WO2017006227A1 - Procédé de préparation de dichlorhydrate de daclatasvir amorphe, dispersion solide amorphe de ce dernier, et procédés de préparation de ces derniers - Google Patents

Procédé de préparation de dichlorhydrate de daclatasvir amorphe, dispersion solide amorphe de ce dernier, et procédés de préparation de ces derniers Download PDF

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Publication number
WO2017006227A1
WO2017006227A1 PCT/IB2016/053968 IB2016053968W WO2017006227A1 WO 2017006227 A1 WO2017006227 A1 WO 2017006227A1 IB 2016053968 W IB2016053968 W IB 2016053968W WO 2017006227 A1 WO2017006227 A1 WO 2017006227A1
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Prior art keywords
solvent
daclatasvir dihydrochloride
amorphous
daclatasvir
dihydrochloride
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PCT/IB2016/053968
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English (en)
Inventor
Ramakoteswara Rao Jetti
Satish BEERAVELLY
Amit Singh
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Mylan Laboratories Limited
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Publication of WO2017006227A1 publication Critical patent/WO2017006227A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to a process for the preparation of amorphous daclatasvir dihydrochloride.
  • the present invention also relates to a process for the preparation of amorphous solid dispersion of daclatasvir dihydrochloride together with pharmaceutically acceptable carriers.
  • Daclatasvir dihydrochloride is chemically named as methyl ((lS)-l-(((2S)-2-(5-(4'-(2- ((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl-2-pyrrolidinyl)-lH-imidazol-5- yl)-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)carbonyl)-2-methylpropyl) carbamate dihydrochloride and is re resented by the following chemical structure:
  • Daclatasvir is disclosed in U.S Patent No. 8,329,159 B2, which is hereby incorporated by reference.
  • U.S. Patent Publication No. 2013/0172239 Al which is hereby incorporated by reference, discloses an amorphous solid composition comprising an HCV inhibitor, a pharmaceutically acceptable hydrophilic polymer, and optionally a pharmaceutically acceptable surfactant.
  • PCT Patent App. Publication No. WO2016/075588 Al which is hereby incorporated by reference, discloses a stable amorphous form of daclatasvir dihydrochloride and a process for the preparation thereof.
  • the inventors of the present disclosure developed a process for the preparation of amorphous daclatasvir dihydrochloride and also a process for the preparation of amorphous solid dispersions of daclatasvir dihydrochloride together with pharmaceutically acceptable carriers.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that includes the steps of dissolving daclatasvir dihydrochloride in a solvent; and removing the solvent to obtain amorphous daclatasvir dihydrochloride.
  • the solvent may be a polar solvent.
  • suitable polar solvents include, but are not limited to, water, methanol, ethanol, isopropanol, isobutanol, acetone, ethyl acetate, acetonitrile, and mixtures thereof.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of:
  • step (b) adding a second solvent to the reaction mass obtained in step (b);
  • the first solvent may be a polar solvent, and examples of suitable polar solvents include, but are not limited to, water, methanol, ethanol, isopropanol, isobutanol, acetone, ethyl acetate, acetonitrile, and mixtures thereof.
  • the second solvent may be a non-polar solvent, with suitable non-polar solvents including, but not being limited to, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, heptane, hexane, cyclohexane, and mixtures thereof.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of:
  • the solvent may be a polar solvent, with suitable examples including, but not being limited to, methanol, ethanol, propanol, isopropanol, isobutanol, acetonitrile, dichloromethane, ethyl acetate, and mixtures thereof.
  • the anti-solvent may be a non-polar organic solvent, such as, but not limited to, toluene, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, methyl t-butyl ether, isopropyl ether, diethyl ether, and mixtures thereof.
  • a non-polar organic solvent such as, but not limited to, toluene, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, methyl t-butyl ether, isopropyl ether, diethyl ether, and mixtures thereof.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of:
  • the solvent may be a polar solvent, with suitable examples including, but not being limited to, methanol, ethanol, propanol, isopropanol, isobutanol, acetonitrile, dichloromethane, ethyl acetate, and mixtures thereof.
  • the anti-solvent may be a non-polar organic solvent, such as, but not limited to, toluene, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, methyl t-butyl ether, isopropyl ether, diethyl ether, and mixtures thereof.
  • the present invention provides amorphous solid dispersions of daclatasvir dihydrochloride with a pharmaceutically acceptable carrier and methods for generating the same. Specifically, the present invention provides a process for the preparation of amorphous solid dispersion of daclatasvir dihydrochloride including the steps of:
  • the solvent used here may be a polar solvent, such as, but not limited to, water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, dimethyl formamide, and mixtures thereof.
  • a polar solvent such as, but not limited to, water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, dimethyl formamide, and mixtures thereof.
  • a wide variety of pharmaceutically acceptable carriers may be employed within the scope of the present invention. Suitable examples include, but are not limited to, PLASDONE S-630, polyvinylpyrrolidine K-30, ⁇ -cyclodextrin, and hydroxypropyl- ⁇ - cyclodextrin.
  • the present invention provides a process for the preparation of amorphous solid dispersion of daclatasvir dihydrochloride that may include the steps of: a) dissolving daclatasvir dihydrochloride in water;
  • step (b) mixing the solutions obtained in step (a) and step (b);
  • solvent or water may be removed by methods well known in the prior art, such as distillation, spray drying, freeze drying, or by agitated thin film drier.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process.
  • Figure 1 is an X-ray powder diffractogram of amorphous daclatasvir dihydrochloride
  • Figure 2 is an X-ray powder diffractogram of amorphous solid dispersion of daclatasvir dihydrochloride with Plasdone S-630;
  • Figure 3 is an X-ray powder diffractogram of amorphous solid dispersion of daclatasvir dihydrochloride with polyvinylpyrrolidine K-30;
  • Figure 4 is an X-ray powder diffractogram of amorphous solid dispersion of daclatasvir dihydrochloride with ⁇ -cyclodextrin.
  • the present invention generally provides for an amorphous form of daclatasvir dihydrochloride and methods of production thereof. Further, the present invention provides for amorphous solid dispersions of daclatasvir dihydrochloride together with pharmaceutically acceptable carriers, and methods of production thereof.
  • the amorphous daclatasvir dihydrochloride and amorphous solid dispersions of daclatasvir dihydrochloride with pharmaceutically acceptable carriers may be included in pharmaceutical dosage forms suitable for administration to patients in need thereof.
  • the present disclosure relates to a process for the preparation of an amorphous form of daclatasvir dihydrochloride as characterized by the powder X-ray diffraction pattern (PXRD) as shown in FIG. 1.
  • PXRD powder X-ray diffraction pattern
  • the PXRD measurements were carried out using 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.
  • the present disclosure provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of dissolving daclatasvir dihydrochloride in a solvent and removing the solvent to obtain amorphous daclatasvir dihydrochloride.
  • daclatasvir dihydrochloride is dissolved in a solvent.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process.
  • This dissolution step may be conducted under a wide variety of conditions that would be well known to those having ordinary skill in the art. For example, large volumes of solvent held at room temperature may be effective to dissolve an appropriate mass of daclatasvir dihydrochloride. Alternatively, this step may be carried out at an elevated temperature so as to promote dissolution, e.g., about 60+5 °C. Within the context of the present disclosure, "about” means plus or minus 10% of the reported value.
  • the solution is cooled to about 25+5 °C. After that, the solvent is removed to yield amorphous daclatasvir dihydrochloride.
  • the solvent may be a polar solvent.
  • suitable polar solvents include, but are not limited to, water, methanol, ethanol, isopropanol, isobutanol, acetone, ethyl acetate, acetonitrile, and mixtures thereof.
  • the solvent may be removed according to well-known techniques in the art, for example, distillation, evaporation, spray drying, freeze drying (i.e., lyophilization), or by agitated thin film drier.
  • step (b) adding a second solvent to the reaction mass obtained in step (b);
  • daclatasvir dihydrochloride may be dissolved in a first solvent.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process. This step may be carried out at an elevated temperature employed to promote dissolution, e.g., about 60+5 °C.
  • the first solvent may be removed, for example, by distillation, and a second solvent may be added to the reaction mixture. After that, the second solvent may be removed to yield amorphous daclatasvir dihydrochloride.
  • the first solvent may be a polar solvent.
  • suitable polar solvents include, but are not limited to, water, methanol, ethanol, isopropanol, isobutanol, acetone, ethyl acetate, acetonitrile, and mixtures thereof.
  • polar solvents include, but are not limited to, water, methanol, ethanol, isopropanol, isobutanol, acetone, ethyl acetate, acetonitrile, and mixtures thereof.
  • the second solvent may be a non-polar solvent.
  • suitable non-polar solvents include, but are not limited to, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, heptane, hexane, cyclohexane, and mixtures thereof.
  • the solvent may be removed according to well-known techniques in the art, for example, distillation, evaporation, spray drying, freeze drying, or by agitated thin film drier.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of: a) dissolving daclatasvir dihydrochloride in a solvent;
  • daclatasvir dihydrochloride may be dissolved in solvent.
  • the input daclatasvir dihydrochloride for this step may be crystalline or amorphous and may be prepared by any prior-art process.
  • the daclatasvir dihydrochloride solution may then be added to an anti- solvent solution optionally containing amorphous daclatasvir dihydrochloride seeds at room temperature.
  • the anti-solvent solution may be added to the daclatasvir dihydrochloride solution. Regardless of the order of addition, the addition may occur slowly and the resulting solution may be stirred or otherwise agitated until a solid product is generated.
  • the obtained solid amorphous daclatasvir dihydrochloride may then be isolated, for example by filtration, distillation, evaporation, spray drying, freeze drying, or by agitated thin film drier, and dried.
  • the elevated temperature utilized during dissolution of daclatasvir dihydrochloride may range from room temperature to boiling temperature of the solvent, preferably the elevated temperature ranges from 40-75 °C depending on nature of solvent.
  • the solvent may be a polar solvent such as, but not limited to, water, methanol, ethanol, propanol, isopropanol, isobutanol, acetonitrile, dichloromethane, ethyl acetate, and mixtures thereof.
  • the anti-solvent may be a non-polar organic solvent, such as, but not limited to, toluene, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, methyl t-butyl ether, isopropyl ether, diethyl ether, and mixtures thereof.
  • the present invention provides a process for the preparation of amorphous daclatasvir dihydrochloride that may include the steps of:
  • daclatasvir dihydrochloride may be dissolved in a solvent at elevated temperature.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process.
  • the solvent may be removed by distillation or evaporation at elevated temperature, and the reaction mass may be cooled to 25+5 °C. In some embodiments, approximately 75% of the solvent is removed, while in other embodiments, the solvent is completely removed.
  • the daclatasvir dihydrochloride solution may then be added to an anti-solvent solution optionally containing amorphous daclatasvir dihydrochloride seeds at room temperature.
  • the anti-solvent solution may be added to the daclatasvir dihydrochloride solution. Regardless of the order of addition, the addition may occur slowly and the resulting solution may optionally be stirred or otherwise agitated until a solid product is generated. After that, the anti-solvent and any remaining solvent may be removed to yield amorphous daclatasvir dihydrochloride in solid form.
  • the solvent may be a polar solvent such as, but not limited to, methanol, ethanol, propanol, isopropanol, isobutanol, acetonitrile, dichloromethane, ethyl acetate, and mixtures thereof.
  • the anti-solvent may be a non-polar organic solvent, such as, but not limited to, toluene, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, methyl t-butyl ether, isopropyl ether, diethyl ether, and mixtures thereof.
  • the elevated temperature utilized in this embodiment may range from room temperature to boiling temperature of the solvent, preferably the elevated temperature ranges from 40-75 °C depending on nature of solvent.
  • the anti-solvent may be removed according to well-known techniques in the art, for example, distillation, evaporation, spray drying, freeze drying, or by agitated thin film drier.
  • the present invention provides a process for the preparation of amorphous solid dispersion of daclatasvir dihydrochloride that may include the steps of: a) dissolving daclatasvir dihydrochloride and at least one pharmaceutically acceptable carrier in a solvent; and
  • daclatasvir dihydrochloride and one or more pharmaceutically acceptable carriers are dissolved in a solvent.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process. Within the context of this embodiment, this dissolution step may be carried out at a temperature of about 25 °C to about 30 °C.
  • a wide range of pharmaceutically acceptable carriers may be employed.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, PLASDONETM S-630, polyvinylpyrrolidine K-30, ⁇ - cyclodextrin, and hydroxypropyl-P-cyclodextrin (HPBCD).
  • HPBCD hydroxypropyl-P-cyclodextrin
  • the pharmaceutically acceptable carriers may be included at a wide variety of concentrations relative to daclatasvir dihydrochloride, as would be recognized by one having ordinary skill in the art.
  • the solvent employed may be, for example, a polar solvent. In some embodiments of the present invention, the solvent may be water miscible. Suitable polar solvents include, but are not limited to, water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, dimethyl formamide, and mixtures thereof.
  • the solvent may be removed, resulting in an amorphous solid dispersion of daclatasvir dihydrochloride in at least one pharmaceutically acceptable carrier.
  • the solvent may be removed according to well-known techniques in the art, for example, distillation, evaporation, spray drying, freeze drying, or by agitated thin film drier.
  • Another embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of daclatasvir dihydrochloride that may include the steps of: a) dissolving daclatasvir dihydrochloride in water;
  • step (b) mixing the solutions obtained in step (a) and step (b);
  • daclatasvir dihydrochloride and at least one pharmaceutical acceptable carrier are dissolved in water.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process.
  • the dissolution of daclatasvir dihydrochloride may be carried out at a temperature of about 60 °C to about 65 °C.
  • the input daclatasvir dihydrochloride may be crystalline or amorphous and may be prepared by any prior-art process.
  • a wide range of pharmaceutically acceptable carriers may be employed.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, PLASDONETM S-630, polyvinylpyrrolidine K-30, ⁇ - cyclodextrin, and hydroxypropyl-P-cyclodextrin (HPBCD).
  • the pharmaceutically acceptable carriers may be included at a wide variety of concentrations relative to daclatasvir dihydrochloride, as would be recognized by one having ordinary skill in the art.
  • the pharmaceutically acceptable carrier may also be dissolved in water. Within the context of the present embodiment, this dissolution may be carried out at a temperature of about 60 °C to about 65 °C.
  • both solutions may be cooled and mixed together.
  • the water may then be removed.
  • mixing of both solutions may occur in any order.
  • water may be removed according to well-known techniques in the art, for example, distillation, evaporation, spray drying, freeze drying, or by agitated thin film drier.
  • starting material daclatasvir dihydrochloride may be crystalline or amorphous in nature and can be prepared as per the processes disclosed in the prior art, such as U.S. Patent No. 8,329,159 B2.
  • the amorphous solid dispersions of daclatasvir dihydrochloride with pharmaceutically acceptable solvents may be characterized by PXRD.
  • FIG. 2 provides an exemplary PXRD of amorphous solid dispersion of daclatasvir dihydrochloride with PLASDONETM S-630.
  • FIG. 3 shows an exemplary PXRD of amorphous solid dispersion of daclatasvir dihydrochloride with polyvinylpyrrolidine K-30.
  • FIG. 4 displays PXRD of amorphous solid dispersion of daclatasvir dihydrochloride with ⁇ -cyclodextrin.
  • Amorphous daclatasvir dihydrochloride disclosed herein may, in some embodiments, exhibit long-term physical and chemical stability.
  • the physical and chemical stability of amorphous daclatasvir dihydrochloride was determined by storing the samples at 40 °C/75% relative humidity (RH) and at 25 °C/60% RH for two months. The samples were tested for stability of amorphous form by PXRD analysis and for purity by HPLC analysis.
  • Table 1 provides data collected on amorphous daclatasvir dihydrochloride.
  • the stability data demonstrate that amorphous daclatasvir dihydrochloride displays no significant change in PXRD pattern and no significant change in purity for up to two months when stored at 25 °C/60% RH and 40 °C/75% RH.
  • Amorphous solid dispersion of daclatasvir dihydrochloride with pharmaceutically acceptable carriers may exhibit long-term physical and chemical stability.
  • amorphous solid dispersions of daclatasvir dihydrochloride with PLASDONETM S-630 (10% w/w), HPBCD (10% w/w), PVP K-30 (25% and 50% w/w) and ⁇ -cyclodextrin (10%, 25% and 50% w/w ratio) were evaluated by storing the samples at 40 °C/75% RH and at 25 °C/60% RH for two months. The samples were tested for stability of amorphous form by PXRD analysis and for purity by HPLC analysis.
  • Table 2 provides data collected on amorphous solid dispersion of daclatasvir dihydrochloride with PLASDONETM S-630 (10% w/w), and HPBCD (10% w/w).
  • the stability data demonstrate that amorphous solid dispersions of daclatasvir dihydrochloride in these pharmaceutically acceptable carriers display no significant change in PXRD pattern and no significant change in purity for up to two months when stored at 25 °C/60% RH and 40 °C/75% RH.
  • Table 3 provides data collected on amorphous solid dispersion of daclatasvir dihydrochloride with ⁇ -cyclodextrin (10%, 25%, and 50% w/w ratio).
  • the stability data demonstrate that amorphous solid dispersion of daclatasvir dihydrochloride in ⁇ -cyclodextrin display no significant change in PXRD pattern and no significant change in purity for up to two months when stored at 25 °C/60% RH and 40 °C/75% RH.
  • Table 4 provides data collected on amorphous solid dispersion of daclatasvir dihydrochloride with PVP K-30 (25% and 50% w/w).
  • the stability data demonstrate that amorphous solid dispersions of daclatasvir dihydrochloride with PVP K-30 display no significant change in PXRD pattern and no significant change in purity for up to two months when stored at 25 °C/60% RH and 40 °C/75% RH.
  • the amorphous daclatasvir dihydrochloride and amorphous daclatasvir dihydrochloride and a pharmaceutically acceptable excipient as disclosed herein may be included in pharmaceutical dosage forms for administration to patients in need thereof.
  • Daclatasvir and its pharmaceutically acceptable salts are inhibitors of hepatitis C virus nonstructural protein 5A (NS5A).
  • NS5A hepatitis C virus nonstructural protein 5A
  • the amorphous daclatasvir dihydrochloride and amorphous daclatasvir dihydrochloride and a pharmaceutically acceptable excipient as disclosed herein may be useful in treating hepatitis C infections in patients either alone or in combination with other active pharmaceutical agents.
  • amorphous daclatasvir dihydrochloride and amorphous daclatasvir dihydrochloride and a pharmaceutically acceptable excipient may be combined with additional pharmaceutically acceptable excipients in generating an oral dosage form, such as a tablet or capsule.
  • excipients may include, but are not limited to, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green.
  • the oral dosage form may include an effective amount of amorphous daclatasvir dihydrochloride and amorphous daclatasvir dihydrochloride and a pharmaceutically acceptable excipient, for example 30 milligrams, 60 milligrams, or 90 milligrams of daclatasvir dihydrochloride.
  • Example 1 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (10 g) was dissolved in water (200 mL) at 25-30 °C. The clear solution was filtered through Hy-flo to remove any undissolved particulate. The Hy-flo was washed with 10 mL of water. The clear solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 5 mL/min and inlet temperature at 130 °C and with 100% aspiration to yield daclatasvir dihydrochloride amorphous form.
  • a laboratory spray dryer Model Buchi-290
  • Example 2 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (10 g) was dissolved in water (100 mL) at 60-70 °C. The resulting clear solution was cooled to room temperature and filtered through Hy-flo to remove any undissolved particulate. The Hy-flo was washed with 10 mL of water. The solution was then subjected to lyophilization in a laboratory lyophilizer (Model Virtis Advantage Plus) to yield daclatasvir dihydrochloride amorphous form.
  • a laboratory lyophilizer Model Virtis Advantage Plus
  • Example 3 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (1 g) was dissolved in water (20 mL) at 65+5 °C. The resulting clear solution was distilled completely under vacuum at 65+5 °C. Foamy solid was obtained. Heptane (2x30 mL) was added to the foamy solid and distilled completely under vacuum at 65+5 °C. The solid obtained was identified as daclatasvir dihydrochloride amorphous form.
  • Daclatasvir dihydrochloride (1 g) was dissolved in methanol (50 mL) at 45+5 °C. The clear solution was cooled to room temperature and filtered through Hy-flo to remove any undissolved particulate. The Hy-flo was washed with 5 mL of methanol. The resulting clear solution was distilled completely under vacuum at 45+5 °C. To the resulting foamy solid, heptane (20 mL) was added and stirred for 30 minutes. The solid obtained was identified as daclatasvir dihydrochloride amorphous form.
  • Example 5 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (1 g) was dissolved in isobutanol (200 mL) and methanol (50 mL) solvent mixture at 45+5 °C and the resulting clear solution was cooled to 25+5 °C.
  • seeds (0.010 g) of amorphous form of daclatasvir dihydrochloride were suspended in methyl tert-butyl ether (400 mL). To this seed solution, the solution of daclatasvir dihydrochloride in methanol and isobutanol mixture was slowly added and maintained under agitation for 1-2 hours.
  • the solid obtained was filtered, washed with methyl tert-butyl ether (10 mL), and suck-dried at 25+5 °C.
  • the product obtained was identified as daclatasvir dihydrochloride amorphous form.
  • Example 6 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (20 g) was dissolved in water (150 mL) at 60 °C and cooled to 25 °C. The resulting clear solution was filtered through Hy-flo to remove any undissolved particulate and subjected to agitated thin film dryer (Flow rate: 15 mL/minute and inlet temperature 110 °C) to yield an amorphous form of daclatasvir dihydrochloride. Yield: 1.2 g.
  • Example 7 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (10 g) was dissolved in methanol (200 mL) at 60 °C and the solvent was distilled by using rotary evaporator. Then, isopropyl ether (50 mL) was added to the reaction mass and distilled off completely, resulting in free powder. It was further dried under vacuum at 25 °C for 15 hours, The product obtained was identified as an amorphous form of daclatasvir dihydrochloride.
  • Example 8 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (10 g) was dissolved in methanol (100 mL) at 28+2 °C. The resulting clear solution was filtered through Hy-flo to remove any undissolved particulate. The clear solution was heated up to 45-50 °C and distilled out the solvent under vacuum till one quarter of the reaction mass remained. Then, methyl tert-butyl ether (50 mL) was added to the reaction mass and distilled out completely under vacuum. Reaction mass was cooled to 25+5 °C and methyl tert-butyl ether (50 mL) was added. That solution was stirred for 30 minutes.
  • the resulting solid was filtered and washed with methyl tert- butyl ether (10 mL). That solid was dried under vacuum at 30 °C for 15 hours.
  • the product obtained was identified as amorphous form of daclatasvir dihydrochloride.
  • Example 9 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (10 g) was dissolved in methanol (100 mL) at 28+2 °C. The resulting clear solution was filtered through Hy-flo to remove any undissolved particulate. The resulting clear solution was heated up to 45-50 °C and the solvent distilled under vacuum till one quarter of the reaction mass remained. Then, isopropyl ether (50 mL) was added to the reaction mass and distilled out completely under vacuum. Reaction mass was cooled to 25+5 °C and isopropyl ether (50 mL) was added. The solution was stirred for 30 minutes. The resulting solid was filtered and washed with isopropyl ether (10 mL). That solid was dried under vacuum at 30 °C for 15 hours. The product obtained was identified as amorphous form of daclatasvir dihydrochloride.
  • Example 10 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (20 g) was dissolved in methanol (200 mL) at 25-30 °C. Reaction mixture was filtered through Hy-flo to remove any undissolved particulate and the clear solution was subjected to spray drying in a laboratory spray dryer (Model Buchi, B- 290) with inlet temperature of 75 °C and flow rate of 20% to yield amorphous form of daclatasvir dihydrochloride.
  • Example 11 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (1 g) was dissolved in methanol (10 mL) and ethyl acetate (10 mL) solvent mixture at 25-30 °C. Reaction mixture was heated to 60+5 °C and the solvent was distilled out completely by using rotary evaporator, resulting in free powder. The product obtained was identified as an amorphous form of daclatasvir dihydrochloride. Yield: 1.9 g.
  • Example 12 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (7.5 g) was dissolved in methanol (75 mL) at 25-30 °C. Reaction mixture was filtered through Hy-flo at the same temperature to remove any undissolved particulate and the clear solution was subjected to spray drying in a laboratory Spray Dryer (Model Buchi, B-290) with inlet temperature of 75 °C and flow rate of 20% to yield amorphous form of daclatasvir dihydrochloride.
  • Example 13 Preparation of amorphous daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (2 g) was dissolved in methanol (20 mL) at 25-30 °C. The resulting clear solution was filtered through Hy-flo to remove any undissolved particulate. Methyl tert-butyl ether (10 mL) was added to the clear solution. Reaction mixture was heated to 40 °C and distilled out the solvent till till one quarter of the reaction total mass remained by using rotary evaporator. Methyl tert-butyl ether (10 mL) was added to the reaction mass and distilled out solvent till one quarter of the total reaction mass remained. The product was filtered and dried under vacuum at 35 °C for 1 hour. The product obtained was identified as amorphous form of daclatasvir dihydrochloride.
  • Example 14 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (18 g) and PLASDONETM S-630 (2 g) were dissolved in methanol (200 mL) at 25-30 °C. Reaction mixture was filtered through Hy-flo to remove any undissolved particulate. The clear solution was subjected to spray drying in a laboratory spray dryer (Model Buchi, B-290) with inlet temperature of 75 °C and flow rate of 20% to yield premix amorphous form of daclatasvir dihydrochloride with 10% PLASDONETM S- 630 (w/w ratio).
  • Example 15 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (18 g) and hydroxypropyl-P-cyclodextrin (HPBCD) (2 g) were dissolved in methanol (200 mL) at 25-30 °C. Reaction mixture was filtered through Hy-flo to remove any undissolved particulate. The clear solution was subjected to spray drying in a laboratory spray dryer (Model Buchi, B-290) with inlet temperature of 75 °C and flow rate of 20% to yield premix amorphous form of daclatasvir dihydrochloride with 10% hydroxypropyl-P-cyclodextrin (HPBCD) (w/w ratio).
  • HPBCD hydroxypropyl-P-cyclodextrin
  • Example 16 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (9 g) was dissolved in water (150 mL) at 60 °C and cooled to 25 °C.
  • ⁇ -cyclodextrin (1 g) was dissolved in water (30 mL) at 60 °C and cooled to 25 °C. Both solutions were mixed and the resulting clear solution was filtered through Hy-flo at the same temperature to remove any undissolved particulate. The solution was then subjected to lyophilization in a laboratory lyophilizer (Model Heto Power Dry LL3000) to yield premix amorphous form of daclatasvir dihydrochloride with 10% ⁇ - cyclodextrin (w/w ratio).
  • Example 17 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (7.5 g) was dissolved in water (100 mL) at 60 °C and cooled to 25 °C.
  • ⁇ -cyclodextrin (2.5 g) was dissolved in water (85 mL) at 60 °C and cooled to 25 °C. Both solutions were mixed and the resulting clear solution was filtered through Hy-flo at the same temperature to remove any undissolved particulate. The solution was then subjected to lyophilization in a laboratory lyophilizer (Model Heto PowerDry LL3000) to yield premix amorphous form of daclatasvir dihydrochloride with 25% ⁇ -cyclodextrin (w/w ratio).
  • Example 18 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (5 g) was dissolved in water (100 mL) at 60 °C and cooled to 25 °C.
  • ⁇ -cyclodextrin (5 g) was dissolved in water (100 mL) at 60 °C and cooled to 25 °C. Both solutions were mixed and the resulting clear solution was filtered through Hy-flo at the same temperature to remove any undissolved particulate. The solution was then subjected to lyophilization in a laboratory lyophilizer (Model Heto PowerDry LL3000) to yield premix amorphous form of daclatasvir dihydrochloride with 50% ⁇ -cyclodextrin (w/w ratio).
  • Example 19 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (7.5 g) was dissolved in water (100 mL) at 60 °C and cooled to 25 °C.
  • PVP K-30 (2.5 g) was dissolved in water (85 mL) at 60 °C and cooled to 25 °C. Both solutions were mixed and the resulting clear solution was filtered through Hy-flo at the same temperature to remove any undissolved particulate. The solution was subjected to lyophilization in a laboratory lyophilizer (Model Heto PowerDry LL3000) to yield premix amorphous form of daclatasvir dihydrochloride with 25% PVP K- 30 (w/w ratio).
  • Example 20 Preparation of amorphous solid dispersion of daclatasvir dihydrochloride.
  • Daclatasvir dihydrochloride (5 g) was dissolved in water (100 mL) at 60 °C and cooled to 25 °C.
  • PVP K-30 5 g was dissolved in water (100 mL) at 60 °C and cooled to 25 °C. Both solutions were mixed and the resulting clear solution was filtered through Hy-flo at the same temperature to remove any undissolved particulate. The solution was then subjected to lyophilization in a laboratory lyophilizer (Model Heto PowerDry LL3000) to yield premix amorphous form of daclatasvir dihydrochloride with 50% PVP K- 30 (w/w ratio).

Abstract

La présente invention concerne des procédés pour la préparation de dichlorhydrate de daclatasvir amorphe. La présente invention concerne également des procédés pour la préparation de dispersion solide amorphe de dichlorhydrate de daclatasvir dans au moins un excipient pharmaceutiquement acceptable. Les excipients pharmaceutiquement acceptables utilisables comprennent, sans y être limités, le PLASDONETM S-630, la polyvinylpyrrolidine K-30, la β-cyclodextrine et l'hydroxypropyl-β-cyclodextrine (HPBCD).
PCT/IB2016/053968 2015-07-03 2016-07-01 Procédé de préparation de dichlorhydrate de daclatasvir amorphe, dispersion solide amorphe de ce dernier, et procédés de préparation de ces derniers WO2017006227A1 (fr)

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WO2009020828A1 (fr) * 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Forme cristalline de dihydrochlorure de méthyl ((1s)-1-(((2s>2-(5-(4'-(2-((2s)-1-((2s)-2-((méthoxycarbonyl)amino)-3-méthylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphénylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-méthylpropyl)carbamate
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11833209B2 (en) 2020-09-11 2023-12-05 Nammi Therapeutics, Inc. Formulated and/or co-formulated liposome compositions containing PD-1 antagonist prodrugs useful in the treatment of cancer and methods thereof

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