EP2260037A2 - A polymorphic form of a pyrazino [2,3-h] [3] benzazepine derivative - Google Patents

A polymorphic form of a pyrazino [2,3-h] [3] benzazepine derivative

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Publication number
EP2260037A2
EP2260037A2 EP09709821A EP09709821A EP2260037A2 EP 2260037 A2 EP2260037 A2 EP 2260037A2 EP 09709821 A EP09709821 A EP 09709821A EP 09709821 A EP09709821 A EP 09709821A EP 2260037 A2 EP2260037 A2 EP 2260037A2
Authority
EP
European Patent Office
Prior art keywords
varenicline base
varenicline
form ii
base
polymorphic form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09709821A
Other languages
German (de)
French (fr)
Inventor
Stephen Benedict David Winter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medichem SA
Original Assignee
Medichem SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US6603208P priority Critical
Application filed by Medichem SA filed Critical Medichem SA
Priority to PCT/EP2009/051727 priority patent/WO2009101185A2/en
Publication of EP2260037A2 publication Critical patent/EP2260037A2/en
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08Bridged systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34Tobacco-abuse

Abstract

The invention relates generally to a crystalline polymorphic form of 7, 8, 9, 10-tetrahydro-6, 10-methano-6H-pyrazino[2, 3-h][3] benzazepine, varenicline base, i.e. a hydrate of varenicline base, designated herein as Form II, and to a method for preparing and obtaining the same.

Description

A NEW POLYMORPHIC FORM OF A PYRAZINO [2 , 3-h] [3]

BENZAZEPINE DERIVATIVE Field of the invention

The present invention relates to a novel crystalline form of varenicline base, i.e. a hydrate of varenicline base, designated herein as Form II, and to a method for obtaining and preparing the same.

Background of the invention

Varenicline (Compound I) is the international commonly accepted name for 7, 8, 9, 10-tetrahydro-6, 10- methano-6H-pyrazino [2 , 3-h] [3] benzazepine (which is also known as 5, 8, 14-triazatetracyclo [ 10.3.1. O2'11. O4' 9] - hexadeca-2 (11) , 3, 5, 7, 9-pentaene) , and has an empirical formula of C13H13N3 and a molecular weight of 211.26.

(D

The L-tartrate salt of varenicline has been selected for medical purpose and is commercially marketed for the treatment of smoking addiction. Varenicline L-tartrate is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the name Chantix™, and is indicated as an aid to smoking cessation treatment. Varenicline base and its pharmaceutically acceptable acid addition salts are described in U.S. Patent No. 6,410,550. In particular, Example 26 of U.S. Patent No. 6,410,550 describes the preparation of varenicline base, which is subsequently converted into its hydrochloride salt. In this reference, varenicline base is isolated from a dichloromethane solution to afford the compound as a light yellow oil which solidified upon standing to give a solid.

U.S. Patent No. 6,410,550 only reports the melting point of this solid (138-1400C), and does not provide the crystalline data of said compound. Namely, there is no crystal structure data in the literature regarding varenicline base. In our hands, the varenicline base polymorphic form obtained in U.S. Patent No. 6,410,550 has been isolated and characterized as an anhydrous crystalline solid, and has been denominated herein as Form I . International publication No. WO 2008/060487 describes that anhydrous varenicline base shows polymorphism. More precisely, four different crystalline forms of varenicline base are provided in this reference (designated therein as Forms A, C, D, and E) . Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphs differ in their physical properties such as melting point, solubility, chemical reactivity, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. In view of the foregoing, there exists a need for identifying and isolating new polymorphic forms of varenicline base that may have superior chemical and/or physical properties. Further, it would be desirable to have reliable processes for producing varenicline base in one or more of its new polymorphic forms. Additionally, the new polymorphic forms of varenicline base could be used to prepare improved pharmaceutical compositions .

Summary of the Invention

The invention relates generally to a crystalline polymorphic form of 7, 8, 9, 10-tetrahydro-6, 10-methano-6H- pyrazino [2, 3-h] [3] benzazepine, varenicline base, i.e. a hydrate of varenicline base, designated herein as Form II, and to a method for preparing and obtaining the same . Brief Description of the Figures

Figure 1 illustrates the X-ray powder diffractogram (XRD) of varenicline base Form I obtained in Example 1.

Figure 2 illustrates the Infrared (IR) spectrum of varenicline base Form I obtained in Example 1. Figure 3 illustrates the Differential Scanning Calorimetry (DSC) thermogram in an open pan of varenicline base Form I obtained in Example 1.

Figure 4 illustrates the X-ray powder diffractogram (XRD) of varenicline base Form II, i.e. a hydrate of varenicline base, obtained in Example 2.

Figure 5 illustrates the Infrared (IR) spectrum of varenicline base Form II, i.e. a hydrate of varenicline base, obtained in Example 2. Figure 6 illustrates the X-ray powder diffractogram (XRD) of varenicline base mixture of Form I and Form II obtained in Example 3.

Detailed Description of the Invention It has been found that varenicline base can exist in a new crystalline form, i.e. a hydrate of varenicline base. This new form of varenicline base has been prepared and characterized as described herein and is referred to herein as Form II. Following the teachings of Example 26 of U.S. Patent No. 6,410,550, our inventors have isolated anhydrous crystalline solid varenicline base from a dichloromethane solution. The obtained crystalline polymorphic form of varenicline base (i.e. prior art varenicline base) has been designated herein as Form I. Varenicline base polymorphic Form I has been characterized herein by X-ray powder diffraction (XRD) , Infrared spectrometry (IR), and Differential Scanning Calorimetry (DSC) (see Figures 1, 2, and 3, respectively) .

A first aspect of the present invention includes varenicline base polymorphic Form II characterized by its X-ray powder diffraction pattern (XRD) . Figure 4 illustrates the XRD (2θ) (± 0.2°) of varenicline base polymorphic Form II which has its main peaks at approximately 8.8, 9.3, 10.7, 12.0, 13.8, 14.4, 16.2, 17.2, 17.8, 18.6, 20.0, 20.7, 20.8, 21.2, 26.9 and 27.8° with further peaks at 15.6, 19.0, 21.6, 22.8, 28.4 and 28.9° . In an embodiment of the invention varenicline base polymorphic Form II has been characterized by Infrared (IR) spectrum. Figure 5 illustrates the IR spectrum of varenicline base polymorphic Form II.

Another aspect of the present invention is to provide a process for preparing varenicline base Form II, said process comprising (i) dissolving varenicline base in a selected solvent comprising water, to obtain a solution, and (ii) removing the solvent from said solution, to give varenicline base Form II.

The selected solvent comprising water preferably is water.

In an embodiment of the invention, the step (ii) of removing the solvent from said solution is carried out by evaporating the solvent.

In an alternative embodiment of the invention, the step (ii) of removing the solvent from said solution is carried out by leaving the product to precipitate to obtain a suspension, and filtering the suspension.

The varenicline base used for preparing varenicline base Form II can be either varenicline base obtained by a known method.

In another aspect, the varenicline base polymorphic Form II of the invention is a hydrate of varenicline base .

Another aspect of the invention includes a hydrate of varenicline base.

The hydrate of varenicline base of the invention shows a loss on drying of about 4.8% on heating between about 85° and 115 0C, as determined by Thermal Gravimetric Analysis (TGA) . Another aspect of the invention includes the use of varenicline base crystalline Form II, i.e. a hydrate of varenicline base, for preparing varenicline base polymorphic Form I, i.e. anhydrous varenicline base. In an embodiment, the invention includes a process for preparing varenicline base polymorphic Form I, said process comprising removing the water from varenicline base Form II by means of azeotropic distillation.

In an alternative embodiment, the invention includes a process for preparing varenicline base polymorphic Form I, said process comprising removing the water from varenicline base Form II by means of heat- drying said varenicline base Form II.

The heat-drying can be carried out under reduced pressure.

In an embodiment, the present invention also relates to mixtures of varenicline base Form I and Form II. The inventors have found that by dissolving varenicline base in a solvent comprising water and ethanol and removing the solvent, varenicline base mixture of Form I and Form II is obtained (see Example 3) .

Another aspect of the invention includes the use of varenicline base crystalline Form II for preparing and obtaining pharmaceutically acceptable salts of varenicline .

Another aspect of the invention includes the use of varenicline base crystalline Form II for preparing and obtaining varenicline L-tartrate. Examples

General Experimental Conditions :

X-ray Powder Diffraction (XRD)

The XRD diffractograms were obtained using a RX SIEMENS D5000 diffTactometer with a vertical goniometer, a copper anodic tube, and radiation CuKα , λ= 1, 54056 A.

Infrared Spectrometry (IR)

Fourier transform IR spectra (in potassium bromide pellets) were acquired on a Thermo Nicolet Nexus spectrometer.

Differential Scanning Calorimetry (DSC)

DSC measurement was performed in vented pan at a scan rate of 10° C/minute from 25.0° C to 270.0° C under a nitrogen purge with a DSC823 available from Mettler- Toledo.

Example 1 : Preparation of varenicline base Form I

This example has been carried out following the isolation step described in Example 26 of U.S. Patent No. 6,410,550. Varenicline tartrate (2.0 g) was stirred in aqueous sodium hydroxide solution (IN, 100 mL) , for two minutes and extracted with dichloromethane (3 x 50 mL) . The organic layers were combined, washed with deionised water (50 mL) , dried with sodium sulfate, filtered and concentrated to dryness to give varenicline base Form I, 1.0 g.

Analytical data: XRD: Form I, See Figure 1. IR: Form I, See Figure 2; DSC (open pan) : Form I, See Figure 3. Example 2: Preparation of varenicline base Form II (i.e. a hydrate of varenicline base)

Varenicline base (100 mg) was dissolved in water (0.5 mL) and heated to 700C for one hour. The solution was allowed to cool to room temperature, and stirred for 24 hours at this temperature before evaporation of the solvent (by opening the vial and allowing to evaporate under ambient temperature conditions) .

Analytical data: XRD: Form II, See Figure 4. IR: Form II, See Figure 5.

Example 3 : Preparation of a mixture of varenicline base Form I and Form II

Varenicline base (100 mg) was dissolved in a 20:80 mixture of water and ethanol (0.5 mL) and heated to 700C for one hour. The solution was allowed to cool to room temperature, and stirred for 24 hours at this temperature before evaporation of the solvent (by opening the vial and allowing to evaporate under ambient temperature conditions) . Analytical data: XRD: Mixture of Form I and Form II, See Figure 6.

Claims

CLAIMS :
1. Varenicline base polymorphic Form II having an X-ray diffraction pattern (2θ) having characteristic peaks at approximately 8.8, 9.3, 10.7, 12.0, 13.8, 14.4, 16.2, 17.2, 17.8, 18.6, 20.0, 20.7, 20.8, 21.2, 26.9 and 27.8°.
2. A process for preparing varenicline base Form II, said process comprising: i. dissolving varenicline base in a solvent comprising water, to obtain a solution, and ii. removing the solvent from said solution, to give varenicline base Form II.
3. The process of claim 2, wherein the solvent comprising water is water.
4. The varenicline base polymorphic Form II of any of claims 1 to 3, wherein said varenicline base polymorphic Form II is a hydrate of varenicline base.
5. The hydrate of varenicline base polymorphic Form II of claim 4, wherein said hydrate of varenicline base shows a loss on drying of about 4.8% on heating between about 85° and 115 0C, as determined by Thermal Gravimetric Analysis.
6. A process for preparing varenicline base polymorphic Form I, said process comprising using varenicline base Form II.
EP09709821A 2008-02-15 2009-02-13 A polymorphic form of a pyrazino [2,3-h] [3] benzazepine derivative Withdrawn EP2260037A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US6603208P true 2008-02-15 2008-02-15
PCT/EP2009/051727 WO2009101185A2 (en) 2008-02-15 2009-02-13 A polymorphic form of a pyrazino [2, 3-h] [3] benzazepine derivative

Publications (1)

Publication Number Publication Date
EP2260037A2 true EP2260037A2 (en) 2010-12-15

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EP09709821A Withdrawn EP2260037A2 (en) 2008-02-15 2009-02-13 A polymorphic form of a pyrazino [2,3-h] [3] benzazepine derivative

Country Status (2)

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EP (1) EP2260037A2 (en)
WO (1) WO2009101185A2 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1044189B2 (en) * 1997-12-31 2015-02-25 Pfizer Products Inc. Aryl fused azapolycyclic compounds
YU34501A (en) * 2000-05-26 2003-10-31 Pfizer Products Inc. Reactive crystallization method to improve particle size
EP1383733B1 (en) * 2001-04-20 2008-03-05 Pfizer Products Inc. Process for the preparation of 1,3-substituted indenes and aryl-fused azapolycyclic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009101185A2 *

Also Published As

Publication number Publication date
WO2009101185A2 (en) 2009-08-20
WO2009101185A3 (en) 2009-12-03

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