(12) United States Patent
`Garti et al.
`
`USOO6861426B2
`US 6,861,426 B2
`Mar. 1, 2005
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) CRYSTAL FORMS OF LAMOTRIGINE AND
`PROCESSES FOR THEIR PREPARATIONS
`
`(75) Inventors: Nissim Garti, Ramot (IL); Yana
`Berkovich, Jerusalem (IL); Ben-Zion
`Dolitzky, Petach Tiqva (IL); Judith
`Aronhime, Rehovot (IL); Claude
`Singer, Kfar Saba (IL); Anita
`Liebermann, Tel-Aviv (IL); Neomi
`Gershon, Rosh Ha-Ain (IL)
`(73) Assignee: Teva Pharmaceutical Industries Ltd.,
`Petah Tiqva (IL)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(*) Notice:
`
`(21) Appl. No.: 10/086,157
`(22) Filed:
`Feb. 27, 2002
`(65)
`Prior Publication Data
`US 2003/0018030 A1 Jan. 23, 2003
`Related U.S. Application Data
`(60) Provisional application No. 60/271,688, filed on Feb. 27,
`2001.
`(51) Int. Cl." ..................... A61K 31/35; CO7D 253/075
`(52) U.S. Cl. ........................................ 514/242; 544/182
`
`(58) Field of Search ........................... 544/182, 514/242
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,560,687 A 12/1985 Baxter et al. ............... 544/182
`6,124.308 A 9/2000 Nobbs et al. ............... 544/182
`OTHER PUBLICATIONS
`Janes et al., “Structure of Lamotrigine Methanol Solvate:
`3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triaz
`ine-Methanol, a Novel Anticonvulsant Drug.” Acta Cryst.,
`1989, C45, 129-132.
`Pharmacopeial Forum, Vol. 24, No. 1, (Jan.-Feb. 1998) p.
`5438-5440.
`E. Schmitt et al “Moisture-Dependent Crystallization of
`Amorphous Lamotrigine Mesylate” Journal of Pharmaceu
`tical Sciences vol. 85, No. 11, Nov. 1996, pp. 1215-1219.
`Primary Examiner Richard L. Raymond
`(74) Attorney, Agent, or Firm-Kenyon & Kenyon
`(57)
`ABSTRACT
`The present invention relates to lamotrigine, a useful agent
`for anti-epilepsia. New crystal forms of lamotrigine con
`taining molecules of the Solvent in Stoichiometric ratioS are
`disclosed. The present invention also provides processes for
`preparing the new crystal forms of lamotrigine.
`
`100 Claims, 18 Drawing Sheets
`
`Merck Exhibit 2171, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
`
`Mar. 1, 2005
`
`Sheet 1 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 2
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`IPR2020-00040
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 2 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 3
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 3 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 4
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`IPR2020-00040
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 4 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 5
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 5 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 6
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`U.S. Patent
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`Mar. 1, 2005
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`Merck Exhibit 2171, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 7 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 8
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`IPR2020-00040
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`U.S. Patent
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`Mar. 1, 2005
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 10
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`U.S. Patent
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`Mar. 1, 2005
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`Merck Exhibit 2171, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 11 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 12
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 12 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 13
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`IPR2020-00040
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 13 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 14
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 14 of 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 16
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`Merck Exhibit 2171, Page 17
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`U.S. Patent
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`Mar. 1, 2005
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`Sheet 17 0f 18
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`US 6,861,426 B2
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`Merck Exhibit 2171, Page 18
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`Merck Exhibit 2171, Page 19
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`US 6,861,426 B2
`
`1
`CRYSTAL FORMS OF LAMOTRIGINE AND
`PROCESSES FOR THEIR PREPARATIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`This application claims the benefit under 35 U.S.C. S
`1.119(e) of Provisional Application Ser. No. 60/271,688,
`filed Feb. 27, 2001, the disclosure of which is incorporated
`by reference in its entirety herein.
`FIELD OF THE INVENTION
`The present invention relates to new crystal forms of
`lamotrigine, related pharmaceutical composition, and pro
`ceSSes for their preparation.
`BACKGROUND OF THE INVENTION
`Lamotrigine is known as 6-(2,3-Dichlorophenyl)-1,2,4-
`triazine-3,5-diamine or 3,5-diamino - 6-(2,3-
`dichlorophenyl)-1,2,4-triazine and has the following chemi
`cal formula (I).
`
`15
`
`(I)
`
`25
`
`Cl
`
`Cl
`
`HN
`
`N S. NN l.
`
`N
`
`NH2
`
`2
`The present invention provides a new crystal form D of
`lamotrigine (a solvate of DMF), characterized by an X-ray
`powder diffraction pattern having a Strong peak at about
`14.1, 15.9, 18.2, 20.6, 30.8+0.2 degrees two-theta and other
`typical peaks at about 13.2, 14.9, 17.2, 18.0, 19.0, 19.5, 22.7,
`23.0, 23.5, 26.2, 27.0, 27.8, 28.2, 28.6, 29.0, 29.5, 31.0, 32.9,
`33.8+0.2 degrees two-theta.
`The present invention provides a new crystal form E of
`lamotrigine (a methanolate), characterized by an X-ray
`powder diffraction pattern having a Strong peak at about 9.5,
`11.5, 13.8, 23.2, 26.7+0.2 degrees two-theta and other
`typical peaks at about 13.0, 14.3, 14.9, 15.7, 17.9, 19.4, 20.9,
`24.5, 25.6, 27.3, 32.2+0.2 degrees two-theta.
`The present invention provides a new crystal form E1 of
`lamotrigine (an ethanolate), characterized by an X-ray pow
`der diffraction pattern having a strong peak at about 9.6,
`13.8, 15.8, 23.1, 26.7+0.2 degrees two-theta and other
`typical peaks at about 11.6, 13.0, 14.4, 15.2, 16.2, 17.8, 18.9,
`20.1, 21.8, 24.6, 25.6, 26.3, 27.3, 27.7, 28.8, 30.0, 30.7, 31.9,
`32.3, 32.7, 34.3, 35.9+0.2 degrees two-theta.
`The present invention provides a new crystal form F of
`lamotrigine (an acetonate), characterized by an X-ray pow
`der diffraction pattern having a Strong peak at about 17.2,
`18.7, 26.5, 27.0, 28.0+0.2 degrees two-theta and other
`typical peaks at about 9.7, 11.8, 12.7, 13.4, 14.6, 15.4, 20.2,
`20.7, 21.3.21.6, 22.0, 24.6, 25.1, 25.5, 28.2, 29.4, 30.1,
`31.8+0.2 degrees two-theta.
`The present invention provides a new crystal form H of
`lamotrigine (an ethanolate), characterized by an X-ray pow
`der diffraction pattern having Strong peaks at about 9.6, 10.5,
`21.8, 22.2, 27.5+0.2 degrees two-theta and other peaks at
`about 12.2, 13.5, 14.7, 15.1, 16.5, 16.7, 17.0, 18.5, 19.5,
`20.5, 24.0, 24.6, 25.7, 26.3, 28.4, 28.9, 29.4, 30.5, 31.1, 31.8,
`33.3, 35.1+0.2 degrees two-theta.
`The present invention provides a new crystal form J of
`lamotrigine (an isopropanolate), characterized by an X-ray
`powder diffraction pattern having Strong peaks at about 9.5,
`10.0, 20.2, 26.0+0.2 degrees two-theta and other peaks at
`about 11.6 12.4, 13.7, 14.8, 15.9, 16.3, 16.6, 17.3, 18.0, 18.5,
`20.4, 21.0, 21.3, 24.2, 24.4, 24.7, 25.0, 25.5, 26.4, 26.7, 27.6,
`27.8, 28.3, 28.7, 29.2, 30.4, 30.6, 35.1+0.2 degrees two
`theta.
`The present invention provides a new crystal form K of
`lamotrigine (a solvate of THF), characterized by an X-ray
`powder diffraction pattern having Strong peaks at about 11.2,
`12.9, 17.2, 21.5, 22.3+0.2 degrees two-theta and other peaks
`at about 13.5, 17.8, 18.4, 19.2, 20.4, 24.3, 25.3, 25.9, 26.7,
`27.0, 28.0, 28.4, 29.0, 29.6, 30.2, 30.6, 31.4, 32.4, 34.7+0.2
`degrees two-theta.
`The present invention provides a new crystal form L of
`lamotrigine (a Solvate of acetonate), characterized by an
`X-ray powder diffraction pattern having Strong peaks at
`about 12.9, 14.9, 18.2, 20.5, 25.8+0.2 degrees two-theta, and
`other typical peaks at about 8.3, 11.3, 11.7, 12.4, 14.1, 16.7,
`17.6, 18.4, 19.0, 20.1, 21.7, 22.6, 23.6, 24.6, 26.3, 26.8, 27.8,
`28.4, 28.9, 31.1, 31.9, 33.3+0.2 degrees two-theta.
`The present invention provides a crystal form M of
`lamotrigine (a Solvate of DMA), characterized by an X-ray
`powder diffraction pattern having Strong peaks at about 10.0,
`16.5, 16.8, 25.5, 27.4+0.2 degrees two-theta, and other
`typical peaks at about 9.0, 11.4, 13.0, 13.8, 15.1, 17.4, 17.8,
`18.6, 21.1, 21.9, 23.8, 26.5, 27.0, 28.0, 28.6, 29.0, 30.1, 32.1,
`33.1, 33.6+0.2 degrees two-theta
`The present invention provides a crystal form N of
`lamotrigine (hydrate), characterized by an X-ray powder
`diffraction pattern having Strong peaks at about 11.6, 13.4,
`
`40
`
`45
`
`50
`
`Lamotrigine is an anti-epileptic drug of the phenyltriazine
`class and is chemically unrelated to other existing anti
`epileptic drugs. This drug is produced by GlaxoWellcome
`35
`and is sold under the trademark LAMICTALE). LAMIC
`TAL(R) is produced in the form of chewable dispersible
`tablets and is available in different Strengths (from 2 mg to
`200 mg).
`The crystallographic structure of lamotrigine methanolate
`is known (Acta Cryst., (1989, C45, 129-132)).
`No indication was found in the literature concerning the
`existence of other types of crystal forms of lamotrigine.
`There is a need to develop various crystal forms of lamot
`rigine for better formulation.
`OBJECTS AND SUMMARY OF THE
`INVENTION
`An object of the present invention is to provide new
`Solvated forms and hydrate forms of lamotrigine.
`Another object of the present invention is to provide
`proceSS for obtaining an anhydrous form A by heating to
`prepare Solvated and hydrate forms of lamotrigine.
`The present invention provides a new crystal form B of
`lamotrigine (a solvate of DMF), characterized by an X-ray
`powder diffraction pattern having Strong peaks at about 10.3,
`24.2, 25.0, 26.4, 32.3+0.2 degrees two-theta, and other
`typical peaks at about 13.0, 15.8, 17.2, 18.5, 20.5, 21.1, 21.7,
`26.1, 27.7, 29.5, 30.9+0.2 degrees two-theta.
`The present invention provides a new crystal form C of
`lamotrigine (a solvate of DMF), characterized by an X-ray
`powder diffraction pattern having a Strong peak at about
`10.1, 10.5, 17.2, 18.4, 26.6+0.2 degrees two-theta, and other
`typical peaks at about 12.4, 13.1, 13.6, 14.4, 16.3, 21.6, 22.5,
`23.1, 24.4, 27.4, 27.8, 28.4, 32.7, 33.6, 34.6+0.2 degrees
`two-theta.
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`3
`15.0, 26.9, 27.7+0.2 degrees two-theta, and other typical
`peaks at about 15.9, 16.5, 19.1, 22.2, 22.4, 23.2, 23.5, 26.7,
`28.6, 29.9, 30.1, 30.4, 30.7, 31.4, 31.9, 32.9, 33.3, 34.4, 35.0,
`36.2+0.2 degrees two-theta.
`The present invention provides a new crystal form O of
`lamotrigine (a Solvate of methanolate), characterized by an
`X-ray powder diffraction pattern having Strong peaks at
`about 9.5, 13.7, 23.0, 26.7, 28.7+0.2 degrees two-theta, and
`other typical peaks at about 8.5, 11.4, 14.2, 15.7, 18.0, 18.9,
`24.2, 25.6, 25.9, 27.7, 30.0, 30.7, 32.6, 34.3, 34.8+0.2
`degrees two-theta.
`The present invention provides a crystal form P of lam
`otrigine (a solvate of DMF), characterized by an X-ray
`powder diffraction pattern having Strong peaks at about 16.1,
`18.1, 18.7, 26.0+0.2 degrees two-theta, and other typical
`peaks at 8.4, 9.0, 10.1, 12.1, 13.3, 19.5, 20.4, 21.8, 22.5,
`24.0, 24.4, 27.4, 28.3+0.2 degrees two-theta.
`The present invention provides a crystal form Q of
`lamotrigine (a monoSolvate of isopropanolate), character
`ized by an X-ray powder diffraction pattern having Strong
`peaks at about 12.4, 13.8, 14.1, 16.6, 17.4, 17.9, 20.0, 21.0,
`23.6, 28.8, 30.9+0.2 degrees two-theta and other typical
`peaks at about 9.4, 10.0, 26.7, 27.8, and 28.4+0.2 degrees
`two-theta.
`The present invention provides a crystal form R of
`lamotrigine (a monoSolvate of methyl-isobutyl-ketone),
`characterized by an X-ray powder diffraction pattern having
`strong peaks at about 10.9, 12.2, 21.0, 27.3, 28.6, 32.5+0.2
`degrees and other typical peaks at about 8.2, 15.7, 19.0, 23.5
`and 25.4+0.2 degrees two-theta.
`The present invention provides a crystal form S of lam
`otrigine (anhydrous), characterized by an X-ray powder
`diffraction pattern having Strong peaks at about 13.4, and
`18.7+0.2 degrees two-theta and other typical peaks at about
`22.4, 26.0, 27.6, and 31.3+0.2 degrees two-theta.
`The present invention provides a crystal form U of
`lamotrigine (a monosolvate of MTBE), characterized by an
`X-ray powder diffraction pattern having Strong peaks at
`about 12.4, 19.5, 28.4, 32.1+0.2 degrees two-theta and other
`typical peaks at about 11.5, 15.9, 17.9, 25.4, 25.8, and
`26.6+0.2 degrees two-theta.
`The present invention provides a method of making
`lamotrigine forms B, C, D, E, E1, and F by solvent/anti
`Solvent crystallization.
`The present invention provides a method of making
`lamotrigine forms H, O, and J by crystallization in Solution.
`The present invention provides a method of making
`lamotrigine forms C, H, J, K, L, M, and N by treating
`lamotrigine anhydrous in Solvents.
`The present invention provides a method of making
`lamotrigine form P by heating form C at about 80° C. to
`about 110° C. for about 1 hour.
`The present invention provides a method of preparing a
`lamotrigine form B, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF at about 70° C.; 2) precipi
`tating the lamotrigine form B by adding water at about 0°C.;
`and 3) filtering the lamotrigine form B.
`The present invention provides a method of preparing a
`lamotrigine form C, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF at about 70° C.; 2) precipi
`tating the lamotrigine form C by adding chloroform at about
`0° C.; and 3) filtering the lamotrigine form C.
`The present invention provides a method of preparing a
`lamotrigine form C, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF at about 70° C.; 2) precipi
`
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`tating the lamotrigine form C by adding toluene at about 0.
`C.; and 3) filtering the lamotrigine form C.
`The present invention provides a method of preparing a
`lamotrigine form C, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF at about 70° C.; 2) precipi
`tating the lamotrigine form C by adding acetone at about 0.
`C.; and 3) filtering the lamotrigine form C.
`The present invention provides a method of preparing
`lamotrigine form C, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF to form a solution; 2) stirring
`the solution at about 25 C. for about 24 hours; and 3)
`filtering the lamotrigine form C.
`The present invention provides a method of preparing a
`lamotrigine form D, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMF at about 70° C.; 2) precipi
`tating the lamotrigine form D by adding water; and 3)
`filtering the lamotrigine form D.
`The present invention provides a method of preparing a
`lamotrigine form E, comprising the steps of 1) dissolving
`lamotrigine anhydrous in methanol at about 55 C.; 2)
`precipitating the lamotrigine form E by adding toluene at
`about 0° C.; and 3) filtering the lamotrigine form E.
`The present invention provides a method of preparing a
`lamotrigine form E1, comprising the steps of 1) dissolving
`lamotrigine anhydrous in ethanol at about 0° C.; 2) precipi
`tating the lamotrigine form E1 by adding toluene at about
`55 C., and 3) precipitating the lamotrigine form E1.
`The present invention provides a method of preparing
`lamotrigine form F, comprising the Steps of 1) dissolving
`lamotrigine anhydrous in acetone at about 70° C.; 2) pre
`cipitating the lamotrigine form F by adding cyclohexane at
`about 0° C.; and 3) precipitating the lamotrigine by adding
`cyclohexane.
`The present invention provides a method of preparing
`lamotrigine form H, comprising the steps of 1) dissolving
`lamotrigine anhydrous in ethanol to form a Solution; 2)
`stirring the solution at about 25 C. for about 24 hours; and
`3) filtering the lamotrigine form H.
`The present invention provides a method of preparing
`lamotrigine form H, comprising the steps of 1) dissolving
`lamotrigine anhydrous in isopropanol to form a Solution; 2)
`heating the solution at about 65° C.; 3) cooling the solution
`to about 25 C. for about 5.5 hours; 4) filtering the solution;
`and 5) drying the solution at about 50° C. for about 17 hours
`at about 10 mmHg.
`The present invention provides a method of preparing
`Lamotrigine form J, comprising the steps of 1) dissolving
`lamotrigine anhydrous in isopropanol to form a Solution; 2)
`heating the solution to about 65° C.; 3) cooling the solution
`to about 25 C. for about 5.5 hours; 4) filtering the solution;
`and 5) drying the solution at about 50° C. for about 17 hours
`at about 10 mmHg.
`The present invention provides a method of preparing
`lamotrigine form K, comprising the steps of 1) dissolving
`lamotrigine anhydrous in THF to form a solution; 2) stirring
`the solution at about 25 C. for about 24 hours; and 3)
`filtering the lamotrigine form K.
`The present invention provides a method of preparing
`lamotrigine form L, comprising the steps of 1) dissolving
`lamotrigine anhydrous in acetone to form a Solution; 2)
`stirring the solution at about 25 C. for about 24 hours; 3)
`concentrating the Solution to dryness; 4) adding acetone; and
`5) filtering the lamotrigine form L.
`The present invention provides a method of preparing
`lamotrigine form M, comprising the steps of 1) dissolving
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`US 6,861,426 B2
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`S
`lamotrigine anhydrous in DMA to form a solution; 2)
`stirring the solution at about 25 C. for about 24 hours; and
`3) filtering the lamotrigine form M.
`The present invention provides a method of preparing
`lamotrigine form N, comprising the steps of 1) dissolving
`lamotrigine anhydrous in water to form a Solution; 2) Stirring
`the solution at about 25 C. for about 24 hours; and 3)
`filtering the lamotrigine form N.
`The present invention provides a method of preparing
`lamotrigine form 0, comprising the steps of 1) dissolving
`lamotrigine anhydrous in methanol to form a Solution; 2)
`heating the solution to about 65 C.; 3) cooling the solution
`to about 25 C. for about 5.5 hours; 4) filtering the solution;
`and 5) drying the solution at 60° C. for about 17 hours at
`about 10 mmHg.
`The present invention provides a method of preparing
`lamotrigine form P, wherein the lamotrigine from P is
`prepared by heating lamotrigine form C monoSolvate at
`about 80° C. for about 1 hour.
`The present invention provides a method of preparing
`lamotrigine amorphous, wherein the lamotrigine amorphous
`is produced by heating lamotrigine form Jisopropanolate at
`about 80° C. for about 1 hour.
`The present invention provides a method of preparing
`lamotrigine form Q, comprising the steps of 1) dissolving
`lamotrigine anhydrous in isopropanol to form a Solution; 2)
`heating the solution at about 65° C. for about 5 minutes; 3)
`cooling the Solution to room temperature; and 3) filtering the
`lamotrigine form Q.
`The present invention provides a method of preparing
`lamotrigine form R, comprising the steps of 1) dissolving
`lamotrigine anhydrous in methyl-isobutyl-ketone (MIBK) to
`form a solution; 2) heating the solution at about 65° C. for
`about 5 minutes; 3) cooling the Solution to room tempera
`ture; 4) stirring the Solution; and 5) filtering the lamotrigine
`form R.
`The present invention provides a method of preparing
`lamotrigine form S, comprising the steps of 1) dissolving
`lamotrigine anhydrous in DMC to form a solution; 2)
`heating the solution at about 65° C. for about 5 minutes; 3)
`cooling the Solution to room temperature; 4) stirring the
`Solution; and 5) filtering the lamotrigine form S.
`The present invention provides a method of preparing
`lamotrigine form U, comprising the steps of 1) dissolving
`lamotrigine anhydrous in MTBE to form a solution; 2)
`heating the solution at about 65° C. for about 5 minutes; 3)
`cooling the Solution to room temperature; 4) stirring the
`Solution; and 5) filtering the lamotrigine form U.
`BRIEF DESCRIPTION OF THE FIGURES
`FIG. 1 shows the X-ray diffraction pattern of lamotrigine
`form B.
`FIG. 2 shows the X-ray diffraction pattern of lamotrigine
`form C.
`FIG. 3 shows the X-ray diffraction pattern of lamotrigine
`form D.
`FIG. 4 shows the X-ray diffraction pattern of lamotrigine
`form E.
`FIG. 5 shows the X-ray diffraction pattern of lamotrigine
`form E1.
`FIG. 6 shows the X-ray diffraction pattern of lamotrigine
`form F.
`FIG. 7 shows the X-ray diffraction pattern of lamotrigine
`form H.
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`FIG. 8 shows the X-ray diffraction pattern of lamotrigine
`form.
`FIG. 9 shows the X-ray diffraction pattern of lamotrigine
`form K.
`FIG. 10 shows the X-ray diffraction pattern of lamotrigine
`form L.
`FIG. 11 shows the X-ray diffraction pattern of lamotrigine
`form M.
`FIG. 12 shows the X-ray diffraction pattern of lamotrigine
`form N.
`FIG. 13 shows the X-ray diffraction pattern of lamotrigine
`form O.
`FIG. 14 shows the X-ray diffraction pattern of lamotrigine
`form P.
`FIG. 15 shows the X-ray diffraction pattern of lamotrigine
`form O.
`FIG.16 shows the X-ray diffraction pattern of lamotrigine
`form R.
`FIG. 17 shows the X-ray diffraction pattern of lamotrigine
`form S.
`FIG. 18 shows the X-ray diffraction pattern of lamotrigine
`form U.
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`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Definitions:
`As used herein, the term “TGA” refers to thermogravi
`metric analysis. The Karl Fisher assay for determining water
`content is used which is described in Pharmacopeial Form,
`Vol. 24, No. 1, p. 5438 (January–February 1998). Such an
`assay permits the determination of water content of a crystal
`form based on the Loss on Drying Method. TGA is a
`measure of the thermally induced weight loss of a material
`as a function of the applied temperature. TGA is restricted to
`transitions that involve either again or a loSS of mass, and
`it is most commonly used to study desolvation processes and
`compound decomposition. One skilled in the art will appre
`ciate that other commonly thermal analyses can also be used,
`Such as differential Scanning calorimetry.
`As used herein, the term “DMF' refers to dimethylfor
`mamide; the term “THF refers to tetrahydrofuran; the term
`“MIBK” refers to methyl-isobutyl-ketone; the term “DMC”
`refers to dimethylcarbinol; the term “MTBE” refers to
`methyl tertiary-butyl ether; the term “IPA” refers to isopro
`pyl alcohol; the term “THF refers to tetrahydrofuran; and
`the term “DMA” refers to dimethylamine. One skilled in the
`art will appreciate the term “anti-Solvent refer to a Solvent,
`when added to a Solution of a lamotrigine, causes the
`precipitation of lamotrigine. Exemplary anti-Solvents
`include acetone, toluene, cyclohexane, water and the like.
`As used herein, the term “anhydrous” when used in
`reference to lamotrigine refers to a lamotrigine crystal form
`that is substantially free of water.
`AS used herein, the terms “methanolate”, “ethanolate” and
`"isopropanolate” refer to lamotrigine in which the respective
`Solvent is contained within the crystal lattice of lamotrigine
`in a quantity above 1%
`AS used herein, the term "monosolvate of DMF' when
`used in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loss up to about 20%.
`As used herein, the term “sesquisolvate of DMF' when
`used in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loss up to about 30%.
`AS used herein, the term “% Solvate of DMF' when used
`in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loSS up to about 16%.
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`AS used herein, the term “% methanolate” when used in
`reference to lamotrigine describes a crystal form of lamot
`rigine having a TGA weight loSS up to about 8%.
`AS used herein, the term “/3 Solvate of acetone' when
`used in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loSS up to about 6.3%.
`AS used herein, the term "monosolvate of ethanol” when
`used in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loSS up to about 15%.
`AS used herein, the term "monosolvate of methanol'
`when used in reference to lamotrigine describes a crystal
`form of lamotrigine having a TGA weight loSS up to about
`11%.
`AS used herein, the term "monoSolvate of isopropanol'
`when used in reference to lamotrigine describes a crystal
`form of lamotrigine having a TGA weight loSS up to about
`19%.
`AS used herein, the term “Solvate of THF' when used in
`reference to if lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loSS up to about 23%.
`AS used herein, the term “Solvate of acetone' when used
`in reference to lamotrigine describes a crystal form of
`lamotrigine having a TGA weight loss up to about 19%.
`AS used herein, the term "solvate of DMF' when used in
`reference to lamotrigine describes a crystal form of lamot
`rigine having a TGA weight loss up to about 20%.
`As used herein, the term “hydrate” when used in reference
`to lamotrigine describes a crystal form of lamotrigine having
`a water content up to about 6.6%.
`AS used herein, the term “% methanolate” when used in
`reference to lamotrigine describes a crystal form of lamot
`rigine having a TGA weight loSS up to about 7.2%.
`Solid-state chemistry of a crystal cannot predicate
`whether an organic Solvent can incorporate into the crystal.
`The manner in which Salvation of a crystal may occur is also
`unpredictable. There are no rules exist that allow prediction
`of whether a compound will exist as Solvated forms of an
`organic Solvent.
`The discovery of new solvated forms of a pharmaceuti
`cally useful compound may provide an opportunity to
`improve the performance characteristics of a pharmaceutical
`product. It enlarges the repertoire of materials that a formu
`lation Scientist has available for designing, for example, a
`pharmaceutical dosage form of a drug with a targeted release
`profile or other desired characteristic. It is clearly advanta
`geous when this repertoire is enlarged by the discovery of
`new Solvated crystalline forms of a useful compound.
`The present invention relates to the Solvated crystal forms
`of lamotrigine. Different crystal forms of lamotrigine may
`possess different physical properties include, for example,
`the flowability of the milled solid. Flowability affects the
`ease with which the material is handled during processing
`into lamotrigine. When particles of the powdered compound
`do not flow past each other easily, a formulation specialist
`must take that fact into account in developing a tablet or
`capsule formulation, which may necessitate the use of
`glidants Such as colloidal Silicon dioxide, talc, Starch or
`tribasic calcium phosphate.
`Another important physical property of Solvated/hydrated
`crystal forms of lamotrigine relate to its rate of dissolution
`in aqueous fluid. The rate of dissolution of an active ingre
`dient in a patient's Stomach fluid can have therapeutic
`consequences since it imposes an upper limit on the rate at
`which an orally-administered active ingredient can reach the
`patient's bloodstream. The rate of dissolution is also a
`consideration in formulating Syrups, elixirs and other liquid
`medicaments. The Solid State form of a compound may also
`affect its behavior on compaction and its Storage Stability.
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`All X-ray powder diffraction patterns were obtained by
`methods known in the art. One method employs the use of
`a Philips X-Ray powder diffractometer, Goniometer model
`1050/70 at a scanning speed of 20 per minute. Another
`method employs the use of a Scintag XTRAX-ray powder
`diffractometer, equipped with a Solid State Si(Li) detector
`thermoelectrically cooled, at a scanning speed of 30 min.'
`Scanning range 240 degrees two-theta. Copper radiation of
`1.5418. A was used.
`The properties of Solvated crystal forms of lamotrigine
`may differ from that of LAMICTAL; they include solubility,
`Stability, hygroscopicity (ability to remove moisture from
`air), tabletability, bioavailability, storage life (shelf life), and
`flow properties.
`Preparation of Anhydrous Form A By Heating
`According to one embodiment, the present invention
`provides a proceSS for preparing lamotrigine form A includ
`ing heating lamotrigine Solvates at temperatures elevated
`enough to remove all the Solvent from the crystal, usually
`above 100° C. for a period of about 2 hours, preferably
`above 110° C. for a period of about 1 hour, more preferably
`at about 150° C. for a period of about 2 hour.
`Novel Crystal Forms of Lamotrigine Solvates
`Form P-MonoSolvate of DMF
`According to one embodiment, the present invention
`provides a novel crystal form of lamotrigine denominated
`form P, which is a monosolvate of DMF. lamotrigine form
`P exhibits strong X-ray powder diffraction peaks at about
`16.1, 18.1, 18.7, 26.0+0.2 degrees two-theta, and other
`typical peaks at about 8.4, 9.0, 10.1, 12.1, 13.3, 19.5, 20.4,
`21.8, 22.5, 24.0, 24.4, 27.4, 28.3+0.2 degrees two-theta.
`This sample shows a TGA weight loss of about 20%,
`which is a monosolvate of DMF.
`According to another embodiment, the present invention
`provides a proceSS for preparing lamotrigine form Pinclud
`ing heating lamotrigine form C monosolvate of DMF at a
`temperature below the temperature of desolvation, about 60
`C. for a period of about 3 hours, preferably at about 80 C.
`for a period of about 1 hour.
`Amorphous Lamotrigine
`According to one embodiment, the present invention
`provides a novel amorphous form of lamotrigine.
`According to another embodiment, the present invention
`provides a process for preparing lamotrigine amorphous
`including heating lamotrigine J isopropanolate at about 80
`C. for about 1 hour.
`Novel Solvated Crystal Forms Obtained by
`Crystallization Using Solvent/Anti-Solvent
`Technique, and Processes
`Form B-monosolvate of DMF
`According to one embodiment, the present invention
`pro