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WO2014024210A2 - Novel polymorphs of doxercalciferol - Google Patents

Novel polymorphs of doxercalciferol Download PDF

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Publication number
WO2014024210A2
WO2014024210A2 PCT/IN2013/000437 IN2013000437W WO2014024210A2 WO 2014024210 A2 WO2014024210 A2 WO 2014024210A2 IN 2013000437 W IN2013000437 W IN 2013000437W WO 2014024210 A2 WO2014024210 A2 WO 2014024210A2
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WO
WIPO (PCT)
Prior art keywords
doxercalciferol
solid dispersion
pharmaceutically acceptable
solvent
acceptable carrier
Prior art date
Application number
PCT/IN2013/000437
Other languages
French (fr)
Other versions
WO2014024210A3 (en
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Jambula Mukunda Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
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Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2014024210A2 publication Critical patent/WO2014024210A2/en
Publication of WO2014024210A3 publication Critical patent/WO2014024210A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

  • the present invention provides a novel amorphous Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention also provides a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention further provides a novel crystalline Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
  • Doxercalciferol is chemically, (lS,3i?,5Z,7£,22£)-9,10-Secoergosta-5,7,10,22- tetraene-l ,3-diol and has the structural formula:
  • Doxercalciferol (trade name Hectorol) is drug for secondary hyperparathyroidism and metabolic bone disease. It is a synthetic analog of ergocalciferol (vitamin D 2 ). It suppresses parathyroid synthesis and secretion. Doxercalciferol and its process were disclosed in U.S. patent no. 3,907,843.
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Doxercalciferol can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • doxercalciferol a novel amorphous Form of doxercalciferol.
  • the amorphous Form of doxercalciferol is stable, reproducible and so, suitable for pharmaceutical preparations.
  • an object of the present invention is to provide a novel amorphous Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a novel crystalline Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides a doxercalciferol amorphous Form.
  • the present invention provides a process for the preparation of doxercalciferol amorphous Form, which comprises:
  • the present invention provides a pharmaceutical composition comprising amorphous Form of doxercalciferol and pharmaceutically acceptable excipients.
  • the present invention provides a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier.
  • the present invention there is provided a process for the preparation of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, which comprises:
  • compositions comprising a therapeutically effective amount of solid dispersion of doxercalciferoi along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • the present invention provides a crystalline Form of doxercalciferoi designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 3.1, 13.9, 15.8, 16.4 and 16.8 ⁇ 0.2 degrees.
  • the present invention provides a process for the preparation of doxercalciferoi crystalline Form HI , which comprises:
  • step (b) adding water to the solution obtained in step (a);
  • the present invention provides a pharmaceutical composition comprising crystalline Form HI of doxercalciferoi and pharmaceutically acceptable excipients.
  • Figure 1 is an X-ray powder diffraction spectrum of doxercalciferoi amorphous
  • Figure 2 is an X-ray powder diffraction spectrum of solid dispersion of doxercalciferoi in combination with a pharmaceutically acceptable carrier.
  • Figure 3 is an X-ray powder diffraction spectrum of doxercalciferoi crystalline Form HI.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- ⁇ radiation. Approximately 500 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • doxercalciferol amorphous Form The powdered x-ray diffractogram (PXRD) of doxercalciferol amorphous Form is shown in figure 1.
  • a process for the preparation of doxercalciferol amorphous Form which comprises:
  • the alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butainol and isobutyl alcohol. More preferably the alcoholic solvent is ethanol.
  • Spray drying refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
  • a pharmaceutical composition comprising amorphous Form of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the amorphous Form may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is provided.
  • the powdered x-ray diffractogram (PXRD) of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is shown in figure 2.
  • Solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is found to be stable.
  • the solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier may be amorphous.
  • the ratio of doxercalciferol to the pharmaceutically acceptable carrier is 1:0.5 to 1 :4.0.
  • the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus.
  • a process for the preparation of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier which comprises:
  • Doxercalciferol used in step (a) may preferably be doxercalciferol obtained by the known process.
  • the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from water, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol. More preferably the solvents are water, methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, ethanol and methanol.
  • the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus, povidone or hydroxypropyl methylcellulose.
  • the solvent may be removed from the solution in step (b) by known methods, for example, distillation, freeze drying or spray drying.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • compositions comprising a therapeutically effective amount of solid dispersion of doxercalciferol along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • the solid dispersion of doxercalciferol may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • a crystalline Form of doxercalciferol designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 3.1, 13.9, 15.8, 16.4 and 16.8 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of doxercalciferol crystalline Form HI is shown in figure 3.
  • a process for the preparation of doxercalciferol crystalline Form HI which comprises:
  • step (b) adding water to the solution obtained in step (a);
  • Doxercalciferol used in step (a) may preferably be doxercalciferol obtained by the known process.
  • the step (c) may conveniently be carried out at room temperature.
  • the doxercalciferol crystalline Form HI may be isolated in step (d) by methods known such as filtration or centrifugation.
  • a pharmaceutical composition comprising crystalline Form HI of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the crystalline Form HI may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • Doxercalciferol (10 gm) was dissolved in ethanol (100 ml) under stirring and filtered. The resulting filtrate was subjected to spray drying at 85 to 90°C to provide 7.5 gm of doxercalciferol amorphous Form.
  • Doxercalciferol (5 gm) was dissolved in methanol (40 ml) under stirring and filtered. The resulting filtrate was subjected to spray drying at 85 to 90°C to provide 3.5 gm of doxercalciferol amorphous Form.
  • a mixture of doxercalciferol (10 gm) and povidone (10 gm) was dissolved in methanol (300 ml) at room temperature. The contents were heated to 50°C and maintained for 2 hours. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 19.5 gm of doxercalciferol solid dispersion with povidone.
  • a mixture of doxercalciferol (5 gm) and povidone (5 gm) was dissolved in ethanol (100 ml) at room temperature. The contents were heated to 50°C and maintained for 2 hours. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with povidone.
  • Example 4 was repeated using dimethylformamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
  • Example 4 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
  • Example 4 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
  • Example 4 was repeated using methylene chloride solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
  • Example 10 was repeated using dimethylformamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 10 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 10 was repeated using dimethyl sulfoxide e solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 10 was repeated using methylene chloride solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 10 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 16 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
  • Example 16 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 18 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 16 was repeated using dimethyl formamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 19 was repeated using dimethyl formamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 16 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 20 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 16 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 21 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • Example 16 Preparation of doxercalciferol solid dispersion with copovidone Example 16 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
  • a mixture of doxercalciferol (5 gm) and soluplus (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with soluplus.
  • a mixture of doxercalciferol (5 gm) and polyethylene glycol (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with polyethylene glycol.
  • Doxercalciferol (10 gm) was dissolved in dimethylformamide (40 ml) under stirring to provide a clear solution. To the solution was added water (400 ml) slowly for 20 minutes and maintained for 6 hours at room temperature. The separated solid was filtered and then dried to provide 9 gm of doxercalciferol crystalline Form HI.

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Abstract

The present invention provides a novel amorphous Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel crystalline Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.

Description

NOVEL POLYMORPHS OF DOXERCALCIFEROL
This application claims the benefit of Indian Provisional Patent Application No. 3299/CHE/2012, filed on August 10, 2012, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel amorphous Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel crystalline Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Doxercalciferol is chemically, (lS,3i?,5Z,7£,22£)-9,10-Secoergosta-5,7,10,22- tetraene-l ,3-diol and has the structural formula:
Figure imgf000002_0001
Doxercalciferol (trade name Hectorol) is drug for secondary hyperparathyroidism and metabolic bone disease. It is a synthetic analog of ergocalciferol (vitamin D2). It suppresses parathyroid synthesis and secretion. Doxercalciferol and its process were disclosed in U.S. patent no. 3,907,843.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Doxercalciferol can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. patent application publication no. 2012/108554 disclosed crystalline Form of doxercalciferol.
We have found a novel amorphous Form of doxercalciferol. The amorphous Form of doxercalciferol is stable, reproducible and so, suitable for pharmaceutical preparations.
We have also found a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier. The solid dispersion of doxercalciferol is stable, reproducible and so, suitable for pharmaceutical preparations.
We have also found a novel crystalline Form of doxercalciferol. The novel Form is stable, reproducible and so, suitable for pharmaceutical preparations. Thus, an object of the present invention is to provide a novel amorphous Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a novel crystalline Form of doxercalciferol, process for its preparation and pharmaceutical compositions comprising it.
Summary of the Invention
In one aspect, the present invention provides a doxercalciferol amorphous Form. In another aspect, the present invention provides a process for the preparation of doxercalciferol amorphous Form, which comprises:
a) dissolving doxercalciferol in an alcoholic solvent; and
b) subjecting the resulting solution to spray drying to obtain doxercalciferol
amorphous Form.
In another aspect, the present invention provides a pharmaceutical composition comprising amorphous Form of doxercalciferol and pharmaceutically acceptable excipients.
In another aspect, the present invention provides a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention there is provided a process for the preparation of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of doxercalciferol and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a solvent; and
b) removing the solvent to obtain a solid dispersion of doxercalciferol in
combination with a pharmaceutically acceptable carrier. In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of solid dispersion of doxercalciferoi along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
In another aspect, the present invention provides a crystalline Form of doxercalciferoi designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 3.1, 13.9, 15.8, 16.4 and 16.8 ± 0.2 degrees.
In another aspect, the present invention provides a process for the preparation of doxercalciferoi crystalline Form HI , which comprises:
a) dissolving doxercalciferoi in dimethylformamide;
b) adding water to the solution obtained in step (a);
c) maintaining the reaction mass; and
d) isolating doxercalciferoi crystalline Form HI .
Yet in another aspect, the present invention provides a pharmaceutical composition comprising crystalline Form HI of doxercalciferoi and pharmaceutically acceptable excipients.
Brief Description of the Drawings
Figure 1 is an X-ray powder diffraction spectrum of doxercalciferoi amorphous
Form.
Figure 2 is an X-ray powder diffraction spectrum of solid dispersion of doxercalciferoi in combination with a pharmaceutically acceptable carrier.
Figure 3 is an X-ray powder diffraction spectrum of doxercalciferoi crystalline Form HI.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- α radiation. Approximately 500 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA. Detailed Description of the Invention
The term "room temperature" refers to temperature at about 25 to 35°C.
According to one aspect of the present invention, there is provided a
doxercalciferol amorphous Form. The powdered x-ray diffractogram (PXRD) of doxercalciferol amorphous Form is shown in figure 1.
According to another aspect of the present invention, there is provided a process for the preparation of doxercalciferol amorphous Form, which comprises:
a) dissolving doxercalciferol in an alcoholic solvent; and
b) subjecting the resulting solution to spray drying to obtain doxercalciferol
amorphous Form.
The alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butainol and isobutyl alcohol. More preferably the alcoholic solvent is ethanol.
The term "Spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous Form of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous Form may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
According to another aspect of the present invention, there is provided a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier.
The powdered x-ray diffractogram (PXRD) of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is shown in figure 2.
Solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is found to be stable.
Preferably, the solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier may be amorphous.
Preferably, the ratio of doxercalciferol to the pharmaceutically acceptable carrier is 1:0.5 to 1 :4.0. Preferably the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus.
According to another aspect of the present invention, there is provided a process for the preparation of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of doxercalciferol and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a solvent; and
b) removing the solvent to obtain a solid dispersion of doxercalciferol in
combination with a pharmaceutically acceptable carrier.
Doxercalciferol used in step (a) may preferably be doxercalciferol obtained by the known process.
The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from water, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol. More preferably the solvents are water, methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, ethanol and methanol.
Preferably the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus, povidone or hydroxypropyl methylcellulose.
The solvent may be removed from the solution in step (b) by known methods, for example, distillation, freeze drying or spray drying.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.
The term "Freeze drying" refers to a sublimation process that removes free water in the form of solid. According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of solid dispersion of doxercalciferol along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The solid dispersion of doxercalciferol may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
According to another aspect of the present invention* there is provided a crystalline Form of doxercalciferol designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 3.1, 13.9, 15.8, 16.4 and 16.8 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of doxercalciferol crystalline Form HI is shown in figure 3.
According to another aspect of the present invention, there is provided a process for the preparation of doxercalciferol crystalline Form HI, which comprises:
a) dissolving doxercalciferol in dimethylformamide;
b) adding water to the solution obtained in step (a);
c) maintaining the reaction mass; and
d) isolating doxercalciferol crystalline Form HI .
Doxercalciferol used in step (a) may preferably be doxercalciferol obtained by the known process.
The step (c) may conveniently be carried out at room temperature.
The doxercalciferol crystalline Form HI may be isolated in step (d) by methods known such as filtration or centrifugation.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form HI of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline Form HI may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 : Preparation of doxercalciferol
(lR,3S,5Z)-5-((8E)-2-((lR,3aS,7aR)-hexahydro-7a-methyl-l-((E,2R,5R)-5,6- dimethylhept-3-en-2-yl)-lH-inden-4-(7aH)-ylidene)ethylidene)-4- methylenecyclohexane-l,3-diol (16 gm), ethyl acetate (96 ml) and maleic anhydride (2.3 gm) were added and then maintained for 5 hours at room temperature. The solvent was distilled off under vacuum at below 35°C to obtain residual mass and then added methylene chloride (2800 ml). The residual mass was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane (1500 ml) for the elution. There were obtained 4 gm of doxercalciferol.
Example 2:
Preparation of doxercalciferol amorphous Form
Doxercalciferol (10 gm) was dissolved in ethanol (100 ml) under stirring and filtered. The resulting filtrate was subjected to spray drying at 85 to 90°C to provide 7.5 gm of doxercalciferol amorphous Form.
Example 3:
Preparation of doxercalciferol amorphous Form
Doxercalciferol (5 gm) was dissolved in methanol (40 ml) under stirring and filtered. The resulting filtrate was subjected to spray drying at 85 to 90°C to provide 3.5 gm of doxercalciferol amorphous Form.
Example 4:
Preparation of doxercalciferol solid dispersion with povidone
A mixture of doxercalciferol (10 gm) and povidone (10 gm) was dissolved in methanol (300 ml) at room temperature. The contents were heated to 50°C and maintained for 2 hours. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 19.5 gm of doxercalciferol solid dispersion with povidone.
Example 5: Preparation of doxercalciferol solid dispersion with povidone
A mixture of doxercalciferol (5 gm) and povidone (5 gm) was dissolved in ethanol (100 ml) at room temperature. The contents were heated to 50°C and maintained for 2 hours. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with povidone.
Example 6:
Preparation of doxercalciferol solid dispersion with povidone
Example 4 was repeated using dimethylformamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
Example 7:
Preparation of doxercalciferol solid dispersion with povidone
Example 4 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
Example 8:
Preparation of doxercalciferol solid dispersion with povidone
Example 4 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
Example 9:
Preparation of doxercalciferol solid dispersion with povidone
Example 4 was repeated using methylene chloride solvent instead of methanol solvent to provide doxercalciferol solid dispersion with povidone.
Example 10:
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose A mixture of doxercalciferol (5 gm) and hydroxypropyl methylcellulose (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50 C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
Example 1 1 :
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose
Example 10 was repeated using dimethylformamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
Example 12:
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose
Example 10 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
Example 13:
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose
Example 10 was repeated using dimethyl sulfoxide e solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
Example 14:
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose
Example 10 was repeated using methylene chloride solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose.
Example 15:
Preparation of doxercalciferol solid dispersion with hydroxypropyl methylcellulose
Example 10 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with hydroxypropyl methylcellulose. Example 16:
Preparation of doxercalciferol solid dispersion with copovidone
A mixture of doxercalciferol (5 gm) and copovidone (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with copovidone. Example 17:
Preparation of doxercalciferol solid dispersion with copovidone
Example 16 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone. Example 18:
Preparation of doxercalciferol solid dispersion with copovidone
Example 16 was repeated using dimethyl formamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone. Example 19:
Preparation of doxercalciferol solid dispersion with copovidone
Example 16 was repeated using dimethylacetamide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone. Example 20:
Preparation of doxercalciferol solid dispersion with copovidone
Example 16 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone. Example 21 :
Preparation of doxercalciferol solid dispersion with copovidone Example 16 was repeated using ethanol solvent instead of methanol solvent to provide doxercalciferol solid dispersion with copovidone.
Example 22:
Preparation of doxercalciferol solid dispersion with soluplus
A mixture of doxercalciferol (5 gm) and soluplus (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with soluplus.
Example 23:
Preparation of doxercalciferol solid dispersion with polyethylene glycol
A mixture of doxercalciferol (5 gm) and polyethylene glycol (5 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and maintained for 2 hours to obtain a clear solution. The solution was then cooled to room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 9 gm of doxercalciferol solid dispersion with polyethylene glycol.
Example 24:
Preparation of doxercalciferol crystalline Form HI
Doxercalciferol (10 gm) was dissolved in dimethylformamide (40 ml) under stirring to provide a clear solution. To the solution was added water (400 ml) slowly for 20 minutes and maintained for 6 hours at room temperature. The separated solid was filtered and then dried to provide 9 gm of doxercalciferol crystalline Form HI.
Example 25:
Preparation of doxercalciferol crystalline Form HI Doxercalciferol (10 Kg) was dissolved in dimethylformamide (35 L) under stirring to provide a clear solution. To the solution was added water (300 L) slowly for 20 minutes and maintained for 6 hours at room temperature. The separated solid was filtered and then dried to provide 8.9 Kg of doxercalciferol crystalline Form HI .

Claims

We claim:
1. Doxercalciferol amorphous Form.
2. The amorphous Form of claim 1, having a powder X-ray diffractogram as shown in figure 1.
3. A process for the preparation of doxercalciferol amorphous Form of claim 1, which comprises:
a. dissolving doxercalciferol in an alcoholic solvent; and
b. subjecting the resulting solution to spray drying to obtain doxercalciferol amorphous Form.
4. The process as claimed in claim 3, wherein the alcoholic solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol.
5. The process as claimed in claim 4, wherein the alcoholic solvent is ethanol.
6. A solid dispersion of doxercalciferol in combination with a pharmaceutically
acceptable carrier.
7. The solid dispersion of claim 6, having a powder X-ray diffractogram as shown in figure 2.
8. The solid dispersion of claim 6, wherein the solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier is amorphous.
9. The solid dispersion of claim 6, wherein the ratio of doxercalciferol to the
pharmaceutically acceptable carrier is 1 :0.5 to 1 :4.0.
10. The solid dispersion of claim 6, wherein the pharmaceutically acceptable carrier comprises one or more of copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus.
11. A process for the preparation of solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier of claim 6, which comprises:
a. preparing a solution comprising a mixture of doxercalciferol and one or more pharmaceutically acceptable carriers selected from
copovidone, ethyl cellulose, povidone, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a solvent; and b. removing the solvent to obtain a solid dispersion of doxercalciferol in combination with a pharmaceutically acceptable carrier.
12. The process as claimed in claim 11, wherein the solvent used in step (a) is a solvent or a mixture of solvents selected from water, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol.
13. The process as claimed in claim 12, wherein the solvents are water, methylene
chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, ethanol and methanol.
14. The process as claimed in claim 1 1 , wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus, povidone or hydroxypropyl methylcellulose.
15. Doxercalciferol crystalline Form HI, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 3.1, 13.9, 15.8, 16.4 and 16.8 ± 0.2 degrees.
16. The doxercalciferol crystalline Form HI of claim 15, having a powder X-ray
diffractogram as shown in figure 3.
17. A process for the preparation of doxercalciferol crystalline Form HI of claim 15, which comprises:
a. dissolving doxercalciferol in dimethylformamide;
b. adding water to the solution obtained in step (a);
c. maintaining the reaction mass; and
d. isolating doxercalciferol crystalline Form HI.
18. The process as claimed in claim 17, wherein the step (c) is carried out at room
temperature.
19. A pharmaceutical composition that comprises amorphous Form of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
20. Pharmaceutical compositions comprising a therapeutically effective amount of solid dispersion of doxercalciferol along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
21. A pharmaceutical composition that comprises crystalline Form HI of doxercalciferol and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
22. The pharmaceutical composition as claimed in claim 19, 20 and 21, wherein the amorphous Form, crystalline Form HI or solid dispersion of doxercalciferol is formulated into tablets, capsules, suspensions, dispersions or injectables.
PCT/IN2013/000437 2012-08-10 2013-07-16 Novel polymorphs of doxercalciferol WO2014024210A2 (en)

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