 were stored for 15 hours over P 2 0 5 (providing an atmosphere of about 0% relative humidity) resulting in polymorphically pure form G.
  • Table 5 Crystal data and structure refinement of the methanol solvate of rilpivirine hydrochloride prepared according to example 3.
  • Example 5 Tablet formulation comprising rilpivirine hydrochloride form G

Abstract

La présente invention concerne un nouveau polymorphe et une nouvelle forme solvatée de chlorhydrate de rilpivirine dans le méthanol, ainsi que leur préparation. La nouvelle forme solvatée dans le méthanol constitue un intermédiaire valorisable dans la préparation du nouveau polymorphe du chlorhydrate de rilpivirine selon la présente invention. De plus, la présente invention concerne l'utilisation du nouveau polymorphe dans la préparation d'un médicament. La présente invention concerne en outre des compositions pharmaceutiques comprenant une quantité efficace du nouveau polymorphe de chlorhydrate de rilpivirine et leurs procédés de préparation. Pour finir, la présente invention concerne des compositions pharmaceutiques comprenant une quantité efficace du nouveau polymorphe de chlorhydrate de rilpivirine et d'autres agents thérapeutiques.
PCT/EP2013/057597 2012-04-11 2013-04-11 Polymorphe de chlorhydrate de rilpivirine WO2013153162A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12163723 2012-04-11
EP12163723.5 2012-04-11

Publications (1)

Publication Number Publication Date
WO2013153162A1 true WO2013153162A1 (fr) 2013-10-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220331307A1 (en) * 2015-01-27 2022-10-20 Janssen Pharmaceutica Nv Dispersible compositions

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1632232A1 (fr) * 2004-09-02 2006-03-08 Janssen Pharmaceutica N.V. Sel de 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
EP1419152B1 (fr) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Derives de pyrimidines inhibiteurs de vih
WO2012143937A2 (fr) * 2011-04-15 2012-10-26 Emcure Pharmaceuticals Limited Procédé perfectionné de préparation de rilpivirine
WO2012147091A2 (fr) * 2011-04-25 2012-11-01 Hetero Research Foundation Procédé de préparation de rilpivirine
WO2013038425A1 (fr) * 2011-09-16 2013-03-21 Hetero Research Foundation Chlorhydrate de rilpivirine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1419152B1 (fr) 2001-08-13 2011-07-27 Janssen Pharmaceutica NV Derives de pyrimidines inhibiteurs de vih
EP1632232A1 (fr) * 2004-09-02 2006-03-08 Janssen Pharmaceutica N.V. Sel de 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
EP1632232B1 (fr) 2004-09-02 2011-05-11 Janssen Pharmaceutica NV Sel de 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]benzonitrile
WO2012143937A2 (fr) * 2011-04-15 2012-10-26 Emcure Pharmaceuticals Limited Procédé perfectionné de préparation de rilpivirine
WO2012147091A2 (fr) * 2011-04-25 2012-11-01 Hetero Research Foundation Procédé de préparation de rilpivirine
WO2013038425A1 (fr) * 2011-09-16 2013-03-21 Hetero Research Foundation Chlorhydrate de rilpivirine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EU PHARMACOPOEIA, vol. 7.5, 2012, pages 1.2

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220331307A1 (en) * 2015-01-27 2022-10-20 Janssen Pharmaceutica Nv Dispersible compositions

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