Crystalline forms of lamotrigine
The invention is directed to novel crystalline forms of lamotrigine. These novel crystalline forms of lamotrigine have improved dissolution and in-vivo absorption profile, as compared to pure lamotrigine. These novel crystalline forms of lamotrigine provide a substantial increase in the blood concentration of lamotrigine, as compared to pure lamotrigine when administered to a subject. These novel crystalline forms of lamotrigine also provide a slower, steady build up of lamotrigine blood concentration suitable for sustained release of lamotrigine in-vivo, as compared to pure lamotrigine.
1. The crystalline form of lamotrigine selected from the group consisting of co-crystals of lamotrigine and methylparaben, co-crystal of lamotrigine and nicotinamide, saccharinate salts of lamotrigine, adipate salts of lamotrigine, malate salts of lamotrigine, methanol solvates of lamotrigine nicotinate salt, dimethanol solvates, of lamotrigine, and ethanolate hydrates of lamotrigine.
2. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is co-crystal lamotrigine:methylparaben form I which: a) has a PXRD diffraction pattern with peaks at about 7.19, 14.4, 16.7, 17.9, 20.75, 26.56, and 32.02+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 1 .
3. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is co-crystal lamotrigine:methylparaben form II which: a) has a PXRD diffraction pattern with peaks at about 15.53, 18.89, 20.74, 22.0, 23.08, 23.95 and 26.89+/−0.2 degrees two-theta; b) has a PXRD diffraction pattern substantially as depicted in FIG. 3 ; and/or c) is characterized by a DSC thermogram with an endothermic peak at about 162.4° C.
4. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is co-crystal lamotrigine:nicotinamide which: a) has a PXRD diffraction pattern with peaks at about 7.79, 14.96, 17.18, 18.98, 23.21, 26.72 and 27.47+/−0.2 degrees two-theta; b) has a PXRD diffraction pattern substantially as depicted in FIG. 7 ; and/or c) is characterized by a DSC thermogram with an endothermic peak at about 167.2° C.
5. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine saccharinate which: a) has a PXRD diffraction pattern with peaks at about 5.19, 13.61, 14.96, 15.26, 24.10, 27.34 and 28.42+/−0.2 degrees two-theta; b) has a PXRD diffraction pattern substantially as depicted in FIG. 10 ; and/or c) is characterized by a DSC thermogram with an endothermic peak at about 262.56° C.
6. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine adipate which: a) has a PXRD diffraction pattern with peaks at about 6.81, 18.09, 21.17, 22.81, 23.90, 25.56, and 28.20+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 14 .
7. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine malate which: a) has a PXRD diffraction pattern with peaks at about 12.89, 19.49, 20.77, 21.76, 24.70, 26.44 and 29.47+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 17 .
8. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine nicotinate methanolate which: a) has a PXRD diffraction pattern with peaks at about 11.54, 11.90, 16.65, 21.07, 21.85, 22.99 and 27.43+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 20 .
9. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine dimethanolate which: a) has a PXRD diffraction pattern with peaks at about 9.17, 14.66, 15.65, 16.52, 19.99, 28.36 and 30.19+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 23 .
10. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form is lamotrigine ethanolate hydrate which: a) has a PXRD diffraction pattern with peaks at about 11.21, 12.44, 20.37, 24.02, 26.07, 26.47, and 27.55+/−0.2 degrees two-theta; and/or b) has a PXRD diffraction pattern substantially as depicted in FIG. 26 .
11. The crystalline form of lamotrigine, wherein said crystalline form is lamotrigine hydrate form II which: a) has a PXRD diffraction pattern with peaks at about 13.28, 15.95, 20.59, 23.53, 26.65, 28.27 and 30.76+/−0.2 degrees two-theta; b) has a PXRD diffraction pattern substantially as depicted in FIG. 29 .
12. A solid pharmaceutical composition comprising an effective amount of one or more of the crystalline forms of lamotrigine of claim 1 and a pharmaceutically acceptable excipient.
13. A solid pharmaceutical composition comprising an effective amount of a crystalline form of lamotrigine, wherein said crystalline form is lamotrigine hydrate form II which: a) has a PXRD diffraction pattern with peaks at t3.28, 15.95, 20.59, 23.53, 26.65, 28.27 and 30.76+/−0.2 degrees two-theta; and b) has a PXRD diffraction pattern substantially as depicted in FIG. 29 .
14. The crystalline form of lamotrigine of claim 1 , wherein said crystalline form of lamotrigine has one or more properties selected from the group consisting of improved solubility as compared to pure lamotrigine; an increased blood concentration as compared to pure lamotrigine; an improved absorption and pharmacokinetic (PK) profile as compared to pure lamotrigine; an increased rate of dissolution as compared to pure lamotrigine; and a sustained release profile as compared to pure lamotrigine.