WO2015166466A1 - Forme cristalline d'acétate de saxagliptine - Google Patents
Forme cristalline d'acétate de saxagliptine Download PDFInfo
- Publication number
- WO2015166466A1 WO2015166466A1 PCT/IB2015/053198 IB2015053198W WO2015166466A1 WO 2015166466 A1 WO2015166466 A1 WO 2015166466A1 IB 2015053198 W IB2015053198 W IB 2015053198W WO 2015166466 A1 WO2015166466 A1 WO 2015166466A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- saxagliptin
- acetate
- process according
- acetate form
- crystalline
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Definitions
- the present invention provides a crystalline form of saxagliptin acetate, designated as Form II, a process for its preparation, and pharmaceutical compositions thereof.
- Saxagliptin of Formula A an orally-active inhibitor of the dipeptidyl peptidase IV enzyme, chemically designated as ( ⁇ S,3S,5S)-2-[(2S)-2-A ino-2-(3- hydroxytricyclo[3.3.1. l 3 ' 7 ]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- U.S. Patent No. 6,395,767 provides a process for the preparation of the saxagliptin trifluoroacetate. This patent also provides the hydrochloride salt of saxagliptin.
- new polymorphic forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, storage stability, and ease of purification, or desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New polymorphic forms of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Accordingly, the present inventors have found a novel crystalline form of saxagliptin acetate, which is
- a first aspect of the present invention provides a crystalline form of saxagliptin acetate, designated as Form II.
- a second aspect of the present invention provides a process for the preparation of crystalline saxagliptin acetate Form II, which comprises treating saxagliptin or salts thereof with acetic acid in the presence of a solvent.
- a third aspect of the present invention provides a pharmaceutical composition comprising crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.
- a fourth aspect of the present invention provides a method of treating type 2 diabetes mellitus which comprises administering to a patient in need thereof a therapeutically effective amount of crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.
- a first aspect of the present invention provides a crystalline form of saxagliptin acetate, designated as Form II.
- Embodiments of this aspect may include one or more of the following features:
- the crystalline saxagliptin acetate Form II of the present invention is characterized by an X-Ray Powder Diffractogram (XRPD) pattern substantially the same as depicted in Figure 1, exhibiting interplanar spacing (d) values at about 11.32, 10.48, 5.53, and 4.81 (A), and further exhibiting interplanar spacing (d) values substantially at about 8.75, 5.88, 5.66, 4.45, 3.75, and 3.70 (A).
- XRPD X-Ray Powder Diffractogram
- the crystalline form of saxagliptin acetate has an XRPD pattern with characteristic peak values (2 ⁇ ) at 7.80, 8.43, 16.01, and 18.43 ⁇ 0.2°, and additional characteristic peak values (2 ⁇ ) at 10.10, 15.05, 15.64, 19.94, 23.68, and 23.97 ⁇ 0.2°.
- the crystalline saxagliptin acetate Form II of the present invention is characterized by a Differential Scanning Calorimetry (DSC) thermogram as depicted in Figure 2, with a characteristic endothermic peak value at about 127.11°C and a characteristic exothermic peak value at about 130.98°C.
- the crystalline saxagliptin acetate Form II of the present invention is characterized by a Thermogravimetric Analysis (TGA) thermogram as depicted in Figure 3.
- TGA Thermogravimetric Analysis
- a second aspect of the present invention provides a process for the preparation of crystalline saxagliptin acetate Form II, which comprises treating saxagliptin or salts thereof with acetic acid in the presence of a solvent.
- the saxagliptin or salts thereof used as the starting material may be prepared by the process exemplified herein or any of the methods known in the art including those described in, for example, U.S. Patent Nos. 6,395,767, and 7,943,656 or PCT Publication Nos. WO 2004/052850, WO 2005/115982, WO 2005/10601 1, WO 2005/108594, WO 2005/094323, WO 2010/115974, WO 2012/017028, WO 2012/017029, WO 2012/047871, WO 2012/162507, and WO 2013/111158.
- the saxagliptin or salts thereof prepared by any of the methods known in the art may be isolated or directly treated with acetic acid in the presence of a solvent.
- the saxagliptin salt may optionally be converted to saxagliptin before treatment with acetic acid.
- the treatment of saxagliptin or salts thereof with acetic acid may include adding, dissolving, slurrying, stirring, or combinations thereof.
- solvent includes any solvent or solvent mixture, such as water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof.
- esters include ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n- butyl acetate, preferably ethyl acetate.
- alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
- suitable alkanols include methanol, ethanol, «-propanol, isopropanol, and butanol.
- halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane.
- ketones include acetone and methyl ethyl ketone.
- ethers include diethyl ether and tetrahydrofuran.
- polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
- saxagliptin in a mixture of ethanol and ethyl acetate is treated with acetic acid at a temperature of from about 5°C to about 15°C, preferably, from about 10°C to about 13°C.
- the formation of the saxagliptin acetate may be accelerated by stirring the reaction mixture for about 20 minutes to about 2 hours at a temperature of from about 0°C to about 30°C, preferably from about 0°C to about 25°C.
- the crystalline saxagliptin acetate Form II can be isolated from the reaction mixture by filtration, decantation, solvent precipitation, trituration, evaporation, distillation, or combinations thereof.
- a third aspect of the present invention provides a pharmaceutical composition comprising crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.
- a fourth aspect of the present invention provides a method of treating type 2 diabetes mellitus which comprises administering to a patient in need thereof a
- Figure 1 depicts the XRPD pattern of crystalline saxagliptin acetate Form II prepared as per Example 1.
- Figure la depicts the associated values of the XRPD pattern depicted in Figure 1.
- Figure 2 depicts the DSC thermogram of saxagliptin acetate Form II prepared as per Example 1.
- Figure 3 depicts the TGA thermogram of saxagliptin acetate Form II prepared as per Example 1.
- the XRPD of the sample was determined by using a PANalytical ® instrument; Mode: X'pert PRO; Detector: X'Celerator ® ; Step size: 0.02; Range: 3-40 degree 2 theta; CuKa radiation at 45kV.
- the DSC of the sample was determined by using a Mettler Toledo ® , DSC 82 le. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.
- the TGA of the sample was determined by using a TA, TGA Q500. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.
- the pH of the reaction mixture was adjusted to 9.62 by the addition of 40% w/v aqueous sodium hydroxide solution at -5°C to 5°C.
- Sodium chloride (380 g) was added to the mixture at 5°C, and then the mixture was stirred for 10 minutes.
- the reaction mixture was allowed to settle, and the organic layer was separated.
- the aqueous layer was extracted twice with dichloromethane (760 mL) at 5°C to 10°C and the organic layer was separated.
- the organic layers were combined, and then washed with a mixture of 20% w/v aqueous ammonium chloride and 20% w/v aqueous sodium chloride solution (380 mL in 1: 1 ratio).
- the organic layer was separated and concentrated under vacuum at 15°C to 20°C to obtain a residue.
- Dichloromethane (1900 mL) was added to the residue and the mixture was stirred for 5 minutes.
- Activated carbon 38 g was added at 15°C and the mixture was stirred for 10 minutes to 15 minutes.
- the reaction mixture was filtered through a Hyflo ® .
- the Hyflo ® was washed with dichloromethane (760 mL).
- the filtrate was concentrated under vacuum at 15°C to 20°C to obtain a residue.
- Ethanol (760 mL) was added to the residue and the mixture was stirred for 10 minutes to obtain a homogenous solution.
- the solution was concentrated under vacuum at 15°C to 20°C to obtain a residue.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une forme cristalline d'acétate de saxagliptine appelée forme (II), un procédé pour sa préparation, et des compositions pharmaceutiques de celle-ci.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1179/DEL/2014 | 2014-05-01 | ||
IN1179DE2014 | 2014-05-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015166466A1 true WO2015166466A1 (fr) | 2015-11-05 |
Family
ID=54358253
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2015/053198 WO2015166466A1 (fr) | 2014-05-01 | 2015-05-01 | Forme cristalline d'acétate de saxagliptine |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015166466A1 (fr) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120283181A1 (en) * | 2007-04-20 | 2012-11-08 | Bristol-Myers Squibb Company | Crystal forms of saxagliptin and processes for preparing same |
WO2014006569A2 (fr) * | 2012-07-02 | 2014-01-09 | Ranbaxy Laboratories Limited | Sels de saxagliptine |
-
2015
- 2015-05-01 WO PCT/IB2015/053198 patent/WO2015166466A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120283181A1 (en) * | 2007-04-20 | 2012-11-08 | Bristol-Myers Squibb Company | Crystal forms of saxagliptin and processes for preparing same |
WO2014006569A2 (fr) * | 2012-07-02 | 2014-01-09 | Ranbaxy Laboratories Limited | Sels de saxagliptine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10035802B2 (en) | Solid state forms of ibrutinib | |
CA3060121C (fr) | Polymorphe de compose, procede de preparation s'y rapportant et utilisation de celui-ci | |
EP3248983B1 (fr) | Forme cristalline a de l'acide obéticholique et son procédé de préparation | |
JP5535082B2 (ja) | ボセンタン、その多形形態及びその塩の合成方法 | |
EP3136857A1 (fr) | Forme cristalline de baricitinib | |
US9676741B1 (en) | Co-crystal of dapagliflozin with citric acid | |
JP2009542787A5 (fr) | ||
JP2021105003A (ja) | 多形体及びキナゾリニル誘導体の調製プロセス | |
US10519117B2 (en) | Crystal forms of 6-bromo-3-hydroxy-2-pyrazinecarboxamide | |
CN102471288B (zh) | 双环杂环化合物的立体选择性合成方法 | |
WO2018185711A1 (fr) | Solvates d'éluxadoline | |
WO2012090221A1 (fr) | Nouveaux sels d'imatinib | |
WO2015166466A1 (fr) | Forme cristalline d'acétate de saxagliptine | |
WO2017191620A1 (fr) | Forme cristalline d'un sel de sacubitril et procédé pour le préparer | |
WO2018185664A1 (fr) | Solvates d'éluxadoline | |
WO2017175184A1 (fr) | Procédé de préparation de la forme amorphe d'idélalisib | |
WO2015092624A1 (fr) | Mono-oxalate de nilotinib et sa forme cristalline | |
MX2013001197A (es) | Proceso para la preparacion del compuesto osi - 906. | |
CA2879824A1 (fr) | Sels de saxagliptine | |
WO2020049598A2 (fr) | Polymorphes d'apalutamide | |
EP3468968A1 (fr) | Formes solides de ceftolozane et procédés de préparation | |
AU2017343384B2 (en) | Method for isolation and purification of naltrexone | |
WO2012046245A1 (fr) | Nouvelle forme polymorphe du lacosamide | |
TW201714878A (zh) | 氘代咪唑酮化合物之晶型i及其製備方法和用途 | |
CN108727351B (zh) | 一种普芦卡必利的精制方法 |
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: 15785523 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15785523 Country of ref document: EP Kind code of ref document: A1 |