(12) United States Patent
`Garti et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,861,426 B2
`Mar. 1, 2005
`
`US006861426B2
`
`(
`
`75
`
`)
`
`(54) CRYSTAL FORMS OF LAMOTRIGINE AND
`PROCESSES FOR THEIR PREPARATIONS
`(
`)
`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
`Ge1‘Sh011, R0Sh Ha-Aifl (IL)
`_
`_
`.
`(73) A551gnee3 Teva Pllarmaceutlcal Industrles Ltd->
`Petah Tlqva (IL)
`.
`.
`.
`.
`Subject. to any disclaimer; the term of this
`gatserg 1:5:’gSnSe%((’1r adlusted under 35
`:
`:
`:
`y
`ays:
`21 A 1. N .: 10 086 157
`)
`pp
`0
`/
`’
`(
`(22)
`Filed:
`Feb. 27, 2002
`
`*
`
`.
`) Notice:
`
`(
`
`(58) Field of Search ......................... .. 544/182; 514/242
`
`(56)
`
`References Cited
`Us’ 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.
`54385440.
`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
`
`(65)
`
`Prior Publication Data
`
`(57)
`
`ABSTRACT
`
`Us 2003/0018030 A1 JaI1- 23; 2003
`,
`, Related, U-,S- Application Data
`§6‘(’)‘i151°na1 apphcatlon NO: 60/271588» filed 0“ Feb: 27>
`'
`Int. Cl.7 ................... .. A61K 31/35; C07D 253/075
`(51)
`(52) U.S. Cl.
`...................................... .. 514/242; 544/182
`
`(60)
`
`The present invention relates to lamotrigine, a useful agent
`f
`t'-'1'.N
`tlf
`fl
`t"
`-
`tifniilfifiieiiili OSEZ E3331 ii)1r:t1cfic?hio:1nIIe1t)riE:1gr121IiieosC(2)1Ir1e
`disclosed. The present invention also provides processes for
`preparing the new crystal forms of lamotrigine.
`
`100 Claims, 18 Drawing Sheets
`
`Janssen Ex. 2024
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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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`Mar. 1, 2005
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`U.S. Patent
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`Mar. 1,2005
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`U.S. Patent
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`Mar. 1,2005
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`U.S. Patent
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`Mar. 1,2005
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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. §
`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
`
`(1)
`
`C1
`
`C1
`
`N\
`\N
`
`1 /1
`
`N
`
`NH2
`
`HZN
`
`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 Glaxo Wellcome
`and is sold under the trademark LAMICTAL®. LAMIC-
`
`TAL® 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, 32310.2 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, 309102 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, 26.6102 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, 34.6102 degrees
`two-theta.
`
`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, 308102 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,
`338102 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, 267102 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, 322102 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, 267102 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, 359102 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, 280102 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,
`318102 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, 275102 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, 351102 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, 260102 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, 351102 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, 223102 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, 347102
`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, 258102 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, 333102 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, 274102 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, 336102 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,
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`15.0, 26.9, 27.7102 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,
`36210.2 degrees two-theta.
`The present invention provides a new crystal form 0 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, 28.7102 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, 34.8102
`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, 26.0102 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, 28.3102 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, 30.9102 degrees two-theta and other typical
`peaks at about 9.4, 10.0, 26.7, 27.8, and 28.4102 degrees
`two-theta.
`
`form R of
`invention provides a crystal
`The present
`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, 32.5102
`degrees and other typical peaks at about 8.2, 15.7, 19.0, 23.5
`and 25.4102 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
`18.7102 degrees two-theta and other typical peaks at about
`22.4, 26.0, 27.6, and 31.3102 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, 32.1102 degrees two-theta and other
`typical peaks at about 11.5, 15.9, 17.9, 25.4, 25.8, and
`26.6102 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
`lamotriginc 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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`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 J isopropanolate at
`about 80° C. for about 1 hour.
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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.
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`FIG. 12 shows the X-ray diffraction pattern of lamotrigine
`form N.
`
`FIG. 13 shows the X-ray diffraction pattern of lamotrigine
`form O.
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`FIG. 14 shows the X-ray diffraction pattern of lamotrigine
`form P.
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`FIG. 15 shows the X-ray diffraction pattern of lamotrigine
`form Q.
`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.
`
`The present invention provides a method of preparing 25
`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.
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`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.
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`FIG. 6 shows the X-ray diffraction pattern of lamotrigine
`form F.
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`FIG. 7 shows the X-ray diffraction pattern of lamotrigine
`form H.
`
`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 a gain 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 “Z/3 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 “Z/3 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 “1/3 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
`1 9%.
`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 “2/3 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 X’TRA X-ray powder
`diffractometer, equipped with a solid state Si(Li) detector
`thermoelectrically cooled, at a scanning speed of 30 min.‘1
`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
`
`invention
`the present
`According to one embodiment,
`provides a process for preparing lamotrigine form A i