WO2012046245A1 - Nouvelle forme polymorphe du lacosamide - Google Patents

Nouvelle forme polymorphe du lacosamide Download PDF

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Publication number
WO2012046245A1
WO2012046245A1 PCT/IN2011/000568 IN2011000568W WO2012046245A1 WO 2012046245 A1 WO2012046245 A1 WO 2012046245A1 IN 2011000568 W IN2011000568 W IN 2011000568W WO 2012046245 A1 WO2012046245 A1 WO 2012046245A1
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WO
WIPO (PCT)
Prior art keywords
solvent
lacosamide
crystalline form
mixture
ketonic
Prior art date
Application number
PCT/IN2011/000568
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English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Puchakayala Srinivasa Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
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
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2012046245A1 publication Critical patent/WO2012046245A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • 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

Definitions

  • the present invention provides novel crystalline form of lacosamide, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention also provides a process for the preparation of lacosamide amorphous form.
  • Lacosamide is chemically, (2 )-2-(acetylamino)-3-methoxy-N- (phenylmethyl)propanamide and has the structural formula:
  • Lacosamide is a medication developed by Union chimique beige (UCB) for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain marketed under the trade name Vimpat ® .
  • 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.
  • Lacosamide can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • crystalline form I of lacosamide was characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 8.3, 13.0,
  • crystalline form II of lacosamide was characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 5.2, 6.7,
  • amorphous form of lacosamide can be prepared by lyophilization of an aqueous solution of lacosamide.
  • amorphous form of lacosamide can also be prepared by dissolving lacosamide in t-butyl alcohol and removing the solvent under reduced pressure.
  • one object of the present invention is to provide novel crystalline form of lacosamide, process for its preparation and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a process for the preparation of lacosamide amorphous form.
  • the present invention provides a crystalline form of lacosamide designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 8.3, 9.5, 13.1, 14.2, 17.7, 19.9, 20.0, 24.8, 24.9, 25.8 and 26.6 ⁇ 0.2 degrees.
  • the present invention provides a process for the preparation of lacosamide crystalline form HI, which comprises:
  • step (b) removing the solvent from the solution obtained in step (a) to obtain a solid; c) adding hydrocarbon solvent to the solid obtained in step (b); and
  • the present invention provides a pharmaceutical composition comprising crystalline form HI of lacosamide and pharmaceutically acceptable excipients.
  • the present invention provides a process for the preparation of lacosamide amorphous form, which comprises providing a solution of lacosamide in a ketonic solvent and removing the solvent to obtain lacosamide amorphous form.
  • Figure 1 is an X-ray powder diffraction spectrum of lacosamide crystalline form
  • Figure 2 is an X-ray powder diffraction spectrum of lacosamide amorphous form.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- Ka radiation. Approximately lgm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees two theta per step and a step time of 10.8 seconds. 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 a temperature of about 20°C to about 30°C.
  • a crystalline form of lacosamide designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 8.3, 9.5, 13.1, 14.2, 17.7, 19.9, 20.0, 24.8, 24.9, 25.8 and 26.6 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of lacosamide crystalline form HI is shown in figure 1.
  • the lacosamide crystalline form HI may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern. Thus, for example, peaks at 9.5, 14.2 and 26.6 degrees 2 ⁇ are present in the PXRD of the lacosamide crystalline form HI of the present invention, but are absent in the PXRD of the crystalline form 1 of lacosamide disclosed in the US patent publication no. 2009/0298947.
  • step (b) removing the solvent from the solution obtained in step (a) to obtain a solid; c) adding hydrocarbon solvent to the solid obtained in step (b); and
  • Lacosamide used in step (a) may preferably be lacosamide obtained by the known process.
  • the chlorinated solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
  • the chlorinated solvent used may alone or in combination with alcoholic solvent or ketonic solvent. More preferably the chlorinated solvent is methylene chloride.
  • the alcoholic solvent may be a solvent or mixture of solvents selected from methanol, ethanol and isopropyl alcohol, and more preferably the alcoholic solvent is methanol.
  • the ketonic solvent may be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferably the ketonic solvent is acetone.
  • Removal of the solvent in step (b) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • the hydrocarbon solvent used in step (c) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is cyclohexane.
  • Lacosamide 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 lacosamide and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the crystalline form HI may preferable be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • a process for the preparation of lacosamide amorphous form which comprises providing a solution of lacosamide in a ketonic solvent and removing the solvent to obtain lacosamide amorphous form.
  • the ketonic solvent used in the process may preferably be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferably the ketonic solvent is acetone.
  • Removal of the solvent in the process may be earned out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • Lacosamide used in the present invention can be prepared by the known process, for example, by
  • step (b) condensing the residual solid obtained in step (b) with benzyl amine in the presence of isobutyl chlproformate or ethyl chloroformate and 4-methyl morpholine to obtain (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide;
  • step (c) deprotecting the (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide obtained in step (c) in an chlorinated solvent in the presence of hydrochloric acid to obtain a residual solid of (R)-2-amino-N-benzyl- 3-methoxypropionamide;
  • step (d) reacting the (R)-2-amino-N-benzyl-3-methoxypropionamide obtained in step (d) with acetic anhydride in the presence of dimethylaminopyridine and tetra-butyl ammonium bromide to obtain lacosamide.
  • the reaction in step (a) may preferably be carried out in an alcoholic solvent.
  • the alcoholic solvent may be selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol, isobutyl alcohol or mixture thereof. More preferably the alcoholic solvent is tert-butyl alcohol.
  • reaction in step (a) may conveniently be carried out at room temperature.
  • the ether solvent used in step (b) may be a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane. More preferably the ether solvent is tetrahydrofuran.
  • reaction in step (b) may preferably be earned out at below 10°C and more preferably at about 0 to 5°C.
  • the reaction in step (c) may preferably be earned out in a chlorinated solvent.
  • the chlorinated solvent may be selected from methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or mixture thereof. More preferable the chlorinated solvent is methylene dichloride.
  • the reaction in step (c) may preferably be carried out at below 5 C and more preferably at about -10 to -5°C.
  • the chlorinated solvent used in step (d) may be a solvent or mixture of solvents selected from methylene chloride, chloroform, carbon tetrachloride and ethylene dichloride. More preferable the chlorinated solvent is methylene dichloride.
  • step (d) may conveniently be carried out at room temperature.
  • the reaction in step (e) may preferably be carried out in an organic solvent.
  • the organic solvent may be selected from methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl formate, toluene, xylene or mixture thereof. More preferably the organic solvent is methylene chloride, ethyl acetate, toluene or mixture thereof.
  • step (e) may preferably be carried out at below 20°C and more preferably at about 0 to 10°C.
  • Tetrahydrofuran 350 ml
  • sodium hydride 40 gm
  • imidazole 5 gm
  • To the reaction mixture was added a solution N-Boc- D-serine (100 gm) in tetrahydrofuran (900 ml) for 30 minutes and then maintained for 30 minutes at 0 to 5°C.
  • Methyl iodide 85 gm was added to the reaction mixture and then maintained for 30 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours.
  • methanol 50 ml
  • Tetrahydrofuran 350 ml was added to imidazole (5 gm) and then cooled to 0 to 5°C.
  • To the reaction mixture was added butyllithium (40 gm) and then added a solution N-Boc-D-serine (100 gm) in tetrahydrofuran (900 ml) for 30 minutes at 0 to 5°C.
  • Methyl iodide (85 gm) was added to the reaction mixture and then maintained for 30 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours.
  • To the reaction mass was added methanol (50 ml) and then concentrated to obtain a residual mass.
  • To the residual mass was added water (1000 ml) and then the layers were separated.
  • Lacosamide (10 gm) as obtained in example 8 was dissolved in methylene chloride (100 ml) and stirred for 15 minutes to obtain a solution. The solution was then cooled to 10 to 15°C and the solvent was distilled off under vacuum at below 30°C to obtain a solid, and then maintained for 2 hours. To the solid was added cyclohexane (100 ml) and maintained for 30 minutes at 10 to 15°C. The separated solid was filtered and dried to obtain 9.3 gm of lacosamide crystalline form HI.
  • Lacosamide (10 gm) was dissolved in chloroform (90 ml) and stirred for 15 minutes. The solution was then cooled to 10 to 15°C and the solvent was distilled off under vacuum at below 30°C to obtain a solid, and then maintained for 2 hours. To the solid was added hexane (100 ml) and maintained for 30 minutes at 10 to 15°C, filtered. The solid obtained was dried to obtain 9.1 gm of lacosamide crystalline form HI.
  • Lacosamide (10 gm) was dissolved in acetone (200 ml) and stirred for 15 minutes to obtain a solution.
  • the solvent was distilled off under vacuum at below 20°C and then maintained for 3 hours to obtain 9.5 gm of lacosamide amorphous form.
  • Lacosamide (5 gm) was dissolved in methyl ethyl ketone (100 ml) and stirred for 15 minutes to obtain a solution. The solvent was distilled off under vacuum at below 20°C and then maintained for 2 hours to obtain 4.5 gm of lacosamide amorphous form.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une nouvelle forme cristalline du lacosamide, son procédé de préparation et des compositions pharmaceutiques le comprenant. La présente invention concerne également un procédé de préparation de la forme amorphe du lacosamide.
PCT/IN2011/000568 2010-10-05 2011-08-23 Nouvelle forme polymorphe du lacosamide WO2012046245A1 (fr)

Applications Claiming Priority (2)

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IN2944CH2010 2010-10-05
IN2944/CHE/2010 2010-10-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111559968A (zh) * 2020-06-03 2020-08-21 上海上药第一生化药业有限公司 一种拉考沙胺晶型ii的制备方法
CN114524746A (zh) * 2022-01-21 2022-05-24 河北广祥制药有限公司 拉考沙胺晶型的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby
US20090298947A1 (en) * 2008-05-28 2009-12-03 Pliva Hrvatska D.O.O. Polymorphic and amorphous forms of lacosamide and amorphous compositions
WO2010052011A1 (fr) * 2008-11-07 2010-05-14 Ucb Pharma, S.A. Procédé inédit de fabrication de dérivés d'acides aminés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby
US20090298947A1 (en) * 2008-05-28 2009-12-03 Pliva Hrvatska D.O.O. Polymorphic and amorphous forms of lacosamide and amorphous compositions
WO2010052011A1 (fr) * 2008-11-07 2010-05-14 Ucb Pharma, S.A. Procédé inédit de fabrication de dérivés d'acides aminés

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111559968A (zh) * 2020-06-03 2020-08-21 上海上药第一生化药业有限公司 一种拉考沙胺晶型ii的制备方法
CN111559968B (zh) * 2020-06-03 2022-11-22 上海上药第一生化药业有限公司 一种拉考沙胺晶型ii的制备方法
CN114524746A (zh) * 2022-01-21 2022-05-24 河北广祥制药有限公司 拉考沙胺晶型的制备方法
CN114524746B (zh) * 2022-01-21 2022-11-11 河北广祥制药有限公司 拉考沙胺晶型的制备方法

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