[go: up one dir, main page]

WO2016193919A1 - Forme polymorphe de ledipasvir - Google Patents

Forme polymorphe de ledipasvir Download PDF

Info

Publication number
WO2016193919A1
WO2016193919A1 PCT/IB2016/053215 IB2016053215W WO2016193919A1 WO 2016193919 A1 WO2016193919 A1 WO 2016193919A1 IB 2016053215 W IB2016053215 W IB 2016053215W WO 2016193919 A1 WO2016193919 A1 WO 2016193919A1
Authority
WO
WIPO (PCT)
Prior art keywords
ledipasvir
solvent
solution
mixtures
process according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2016/053215
Other languages
English (en)
Inventor
Ramakoteswara Rao Jetti
Amit Singh
Satish BEERAVELLY
Sreenivasarao PATHURI
Nagadurgarao BANDI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mylan Laboratories Ltd
Original Assignee
Mylan Laboratories Ltd
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 Mylan Laboratories Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2016193919A1 publication Critical patent/WO2016193919A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present disclosure relates generally to active pharmaceutical ingredients and more specifically to a polymorph of ledipasvir designated as form-Mi.
  • the present disclosure also relates to processes for the preparation of ledipasvir form-Mi.
  • Ledipasvir (sometimes known as GS-5885) is an inhibitor of the hepatitis C virus NS5A protein.
  • a combination drug containing ledipasvir and sofosbuvir is currently marketed as HARVONI ® in the United States by Gilead Sciences.
  • HARVONI ® is indicated for the treatment of hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection.
  • HCV hepatitis C virus
  • Ledipasvir is chemically known as methyl[(2S)-l- ⁇ (6S)-6-[5-(9,9-difluoro-7- ⁇ 2-
  • PCT publication No. WO2013184698A1 discloses various crystalline forms of ledipasvir as well as an amorphous form of ledipasvir.
  • crystalline ledipasvir form-Ml may be characterized by a PXRD pattern having peaks at 2 ⁇ angle positions of 7.1, 9.6, 13.7, 18.2, 20.5 + 0.2 °.
  • the crystalline ledipasvir form-Ml may be further characterized by a PXRD pattern as shown in Figure 1.
  • the crystalline ledipasvir form-Ml may be further characterized by a 13 C-SSNMR spectrum having chemical shift peaks at 125.6, 113.9, and 63.6 ppm + 0.2 ppm.
  • crystalline ledipasvir form-Ml may have a degree of crystallinity below 60%. In some embodiments, the crystalline ledipasvir form- Ml has a degree of crystallinity below 30%.
  • Another aspect of the present invention provides processes for the preparation of ledipasvir form-Ml.
  • ledipasvir form-Ml may be prepared by the following steps: a) dissolving ledipasvir in a solvent or mixtures of solvents to form a solution; b) optionally seeding the solution with ledipasvir form-Ml; and
  • the solvent may be, for example, methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, water, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, or mixtures thereof.
  • ledipasvir form-Ml may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent at an elevated temperature to form a solution;
  • the organic solvent may be, for example, a polar protic solvent, a polar aprotic solvents, or mixtures thereof.
  • Suitable polar protic solvents include methanol, ethanol, isopropanol, 1- butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N- methylpyrrolidone, and mixtures thereof.
  • the anti- may be, for example, an ether solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • the ether solvent is isopropyl ether.
  • the hydrocarbon solvent is heptane.
  • ledipasvir form-Ml may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent at an elevated temperature to get a first solution;
  • the organic solvent may be, for example, a polar protic solvent, a polar aprotic solvents, or mixtures thereof.
  • polar protic solvents examples include methanol, ethanol, isopropanol, 1- butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N- methylpyrrolidone, and mixtures thereof.
  • the anti- may be, for example, an ether solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • the ether solvent is isopropyl ether.
  • the hydrocarbon solvent is heptane.
  • FIG. 1 is a powder X-ray diffraction (PXRD) pattern of ledipasvir form-Ml.
  • FIG. 2 is a differential scanning calorimetry (DSC) thermogram of ledipasvir form-Ml.
  • FIG. 3 is a 13 C solid-state NMR ( 13 C SSNMR) spectrum of ledipasvir form-Ml.
  • FIG. 4 shows 13 C SSNMR spectra of ledipasvir form-Ml and of amorphous ledipasvir.
  • FIG. 5 shows modulated DSC thermograms of ledipasvir form-Ml and of amorphous ledipasvir.
  • One aspect of the present invention provides crystalline ledipasvir form-Ml.
  • Another aspect of the present invention provides a process for the preparation of ledipasvir form-Ml.
  • ledipasvir form-Ml may be prepared by the following steps: a) dissolving ledipasvir in a solvent or mixtures of solvents to get a solution; b) optionally seeding the solution with ledipasvir form-Mi; and
  • ledipasvir may be dissolved a solvent or mixtures of solvents to get a solution.
  • the solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, water, and mixtures thereof.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, and mixtures thereof. In some embodiments, a mixture of acetonitrile and water is used as the solvent.
  • this may be carried out at an elevated temperature.
  • ledipasvir is dissolved in mixture of solvents at a temperature of about 50 °C to about 70 °C.
  • the solution may be cooled.
  • the solution may be cooled to ambient temperature.
  • the solution is slowly cooled to about 35 °C to about 45 °C.
  • the solution may be optionally seeded with ledipasvir form-M 1.
  • stirring the solution after seeding is particularly useful.
  • ledipasvir form-M 1 may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. The solution may be optionally further cooled prior to isolation of ledipasvir form-M 1. For example, in some embodiments, the reaction mixture is cooled to about 20 °C to about 25 °C and maintained at that temperature for about 10 hours to about 13 hours.
  • ledipasvir form-Mi may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent at an elevated temperature to get a solution;
  • ledipasvir may be dissolved in an organic solvent at an elevated temperature to get a solution.
  • ledipasvir is dissolved in an organic solvent at a temperature of about 50 °C to about 75 °C.
  • the organic solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, isopropyl ether, and mixtures thereof.
  • acetonitrile, methanol, dimethyl sulfoxide, isopropyl ether, or mixtures thereof are used as an organic solvent.
  • polar aprotic and polar protic solvents that may be useful within the context of this embodiment.
  • the solution may then be cooled.
  • the solution may be cooled to ambient temperature, or to a temperature of about 20 °C to about 35 °C. In some embodiments, it is found that stirring the solution at this temperature for about 10 hours to about 15 hours is particularly useful.
  • the solution may be optionally seeded with ledipasvir form-M 1.
  • an anti- solvent may optionally be added.
  • adding the anti-solvent slowly is particularly useful and effective at producing the desired solid product.
  • the steps of optionally seeding and optionally adding an anti-solvent may occur in any order.
  • the solution may be seeded followed by addition of an anti- solvent.
  • anti-solvent may be added followed by the addition of seeds of ledipasvir form-Mi.
  • the anti-solvent may be an ether solvent (for example, isopropyl ether), a hydrocarbon solvent (for example, heptane), water, or mixtures thereof.
  • ether solvent for example, isopropyl ether
  • hydrocarbon solvent for example, heptane
  • ledipasvir form-Mi may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. One of skill in the art would recognize a variety of methods that can be used to isolate the solid.
  • the solid may be further treated, for example, by drying under vacuum to get ledipasvir form-M 1.
  • ledipasvir form-Mi may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent to get a solution;
  • ledipasvir may be dissolved in an organic solvent.
  • this may be carried at an elevated temperature to get a solution.
  • ledipasvir is dissolved in an organic solvent at a temperature of about 50 °C to about 75 °C.
  • this step may be carried out at ambient temperatures.
  • the solution may be heated after dissolving the ledipasvir in the organic solvent at ambient temperature.
  • the organic solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • Suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, isopropyl ether, and mixtures thereof.
  • acetonitrile, methanol, dimethyl sulfoxide, isopropyl ether, or mixtures thereof are used as an organic solvent.
  • One of skill in the art will recognize numerous polar aprotic and polar protic solvents that may be useful within the context of this embodiment.
  • the solution may then be cooled.
  • the solution may be cooled to ambient temperature, or to a temperature of about 20 °C to about 35 °C. In some embodiments, it is found that stirring the solution at this temperature for about 10 hours to about 15 hours is particularly useful.
  • cooling the solution to about 60 °C to about 100 °C before carrying out the next step of optionally adding the anti-solvent is useful. After the anti-solvent is added, further cooling the solution to ambient temperature, or about 20 °C to about 35 °C, may be carried out.
  • an anti- solvent may optionally be added.
  • adding the anti-solvent slowly is particularly useful and effective at producing the desired solid product.
  • the anti-solvent may be an ether solvent (for example, isopropyl ether), a hydrocarbon solvent (for example, heptane), water, or mixtures thereof.
  • ether solvent for example, isopropyl ether
  • hydrocarbon solvent for example, heptane
  • ledipasvir form-Mi may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. One of skill in the art would recognize a variety of methods that can be used to isolate the solid.
  • ledipasvir form-Mi may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent at an elevated temperature to get a solution;
  • ledipasvir may be dissolved in an organic solvent at an elevated temperature.
  • ledipasvir is dissolved in an organic solvent at a temperature between about 50 °C to about 75 °C.
  • the organic solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof.
  • acetonitrile is used as an organic solvent.
  • One of skill in the art will recognize numerous polar aprotic and polar protic solvents that may be useful within the context of this embodiment.
  • the solution may then be cooled, for example, to ambient temperature, or to a temperature of about 25 °C to about 30 °C.
  • the solution may then optionally be seeded with ledipasvir form-M 1.
  • an anti-solvent may then be added to the solution.
  • adding the anti- solvent slowly at a temperature of about 25 °C to about 30 °C is particularly useful.
  • stirring the solution is particularly useful.
  • the solution is stirred at about 20 °C to about 35 °C for about 10 hours to about 15 hours.
  • the anti-solvent may be an ether solvent (for example, isopropyl ether), a hydrocarbon solvent (for example, heptane), water, or mixtures thereof.
  • ledipasvir form-Mi may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. One of skill in the art would recognize a variety of methods that can be used to isolate the solid.
  • the solid may be further treated, for example, by drying under vacuum to get ledipasvir form-M 1.
  • ledipasvir form-M 1 may be prepared by the following steps: a) dissolving ledipasvir in an organic solvent at an elevated temperature to get a first solution;
  • ledipasvir may be dissolved in an organic solvent to get a solution.
  • the organic solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof.
  • acetonitrile is used as an organic solvent.
  • the solution may then be cooled, for example, to ambient temperature, or to a temperature of about 25 °C to about 30 °C.
  • seeds of ledipasvir form-M 1 may be added to an anti- solvent.
  • the anti-solvent may be an ether solvent (for example, isopropyl ether), a hydrocarbon solvent (for example, heptane), water, or mixtures thereof.
  • the first solution may be added to the seeded anti-solvent solution. This step may be carried out at ambient temperature, for example, at about 25 °C to about 30 °C. In some embodiments, it is found that adjusting the temperature to about 20 °C to about 35 °C and stirring for about 10 hours to about 15 hours is particularly useful.
  • ledipasvir form-Mi may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. One of skill in the art would recognize a variety of methods that can be used to isolate the solid.
  • the solid may be further treated, for example, by drying under vacuum to get ledipasvir form-Mi.
  • ledipasvir form-Mi may be prepared by the following steps:
  • ledipasvir may be dissolved in an organic solvent at an elevated temperature.
  • ledipasvir is dissolved in an organic solvent at a temperature of about 50 °C to about 65 °C.
  • the organic solvent may be a polar protic or polar aprotic solvent.
  • suitable polar protic solvents include methanol, ethanol, isopropanol, 1-butanol, isobutyl alcohol, 1-pentanol, and mixtures thereof.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof.
  • methanol is used as an organic solvent.
  • One of skill in the art will recognize numerous polar aprotic and polar protic solvents that may be useful within the context of this embodiment.
  • An anti-solvent may then be added to the solution.
  • it is found that adding the anti-solvent slowly and that stirring the solution is particularly useful.
  • the solution is stirred for about 10 minutes to about 15 minutes.
  • the anti-solvent may be an ether solvent (for example, isopropyl ether), a hydrocarbon solvent (for example, heptane), water, or mixtures thereof.
  • ether solvent for example, isopropyl ether
  • hydrocarbon solvent for example, heptane
  • the solution may then be cooled.
  • the solution is cooled to ambient temperature.
  • cooling the solution to a temperature of about 35 °C to about 45 °C was found to be particularly useful.
  • the solution may then be optionally seeded with ledipasvir form-Ml. In some embodiments, it is found that stirring the solution after seeding, for example, for about 1 hour to about 2 hours at the same temperature is useful.
  • ledipasvir form-Ml may be isolated. This may be carried out according to methods well known in the art, for example, by filtering the solution to obtain a solid. One of skill in the art would recognize a variety of methods that can be used to isolate the solid. In some embodiments, further cooling the solution before isolating ledipasvir form-Ml is found to be useful. For example, in some embodiments, the mixture is cooled to about 20 °C to about 30 °C and stirred for about 15 hours to about 16 hours.
  • the solid may be further treated, for example, by drying under vacuum to get ledipasvir form-Ml.
  • the obtained solid is dried under vacuum at about 50 °C to about 60 °C for about 7 hours to about 9 hours to get ledipasvir form-Ml.
  • the ledipasvir material that is dissolved in a solvent may be crystalline or amorphous and may be prepared by any prior-art process.
  • the solid ledipasvir may be crystalline Form- III or crystalline Form II, as disclosed in WO2013184698.
  • HPLC analyses were performed on a Waters Alliance 2695 HPLC system with a 2487 UV detector. Data was collected and analyzed with Empower chromatography software or an equivalent. The below parameters were used to analyze samples: Column: X Select FISS CI 8, 250 x 4.6mm, 3.5 um or its equivalent
  • ledipasvir form-Mi prepared according to the process disclosed herein present may exhibit a purity of more than 99% when analyzed by HPLC.
  • the polymorphic forms of ledipasvir disclosed herein may be characterized by their X-ray powder diffraction (PXRD) pattern.
  • PXRD X-ray powder diffraction
  • the PXRD patterns of the polymorphs of the disclosure were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu- anode X-ray tube is operated at 40kV and 30mA.
  • the experiments were conducted over the 2 ⁇ range of 2.0°- 50.0°, 0.030° step size, and 50 seconds step time.
  • crystalline ledipasvir form-Mi may be characterized by a PXRD pattern having significant peaks at 7.1, 9.6, 13.7, 18.2, 20.5 + 0.2 °2 ⁇ .
  • ledipasvir form-Mi may be further characterized by a PXRD pattern as shown in Figure 1.
  • the polymorphs of ledipasvir disclosed herein may also be characterized by differential scanning calorimetry (DSC) or modulated differential scanning calorimetry (MDSC).
  • DSC differential scanning calorimetry
  • MDSC modulated differential scanning calorimetry
  • the DSC measurements were carried out on TA Q1000 of TA instruments. The experiment were performed from 30 to 250 °C at a heating rate of 10.0 °C/minutes with modulation amplitude of + 0.5 °C, for every 80 seconds and nitrogen purging at a flow rate of 50 mL/minute. MDSC experiments were performed from 30-250 °C at a heating rate of 10.0 °C/minutes with modulation amplitude of + 1 °C for every 80 seconds. Standard aluminum pans covered by lids with five pin holes were used.
  • ledipasvir form-Mi may be characterized by differential scanning calorimetry (DSC) thermogram as shown in Figure 2.
  • DSC differential scanning calorimetry
  • Ledipasvir form-Mi disclosed herein may also be characterized for its water content.
  • Water content for ledipasvir form-Mi was determined on a Metrohm Coulometer (Model: 774-831, with oven and auto sampler) using a Karl Fisher coulometric reagent. The moisture content was determined at 150 °C with sample mass of about 100 mg.
  • Ledipasvir form-Mi disclosed herein also may be characterized by 13 C-solid state NMR ( 13 C SSNMR). Therefore, 13 C SSNMR spectra of ledipasvir form-Mi was measured on a Bruker AVANCE III 500 MHz NMR spectrometer with 3.2 mm triple resonance solid state probe. Approximately 80-100 mg of the fine powdered sample was filled into a 4.0 mm zirconium rotor. The sample was oriented at the magic angle and a spinning rate of 10 KHz was applied to remove broadening. Cross polarization technique was used to enhance the 13 C sensitivity by transferring proton magnetization to carbon. All the spectra were acquired for 2 hours and 24 minutes with a spectral width of 301 ppm. The number of average scans was 864. An external reference of KBr was used as a reference.
  • ledipasvir form-Mi may be characterized by a 13 C SSNMR spectrum having chemical shift peaks at about 125.6, 113.9, and 63.6 ppm + 0.2 ppm.
  • ledipasvir form-Mi may be further characterized by the 13 C-SSNMR spectrum shown in Figure 3.
  • ledipasvir form-Mi may be further characterized by a 13 C SSNMR spectrum having chemical shift peaks at 172.4, 170.7, 156.1, 145.4, 140.7, 137.1, 135.6, 130.2, 125.6, 119.3, 113.9, 110.2, 63.6, 57.9, 51.7, 42.9, 38.9, 35.7, 31.1, 18.2, and 4.6 + 0.2 ppm.
  • ledipasvir form-Mi may be characterized by comparing a 13 C-SSNMR spectrum of the crystalline form-Mi to a 13 C-
  • ledipasvir form-Ml may be characterized by comparing an MDSC thermogram of the crystalline form-Ml to an MDSC thermogram for amorphous ledipasvir. Therefore, an MDSC curve for amorphous ledipasvir was also obtained and compared to the MDSC curve for ledipasvir form-Ml. These curves are shown in Figure 5.
  • the MDSC thermograms in Figure 5 for reversible heat flow show the true melting of form-Ml at 168.7 °C whereas the amorphous form shows a glass transition at 160 °C.
  • Ledipasvir form-Ml disclosed herein may, in some embodiments, exhibit long-term physical and chemical stability.
  • ledipasvir form-Ml The physical and chemical stability of ledipasvir form-Ml was determined by storing the samples at 40 °C/75% relative humidity (RH) and at 25 °C/60% RH for 6 months. The samples were tested for moisture content, stability of crystalline form by PXRD analysis, and purity by HPLC analysis. As an example, Table 1 below is data collected on ledipasvir form-Ml. The stability data shows that ledipasvir form-Ml has no significant change in PXRD pattern, no significant change in purity, and no significant change in moisture content for up to six months when stored at 25 °C/60% RH and 40 °C/75% RH.
  • ledipasvir form-Ml obtained by the processes disclosed herein may be a solvated form of ledipasvir. It is further believed that ledipasvir form-Ml obtained by the processes disclosed herein may be a hydrate.
  • Ledipasvir form-Ml disclosed herein and prepared by the disclosed methods may be used to formulate an oral dosage form, such as a tablet or a capsule. When administered to patients, the ledipasvir of the present invention may be useful treatment of individuals infected with hepatitis C. Ledipasvir may be used singly or in combination with other antiviral drugs, such as sofosbuvir.
  • the ledipasvir form-Ml of the present invention may be formulated into a tablet which may contain inactive ingredients such as colloidal silicon dioxide, polyvinylpyrrolidone (copovidone), croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
  • the tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial colors, and flavors.
  • a coating may contain polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
  • excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
  • the polymorphs of ledipasvir disclosed herein be characterized for their crystallinity index (CI).
  • the CI of some embodiments of ledipasvir form-Ml was calculated quantitatively from the X-ray powder diffractogram by comparing the area of the crystalline peaks (Ac) to the area under the halo-shaped amorphous peak (AA). The sum of Ac and AA equals the total scattered intensity.
  • ledipasvir form-Ml prepared by the methods produced herein, may have a degree of crystallinity below 60%.
  • ledipasvir form-Ml has a degree of crystallinity below 50% as given in Table 2 below.
  • Moisture content was measured for several samples of ledipasvir form-Ml prepared by methods disclosed herein. Table 2 shows that the moisture content of ledipasvir form- Ml has moisture content in the range of about 2% to about 5%.
  • Ledipasvir form-Ill (1.0 g) was dissolved in acetonitrile (5 mL) at 60 °C. The clear solution was then cooled to 25-30 °C and maintained under stirring at 25-30 °C for 15 hours. The reaction mixture was filtered to obtain a solid which was then dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Ledipasvir form-Ill (1.0 g) was dissolved in acetonitrile (5 mL) at 60 °C. The clear solution was then cooled to 25-30 °C and maintained under stirring at 25-30 °C for 15 hours. The reaction mixture was filtered to obtain a solid which was then washed with n- heptane (10 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Ledipasvir form-Ill (1.0 g) was dissolved in acetonitrile (5 mL) at 60 °C. The clear solution was then cooled to 25-30 °C.
  • seeds of ledipasvir form-Ml were suspended in isopropyl ether (15 mL) under stirring at 25-30 °C. The solution of ledipasvir was then slowly added at 25-30 °C. The reaction mass was maintained under stirring for 15 hours at 25-30 °C. The reaction mixture was filtered to obtain a solid which was then washed with isopropyl ether (5 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Ledipasvir form-Ill (1.0 g) was dissolved in acetonitrile (5 mL) at 60 °C. The clear solution was then cooled to 25-30 °C.
  • seeds of ledipasvir form-Ml were suspended in water (15 mL) while stirring the mixture at 25-30 °C. The solution of ledipasvir was then slowly added at 25-30 °C. The reaction mass was maintained under stirring for 15 hours at 25-30 °C. The reaction mixture was filtered to obtain a solid which was then washed with water (5 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml. Yield: 0.80 g
  • Ledipasvir form-Ill (2.5 g) was dissolved in acetonitrile (13 mL) at 60 °C. The clear solution of was then cooled to 25-30 °C and seeds of ledipasvir form-Ml were added. Then n-heptane (35 mL) was added to the reaction mass and the solution was stirred for 15 hours at 25-30 °C. The reaction mixture was filtered to obtain a solid which was then washed with n-heptane (5 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Example 8 Preparation of ledipasvir form-Ml Ledipasvir form-Ill (0.5 g) was dissolved in dimethyl sulfoxide (3 mL) at 25-30 °C.
  • Ledipasvir form-Ill (1.0 g) was dissolved in dimethyl sulfoxide (3 mL) at 25-30 °C. Water (9 mL) was then added to the clear solution at 25-30 °C and stirred for 1 hour. The reaction mixture was filtered to obtain a solid which was then washed with water (1 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Mi.
  • Ledipasvir form- III (1.0 g) was dissolved in methanol (3 mL) at 60 °C. The clear solution of ledipasvir was cooled to 25-30 °C. In another round bottom flask, seeds of ledipasvir form-Mi were suspended in isopropyl ether (10 mL) and the solution of ledipasvir was added slowly at 25-30 °C. The reaction mass was further maintained under stirring for 15 hours at 25-30 °C. The reaction mixture was filtered to obtain a solid which was then washed with isopropyl ether (6 mL) and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Mi.
  • Ledipasvir form II (10 g) was dissolved in acetonitrile (40 mL) at 60-70 °C. The clear solution was then cooled to 20-25 °C and seeds of ledipasvir form-Mi (100 mg) were added. Stirring was continued for 20 hours at 20-25 °C. Water (50 mL) was added over 30 minutes and the solution was stirred for 6 hours. The reaction mixture was filtered to obtain a solid which was then washed with water (10 mL) and dried under vacuum at 50 °C for 15 hours. The solid obtained was identified as ledipasvir form-Mi.
  • Example 12 Preparation of ledipasvir form-Mi Ledipasvir form II (4 g) was dissolved in a mixture of acetonitrile (16 mL) and water
  • Ledipasvir form II (4 g) was dissolved in methanol (28 mL) at 55-60 °C. Water (11 mL) was added to this solution at the rate of 1 niL/minute. After addition of water, the reaction mass was stirred for 10-15 minutes and then cooled to 45 °C at the rate of 0.5 °C per minute. Seeds of ledipasvir form-Mi (80 mg) were then added into the reaction mass and the reaction mass was stirred for 1 hour at 45 °C. The reaction mass was then cooled to 25 °C over the course of 30-35 minutes and stirred for 15-16 hours at 25 + 2 °C. The reaction mixture was filtered to obtain a solid which was then washed with water (8 mL) and dried under vacuum at 50 °C for 8 hours. The solid obtained was identified as ledipasvir form-Mi.
  • Example 14 Preparation of ledipasvir form-Mi Ledipasvir form II (0.5 g) was dissolved in acetonitrile (2.5 mL) at 60 °C. The clear solution of ledipasvir was cooled to 22-25 °C. In another round bottom flask, seeds of ledipasvir form-Mi were suspended in water (7.5 mL) and the solution was stirred for 10-15 minutes. The clear solution of ledipasvir was then slowly added and resulting reaction mixture was maintained at 27 + 2 °C for 15 hours. The reaction mixture was then filtered to obtain a solid which was then washed with water and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Example 15 Preparation of ledipasvir form-Ml
  • ledipasvir Amorphous form of ledipasvir (0.5 g) was dissolved in acetonitrile (2.5 mL) at 60 °C. The clear solution of ledipasvir was cooled to 22-25 °C. In another round bottom flask, seed of ledipasvir form-Ml (1% w/w) were suspended in water (7.5 mL) and the solution was stirred for 10-15 minutes. The clear solution of ledipasvir was then added and solution was maintained at 27 + 2 °C for 15 hours. The reaction mixture was then filtered to obtain a solid which was washed with water and dried under vacuum at 40 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.
  • Amorphous ledipasvir (30 g) was dissolved in acetonitrile (120 mL) at 70 °C and then cooled to 22-25 °C. The solution was then filtered to remove any undissolved particulate matter. The clear filtrate was taken in another round bottom flask and seeds of ledipasvir form-Ml (1% w/w) were added at 22-25 °C. The solution was stirred for 15 hours at 22-25 °C. A thick reaction mass was observed. Water (150 mL) was added to the reaction mixture and stirred for 1-2 hours at 22-25 °C. The reaction mixture was filtered to obtain a solid, which was washed with water (40 mL) and dried under vacuum at 60 °C for 15 hours. The solid obtained was identified as ledipasvir form-Ml.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux polymorphes stables de ledipasvir désignés comme formes M1, ainsi que des procédés de préparation de ceux-ci.
PCT/IB2016/053215 2015-06-05 2016-06-01 Forme polymorphe de ledipasvir Ceased WO2016193919A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2181MU2015 2015-06-05
IN2181/MUM/2015 2015-06-05

Publications (1)

Publication Number Publication Date
WO2016193919A1 true WO2016193919A1 (fr) 2016-12-08

Family

ID=56235857

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/053215 Ceased WO2016193919A1 (fr) 2015-06-05 2016-06-01 Forme polymorphe de ledipasvir

Country Status (1)

Country Link
WO (1) WO2016193919A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184698A1 (fr) 2012-06-05 2013-12-12 Gilead Sciences, Inc. Formes solides d'un composé antiviral

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184698A1 (fr) 2012-06-05 2013-12-12 Gilead Sciences, Inc. Formes solides d'un composé antiviral

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 *

Similar Documents

Publication Publication Date Title
KR101560428B1 (ko) Ｎ-(ｔｅｒｔ-부톡시카르보닐)-3-메틸-ｌ-발릴-(4ｒ)-4-((7-클로로-4-메톡시-1-이소퀴놀리닐)옥시)-ｎ-((1ｒ,2ｓ)-1-((시클로프로필술포닐)카르바모일)-2-비닐시클로프로필)-ｌ-프롤린아미드의 결정질 형태
KR101470715B1 (ko) 다사티닙 다결정체 및 그의 제조방법과 약물 조성물
EP3549932B1 (fr) Nouvelles formes cristallines d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl]amino} acétique et leur procédé de préparation
US10208065B2 (en) Crystalline free bases of C-Met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
US20130035356A1 (en) Crystal of diamine derivative and method of producing same
EP2603503A1 (fr) Mésylate de dabigatran étexilate, ses formes solides et leurs procédés de préparation
US20250243223A1 (en) Solid state forms of ixazomib citrate
US10738071B2 (en) Polymorphic forms of sofosbuvir
KR20240119095A (ko) Fgfr 저해제의 고체 상태 형태
KR20070110128A (ko) 퀴누클리딘 유도체의 신규한 염
WO2016193919A1 (fr) Forme polymorphe de ledipasvir
US10221185B2 (en) Crystal form of substituted aminopyran derivativek
CN108069891B (zh) 一类甲基甲胺盐酸盐的a晶型、制备及其应用
CN117736176A (zh) 雄激素受体拮抗剂的可药用盐及其多晶型物、制备方法和用途
WO2016157136A1 (fr) Formes cristallines de l'idélalisib
CN112225730A (zh) 一种稠环化合物的晶型、其组合物、制备方法及其应用
EP4349835A1 (fr) Forme cristalline d'hydrate de méthanesulfonate de lazertinib, son procédé de préparation et son utilisation
CN111484488A (zh) 一种b-raf激酶二聚体抑制剂的稳定结晶形式a
CN105732596B (zh) N-[3-氯-4-(3-氟苄氧基)苯基]-6-[5-[[2-(甲亚磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺多晶型物及其制备方法
JP2024542427A (ja) エリグルスタットの薬学的に許容される塩及びその結晶形
CA2829186A1 (fr) Forme amorphe d'un melange de lopinavir et de ritonavir
HK1231054A (en) Malate salt of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof
HK1231054A1 (en) Malate salt of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof

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: 16732336

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16732336

Country of ref document: EP

Kind code of ref document: A1