WO2014174529A2 - Polymorphs of avanafil - Google Patents
Polymorphs of avanafil Download PDFInfo
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- WO2014174529A2 WO2014174529A2 PCT/IN2014/000258 IN2014000258W WO2014174529A2 WO 2014174529 A2 WO2014174529 A2 WO 2014174529A2 IN 2014000258 W IN2014000258 W IN 2014000258W WO 2014174529 A2 WO2014174529 A2 WO 2014174529A2
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- Prior art keywords
- avanafil
- solvent
- amorphous
- mixture
- ether
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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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Definitions
- the present invention provides a novel polymorph of avanafil, process for its preparation and pharmaceutical compositions comprising it.
- Avanafil is chemically, 4-(3-Chloro-4-methoxybenzylamino)-2-[2(S)- (hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and has the structure formula:
- Avanafil is a PDE5 inhibitor approved for erectile dysfunction. It acts by inhibiting a specific phosphodiesterase type 5 enzymes which is found in various body tissues, but primarily in the corpus cavernosum penis, as well as the retina.
- the advantage of avanafil is that it has very fast onset of action compared with other PDE5 inhibitors.
- the generic name avanafil is marketed by VIVUS IMC under the brand name Stendra ® .
- 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 (1R).
- XRD X-ray diffraction
- DSC Differential Scanning Calorimetry
- 1R Infrared spectrometry
- Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
- Avanafil can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
- an object of the present invention is to provide amorphous Form of avanafil, process for its preparation and pharmaceutical compositions comprising it.
- the present invention provides an amorphous avanafil.
- the present invention provides a process for the preparation of amorphous avanafil, which comprises:
- the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous avanafil and at least one pharmaceutically acceptable excipient.
- Figure 1 is a powder X-ray diffractogram patterns of amorphous avanafil.
- Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- ⁇ radiation. Approximately 500 mg 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.
- room temperature refers to temperature at about 25 to 35°C.
- an amorphous avanafil there is provided an amorphous avanafil.
- the powdered x-ray diffractogram (PXRD) of amorphous avanafil is shown in figure 1.
- Normally amorphous Forms are hygroscopic.
- Amorphous avanafil is found to be non-hygroscopic.
- amorphous avanafil which comprises:
- step (b) removing the solvent from the solution obtained in step (a) to obtain amorphous avanafil.
- Avanafil used in step (a) may preferably be avanafil obtained by the known process.
- the chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
- the alcoholic solvent used in step (a) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
- the ether solvent used in step (a) may be a solvent or a mixture of solvents selected from tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether and diethyl ether, and more preferably the ether solvent is tetrahydrofuran.
- the solvent may be removed from the solution in step (b) by known methods, for example, distillation 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.
- Spray drying refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
- compositions comprising a therapeutically effective amount of amorphous avanafil, and at least one pharmaceutically acceptable excipient.
- the amorphous avanafil may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
- the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
- pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
- binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
- diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
- Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monol
- disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
- lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
- Coloring agents include any FDA approved colors for oral use.
- the reaction mixture was stirred for 9 hours at room temperature and the mixture was poured into aqueous sodium hydrogen carbonate solution.
- the reaction mixture was extracted with ethyl acetate and the organic layer was dried with sodium sulfate.
- the organic layer was then concentrated to obtain a residual solid.
- To the residual solid was added methanol (900 ml) and stirred for 45 minutes at room temperature.
- the separated solid was filtered and then dried to obtain 68 gm of avanafil.
- Avanafil (10 gm) was dissolved in methylene chloride (100 ml) and stirred for 45 minutes at room temperature. The methylene chloride solvent was distilled off under vacuum and then dried to obtain 9.5 gm of amorphous avanafil.
- Avanafil (10 gm) was dissolved in methanol (1000 ml) and then heated to 50°C for 15 minutes to obtain a clear solution. The solution was then cooled to room temperature and stirred for 14 hours. The methanol solvent was distilled off under vacuum below 50°C and then dried to obtain 9 gm of amorphous avanafil.
- amorphous avanafil Tetrahydrofuran 300 ml was added to avanafil (10 gm) slowly at room temperature to obtain a clear solution. The solution was stirred for 14 hours at room temperature and the tetrahydrofuran solvent was distilled off under vacuum below 50°C to obtain a solid. The solid obtained was then dried to obtain 9.3 gm of amorphous avanafil.
Abstract
The present invention provides a novel polymorph of avanafil, process for its preparation and pharmaceutical compositions comprising it.
Description
POLYMORPHS OF AVANAFIL
This application claims the benefit of Indian Provisional Patent Application No. 1782/CHE/2013, filed on April 23, 2013, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel polymorph of avanafil, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Avanafil is chemically, 4-(3-Chloro-4-methoxybenzylamino)-2-[2(S)- (hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and has the structure formula:
Avanafil is a PDE5 inhibitor approved for erectile dysfunction. It acts by inhibiting a specific phosphodiesterase type 5 enzymes which is found in various body tissues, but primarily in the corpus cavernosum penis, as well as the retina. The advantage of avanafil is that it has very fast onset of action compared with other PDE5 inhibitors. The generic name avanafil is marketed by VIVUS IMC under the brand name Stendra®.
Avanafil and its process were disclosed in U.S. Patent No. 6,656,935.
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 (1R).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Avanafil can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
We have found a novel polymorph of avanafil. The polymorph of avanafil is stable, reproducible and so, the polymorph of avanafil is suitable for pharmaceutical preparations. Object of the Invention
Thus, an object of the present invention is to provide amorphous Form of avanafil, process for its preparation and pharmaceutical compositions comprising it.
Summary of the Invention
In one aspect, the present invention provides an amorphous avanafil.
In another aspect, the present invention provides a process for the preparation of amorphous avanafil, which comprises:
a) preparing a solution of avanafil in an alcoholic solvent, a chlorinated solvent, an ether solvent or a mixture thereof ; and
b) removing the solvent from the solution obtained in step (a) to obtain amorphous avanafil.
Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous avanafil and at least one pharmaceutically acceptable excipient. Brief Description of the Drawing
Figure 1 is a powder X-ray diffractogram patterns of amorphous avanafil.
Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Κα radiation. Approximately 500 mg 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 an amorphous avanafil. The powdered x-ray diffractogram (PXRD) of amorphous avanafil is shown in figure 1.
Normally amorphous Forms are hygroscopic. Amorphous avanafil is found to be non-hygroscopic.
According to another aspect of the present invention, there is provided a process for the preparation of amorphous avanafil, which comprises:
a) preparing a solution of avanafil in an alcoholic solvent, a chlorinated solvent, an ether solvent or a mixture thereof ; and
b) removing the solvent from the solution obtained in step (a) to obtain amorphous avanafil.
Avanafil used in step (a) may preferably be avanafil obtained by the known process.
The chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
Preferably the alcoholic solvent used in step (a) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
The ether solvent used in step (a) may be a solvent or a mixture of solvents selected from tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether and diethyl ether, and more preferably the ether solvent is tetrahydrofuran.
The solvent may be removed from the solution in step (b) by known methods, for example, distillation 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 "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 pharmaceutical compositions comprising a therapeutically effective amount of amorphous avanafil, and at least one pharmaceutically acceptable excipient. The amorphous avanafil may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
Preferably the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose,
mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether and polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine; and the like and mixtures thereof.
Specific examples of disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
Coloring agents include any FDA approved colors for oral use.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Preparation of avanafil
4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethyl-l-pyrrolidinyl)- pyrimidine-5-carboxylic acid (85 gm) was dissolved in N,N-dimethylformamide (1275 ml) and then added l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 gm) and 1 -hydroxybenzotriazole monohydrate (32.2 gm). The reaction mixture was stirred for 20 minutes at room temperature and then added triethylamine (32.8 gm) and 2- aminomethylpyrimidine acetic acid (41.5 gm). The reaction mixture was stirred for 9 hours at room temperature and the mixture was poured into aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate and the organic layer was dried with sodium sulfate. The organic layer was then concentrated to obtain a residual solid. To the residual solid was added methanol (900 ml) and stirred for 45 minutes at room temperature. The separated solid was filtered and then dried to obtain 68 gm of avanafil.
Example 2:
Preparation of amorphous avanafil
Avanafil (10 gm) was dissolved in methylene chloride (100 ml) and stirred for 45 minutes at room temperature. The methylene chloride solvent was distilled off under vacuum and then dried to obtain 9.5 gm of amorphous avanafil.
Example 3:
Preparation of amorphous avanafil
Avanafil (10 gm) was dissolved in methanol (1000 ml) and then heated to 50°C for 15 minutes to obtain a clear solution. The solution was then cooled to room temperature and stirred for 14 hours. The methanol solvent was distilled off under vacuum below 50°C and then dried to obtain 9 gm of amorphous avanafil.
Example 4:
Preparation of amorphous avanafil
Tetrahydrofuran (300 ml) was added to avanafil (10 gm) slowly at room temperature to obtain a clear solution. The solution was stirred for 14 hours at room temperature and the tetrahydrofuran solvent was distilled off under vacuum below 50°C to obtain a solid. The solid obtained was then dried to obtain 9.3 gm of amorphous avanafil.
Claims
1. Amorphous avanafil.
2. The amorphous avanafil of claim 1, having powdered X-ray diffractogram as shown in figure 1.
3. A process for the preparation of amorphous avanafil, which comprises:
a) preparing a solution of avanafil in an alcoholic solvent, a chlorinated solvent, an ether solvent or a mixture thereof ; and
b) removing the solvent from the solution obtained in step (a) to obtain amorphous avanafil.
4. The process as claimed in claim 3, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
5. The process as claimed in claim 3, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol.
6. The process as claimed in claim 3, wherein the ether solvent used in step (a) is a solvent or a mixture of solvents selected from tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether and diethyl ether.
7. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous avanafil and at least one pharmaceutically acceptable excipient.
8. The pharmaceutical composition as claimed in claim 7, wherein the amorphous avanafil is formulated into tablets, capsules, suspensions, dispersions or injectables.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1782/CHE/2013 | 2013-04-23 | ||
| IN1782CH2013 | 2013-04-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2014174529A2 true WO2014174529A2 (en) | 2014-10-30 |
| WO2014174529A3 WO2014174529A3 (en) | 2015-04-02 |
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|---|---|---|---|
| PCT/IN2014/000258 WO2014174529A2 (en) | 2013-04-23 | 2014-04-22 | Polymorphs of avanafil |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336401A (en) * | 2015-07-15 | 2017-01-18 | 山东诚创医药技术开发有限公司 | Refining method for avanafil |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1219609E (en) * | 1999-09-16 | 2007-06-19 | Tanabe Seiyaku Co | Aromatic nitrogenous six-membered ring compounds |
| US7625911B2 (en) * | 2005-01-12 | 2009-12-01 | Mai De Ltd. | Amorphous form of erlotinib hydrochloride and its solid amorphous dispersion |
| PT2637664T (en) * | 2010-10-15 | 2017-06-22 | Gilead Sciences Inc | Compositions and methods of treating pulmonary hypertension |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336401A (en) * | 2015-07-15 | 2017-01-18 | 山东诚创医药技术开发有限公司 | Refining method for avanafil |
| CN106336401B (en) * | 2015-07-15 | 2019-05-28 | 山东诚创医药技术开发有限公司 | A kind of refining methd of avanaphil |
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| WO2014174529A3 (en) | 2015-04-02 |
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