WO2014009970A2 - Linagliptin solid dispersion - Google Patents
Linagliptin solid dispersion Download PDFInfo
- Publication number
- WO2014009970A2 WO2014009970A2 PCT/IN2013/000417 IN2013000417W WO2014009970A2 WO 2014009970 A2 WO2014009970 A2 WO 2014009970A2 IN 2013000417 W IN2013000417 W IN 2013000417W WO 2014009970 A2 WO2014009970 A2 WO 2014009970A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- linagliptin
- solid dispersion
- pharmaceutically acceptable
- amorphous
- solvent
- Prior art date
Links
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
Definitions
- the present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
- Linagliptin chemically 8-[(3i?)-3-aminopiperidin- 1 -yl]-7-(but-2-yn- 1 -yl)-3 methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione and has the structure formula:
- Linagliptin (BI-1356) is a DPP-IV inhibitor. Linagliptin is useful for the prevention or treatment of diabetes mellitus, prediabetes or reduced glucose tolerance.
- the generic name linagliptin is marketed by BOEHRINGER INGELHEIM under the brand name Tradjenta ® .
- 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.
- Linagliptin can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
- amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
- the amorphous solid dispersion of linagliptin is stable, reproducible and so, the amorphous solid dispersion of linagliptin is suitable for formulating linagliptin.
- Normally amorphous Forms are hygroscopic.
- Amorphous solid dispersion of linagliptin is found to be non-hygroscopic.
- an object of the present invention is to provide amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
- the present invention provides amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
- the present invention there is provided a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, which comprises:
- compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
- Figure 1 is a powder X-ray diffractogram patterns of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
- 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.
- amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier there is provided amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
- the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is shown in figure 1.
- Amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is found to be stable.
- the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
- a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier which comprises:
- Linagliptin used in step (a) may preferably be linagliptin obtained by the known process.
- the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol and ethanol.
- the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
- 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.
- pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
- the amorphous solid dispersion of linagliptin may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
- a mixture of linagliptin (25 gm) and hydroxypropyl methylcellulose (12.5 gm) was dissolved in ethanol (750 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 36 gm of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
- Example 3 Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
- Example 2 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
- Example 2 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
- Example 2 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
- Example 2 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
- Example 7 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
- Example 7 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
- Example 7 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
- Example 7 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
- a mixture of linagliptin (20 gm) and soluplus (20 gm) was dissolved in ethanol (300 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 37 gm of amorphous linagliptin solid dispersion with soluplus.
- Example 13 Preparation of amorphous linagliptin solid dispersion with polyethylene glycol
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Description
LINAGLIPTIN SOLID DISPERSION
This application claims the benefit of Indian Provisional Patent Application No. 2780/CHE/2012, filed on July 09, 2012, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Linagliptin, chemically 8-[(3i?)-3-aminopiperidin- 1 -yl]-7-(but-2-yn- 1 -yl)-3 methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione and has the structure formula:
Linagliptin (BI-1356) is a DPP-IV inhibitor. Linagliptin is useful for the prevention or treatment of diabetes mellitus, prediabetes or reduced glucose tolerance. The generic name linagliptin is marketed by BOEHRINGER INGELHEIM under the brand name Tradjenta®.
Linagliptin and its process were disclosed in U.S. Patent No. 7,407,955.
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.
Linagliptin can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
International application publication no. WO 2007/128721 disclosed Polymorph A, Polymorph B, Polymorph C, Polymorph D, Polymorph E and a mixture of Polymorph A and B of linagliptin.
Amorphous Form of linagliptin was reported in IP.com Journal (201 1), 1 1(9A), 22.
It was observed that the crystalline Forms and amorphous Form of linagliptin either not reproducible or not stable.
We have also found a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier. The amorphous solid dispersion of linagliptin is stable, reproducible and so, the amorphous solid dispersion of linagliptin is suitable for formulating linagliptin. Normally amorphous Forms are hygroscopic. Amorphous solid dispersion of linagliptin is found to be non-hygroscopic.
Thus, an object of the present invention is to provide amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Summary of the Invention
In one aspect, the present invention provides amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of linagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
Brief Description of the Drawing
Figure 1 is a powder X-ray diffractogram patterns of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Κ 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 amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
The powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is shown in figure 1.
Amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is found to be stable.
Preferably the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
According to another aspect of the present invention, there is provided a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of linagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
Linagliptin used in step (a) may preferably be linagliptin obtained by the known process.
The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol and ethanol.
Preferably the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
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. According to another aspect of the present invention, , there is provided pharmaceutical compositions comprising a therapeutically effective amount of
amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The amorphous solid dispersion of linagliptin 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 linagliptin
2-Bromo- 1 -(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-y l)methyl)- 1 H- imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (100 gm) was dissolved in dimethylformamide (500 ml) and then added cesium carbonate (180 gm) and (R)-(-)-3- aminopiperidine dihydrochloride (42 gm) at room temperature. The reaction mixture was heated to 120°C and maintained for 12 hours. The reaction mass was then cooled to room temperature and then added water (1000 ml) and dichloromethane (2000 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. Combined organic layers were dried with sodium sulfate and then concentrated to provide 100 gm of linagliptin. Example 2:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
A mixture of linagliptin (25 gm) and hydroxypropyl methylcellulose (12.5 gm) was dissolved in ethanol (750 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 36 gm of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Example 3:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
Example 2 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Example 4:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
Example 2 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Example 5:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
Example 2 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Example 6:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
Example 2 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Example 7:
Preparation of amorphous linagliptin solid dispersion with copovidone
A mixture of linagliptin (10 gm) and copovidone (20 gm) was dissolved in ethanol (150 ml) at room temperature. The contents were heated to 65 to 70°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below
55 C and then dried to provide 28 gm of amorphous linagliptin solid dispersion with copovidone.
Example 8:
Preparation of amorphous linagliptin solid dispersion with copovidone
Example 7 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
Example 9:
Preparation of amorphous linagliptin solid dispersion with copovidone
Example 7 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
Example 10:
Preparation of amorphous linagliptin solid dispersion with copovidone
Example 7 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
Example 1 1 :
Preparation of amorphous linagliptin solid dispersion with copovidone
Example 7 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
Example 12:
Preparation of amorphous linagliptin solid dispersion with soluplus
A mixture of linagliptin (20 gm) and soluplus (20 gm) was dissolved in ethanol (300 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 37 gm of amorphous linagliptin solid dispersion with soluplus.
Example 13:
Preparation of amorphous linagliptin solid dispersion with polyethylene glycol
A mixture of linagliptin (20 gm) and polyethylene glycol (30 gm) was dissolved in ethanol (500 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 46 gm of amorphous linagliptin solid dispersion with polyethylene glycol.
Example 14:
Preparation of amorphous linagliptin solid dispersion with ethyl cellulose
A mixture of linagliptin (10 gm) and ethyl cellulose (10 gm) was dissolved in ethanol (150 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 18 gm of amorphous linagliptin solid dispersion with ethyl cellulose.
Example 15:
Preparation of amorphous linagliptin solid dispersion with copovidone
2-Bromo-l-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-lH- imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (100 gm) was dissolved in dimethylformamide (500 ml) and then added cesium carbonate (180 gm) and (R)-(-)-3- aminopiperidine dihydrochloride (42 gm) at room temperature. The reaction mixture was heated to 120°C and maintained for 12 hours. The reaction mass was then cooled to room temperature and then added water (1000 ml) and dichloromethane (2000 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. Combined organic layers were dried with sodium sulfate and then added copovidone (200 gm) and ethanol (1500 ml) at room temperature. The contents were heated to 65 to 70°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 285 gm of amorphous linagliptin solid dispersion with copovidone.
Example 16:
Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
2-Bromo- 1 -(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)- 1 H- imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (100 gm) was dissolved in dimethylformamide (500 ml) and then added cesium carbonate (180 gm) and (R)-(-)-3- aminopiperidine dihydrochloride (42 gm) at room temperature. The reaction mixture was heated to 120°C and maintained for 12 hours. The reaction mass was then cooled to room temperature and then added water (1000 ml) and dichloromethane (2000 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. Combined organic layers were dried with sodium sulfate and then added hydroxypropyl methylcellulose (50 gm) and ethanol (3000 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 145 gm of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
Claims
1. An amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
2. The amorphous solid dispersion of claim 1, wherein the pharmaceutically acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
3. The amorphous solid dispersion of claim 1, having a powder X-ray diffractogram as shown in figure 1.
4. A process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier of claim 1, which comprises: a. preparing a solution comprising a mixture of linagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and
b. removing the solvent to obtain amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
5. The process as claimed in claim 4, wherein the solvent used in step (a) is a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol.
6. The process as claimed in claim 5, wherein the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol and ethanol.
7. The process as claimed in claim 4, wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus or hydroxypropyl methylcellulose.
8. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
9. The pharmaceutical composition as claimed in claim 8, wherein the amorphous solid dispersion of linagliptin is formulated into tablets, capsules, suspensions, dispersions or injectables.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14/589,495 US9381199B2 (en) | 2012-07-09 | 2013-07-08 | Linagliptin solid dispersion |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| INCH27802012 | 2012-07-09 | ||
| ININ2780/CHE/2012 | 2012-07-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2014009970A2 true WO2014009970A2 (en) | 2014-01-16 |
| WO2014009970A3 WO2014009970A3 (en) | 2015-07-30 |
Family
ID=49916619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2013/000417 WO2014009970A2 (en) | 2012-07-09 | 2013-07-08 | Linagliptin solid dispersion |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2014009970A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9381199B2 (en) | 2012-07-09 | 2016-07-05 | Hetero Research Foundation | Linagliptin solid dispersion |
| WO2016207364A1 (en) * | 2015-06-25 | 2016-12-29 | Boehringer Ingelheim International Gmbh | Process for the preparation of a xanthine-based compound |
| US20190226688A1 (en) * | 2016-05-03 | 2019-07-25 | Carrier Corporation | Packaged air conditioner with vane axial fan |
| CN112961155A (en) * | 2021-03-16 | 2021-06-15 | 华北水利水电大学 | Preparation method of linagliptin |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5955475A (en) * | 1997-06-30 | 1999-09-21 | Endo Pharmaceuticals Inc. | Process for manufacturing paroxetine solid dispersions |
| US7407955B2 (en) * | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| AU2009290911A1 (en) * | 2008-09-10 | 2010-03-18 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
| UY32427A (en) * | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM, PROCEDURE FOR PREPARATION, METHODS OF TREATMENT AND USES OF THE SAME |
| BRPI1009392A2 (en) * | 2009-03-12 | 2016-03-08 | Nordic Bioscience As | "pharmaceutical formulation, and use of a pharmaceutically effective amount of a pharmaceutical formulation." |
-
2013
- 2013-07-08 WO PCT/IN2013/000417 patent/WO2014009970A2/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9381199B2 (en) | 2012-07-09 | 2016-07-05 | Hetero Research Foundation | Linagliptin solid dispersion |
| WO2016207364A1 (en) * | 2015-06-25 | 2016-12-29 | Boehringer Ingelheim International Gmbh | Process for the preparation of a xanthine-based compound |
| JP2018522862A (en) * | 2015-06-25 | 2018-08-16 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Process for the preparation of xanthine-based compounds |
| EP3974431A1 (en) * | 2015-06-25 | 2022-03-30 | Boehringer Ingelheim International GmbH | Process for the preparation of a xanthine-based compound |
| US20190226688A1 (en) * | 2016-05-03 | 2019-07-25 | Carrier Corporation | Packaged air conditioner with vane axial fan |
| CN112961155A (en) * | 2021-03-16 | 2021-06-15 | 华北水利水电大学 | Preparation method of linagliptin |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014009970A3 (en) | 2015-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2707368B1 (en) | Polymorph of linagliptin benzoate | |
| KR102342776B1 (en) | (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 Polymorphic and solid forms of ,2-d][1,4]oxazepin-9-yl)amino)propanamide, and processes for their preparation | |
| US8703788B2 (en) | Polymorph of nilotinib hydrochloride | |
| EP3205653B1 (en) | Crystal form of bisulfate of jak inhibitor and preparation method therefor | |
| WO2014118808A2 (en) | Ticagrelor solid dispersion | |
| WO2015138933A1 (en) | Solid state forms of dolutegravir sodium | |
| WO2013132511A1 (en) | Novel polymorph of lurasidone hydrochloride | |
| US9624207B2 (en) | Polymorphs of azilsartan medoxomil | |
| WO2014009970A2 (en) | Linagliptin solid dispersion | |
| WO2013150544A2 (en) | Ivabradine hydrochloride solid dispersion | |
| TW201829420A (en) | New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
| US9381199B2 (en) | Linagliptin solid dispersion | |
| US8445506B2 (en) | Polymorphs of lopinavir | |
| WO2014195977A2 (en) | Novel polymorphs of vismodegib | |
| CA2811912A1 (en) | Novel polymorphs of febuxostat | |
| WO2014013505A2 (en) | Amorphous vildagliptin | |
| WO2014013511A2 (en) | Rufinamide solid dispersion | |
| EP3317270A1 (en) | (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate | |
| WO2017032705A1 (en) | Crystalline form of omarigliptin | |
| CA2829186A1 (en) | Amorphous form of lopinavir and ritonavir mixture | |
| WO2015186139A2 (en) | Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same | |
| WO2012007952A1 (en) | Novel polymorph of irinotecan hydrochloride | |
| WO2013153558A1 (en) | Anhydrous form of moxifloxacin hydrochloride | |
| US20150291574A1 (en) | Novel polymorphs of azilsartan | |
| WO2011016044A1 (en) | Novel polymorphs of adefovir dipivoxil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13816209 Country of ref document: EP Kind code of ref document: A2 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 14589495 Country of ref document: US |
|
| NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
| 122 | Ep: pct app. not ent. europ. phase |
Ref document number: 13816209 Country of ref document: EP Kind code of ref document: A2 |