Cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-l,3-diol

1. A cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and a zwitterion coformer, wherein the cocrystal is selected from the group consisting of:

a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.8, 11.1 and 15.8±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å;

a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and betaine characterized by having an X-ray diffractogram that comprises characteristic peaks at 9.1, 10.7 and 18.4±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å;

a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-carnitine characterized by having an X-ray diffractogram that comprises characteristic peaks at 6.8, 11.3 and 20.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å;

a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and DL-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.1 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; and

a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid characterized by having an X-ray diffractogram that comprises characteristic at 4.4, 6.2 and 8.3±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

2. The cocrystal according to claim 1 , which is a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.8, 11.1 and 15.8±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

3. The cocrystal according to claim 2 , which is characterized by further comprising characteristic peaks in the X-ray powder diffractogram at 7.4, 11.4 and 21.2±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

4. The cocrystal according to claim 1 , which is a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and betaine characterized by having an X-ray diffractogram that comprises characteristic peaks at 9.1, 10.7 and 18.4±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

5. The cocrystal according to claim 4 , which is characterized by further comprising characteristic peaks in the X-ray powder diffractogram at 5.3 and 13.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

6. The cocrystal according to claim 1 , which is a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-carnitine characterized by having an X-ray diffractogram that comprises characteristic peaks at 6.8, 11.3 and 20.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

7. The cocrystal according to claim 6 , which is characterized by further comprising characteristic peaks in the X-ray powder diffractogram at 12.7, 13.6, and 15.6 and ±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

8. The cocrystal according to claim 1 , which is a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and DL-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.1 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

9. The cocrystal according to claim 8 , which is characterized by further comprising characteristic peaks in the X-ray powder diffractogram at 11.4 and 21.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

10. The cocrystal according to claim 1 , which is a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid characterized by having an X-ray diffractogram that comprises characteristic at 4.4, 6.2 and 8.3±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

11. The cocrystal according to claim 10 , which is characterized by further comprising characteristic peaks in the X-ray powder diffractogram at 10.0, 13.3 and 16.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å.

12. A process for the preparation of the cocrystal selected from the group consisting of:

a) a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.8, 11.1 and 15.8±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and betaine characterized by having an X-ray diffractogram that comprises characteristic peaks at 9.1, 10.7 and 18.4±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-f(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-carnitine characterized by having an X-ray diffractogram that comprises characteristic peaks at 6.8, 11.3 and 20.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and DL-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.1 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid characterized by having an X-ray diffractogram that comprises characteristic at 4.4, 6.2 and 8.3±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; and

b) a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and D-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.2 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å;

wherein:

when the cocrystal is a cocrystal as defined in a), then the process comprises:

(c) slurrying the 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol with the zwitterion coformer and an organic solvent; and

(d) isolating the cocrystal thus obtained;

and

when the cocrystal is the cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and D-proline, then the process comprises:

(c) slurrying the 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol with the zwitterion conformer D-proline and the organic solvent heptane; and

(d) isolating the cocrystal thus obtained.

13. A process for the purification of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol which comprises:

(e) dissociating a cocrystal selected from the group consisting of a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and L-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.8, 11.1 and 15.8±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and betaine characterized by having an X-ray diffractogram that comprises characteristic peaks at 9.1, 10.7 and 18.4±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-0]-5-pentylbenzene-1,3-diol and L-carnitine characterized by having an X-ray diffractogram that comprises characteristic peaks at 6.8, 11.3 and 20.0±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and DL-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.1 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid characterized by having an X-ray diffractogram that comprises characteristic at 4.4, 6.2 and 8.3±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å; and a cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and D-proline characterized by having an X-ray diffractogram that comprises characteristic peaks at 5.7, 11.2 and 15.7±0.3 degrees 2 theta at a Cu-K α radiation, λ=1.5406 Å;

under such reaction conditions to obtain 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol; and

(f) isolating 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol thus obtained.

14. The process according to claim 13 , further comprising steps (c) and (d) before steps (e) and (f), comprising:

(c) slurrying the 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol with the zwitterion coformer and an organic solvent; and

(d) isolating the cocrystal thus obtained.

15. A pharmaceutical composition comprising a pharmaceutically effective amount of the cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and a pharmaceutically acceptable zwitterion coformer as defined in claim 1 together with one or more pharmaceutically acceptable excipients or carriers.

16. A cocrystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and a zwitterion coformer as defined in claim 1 for use as a medicament.

17. The process according to claim 13 , wherein step e) is carried out by dissolving the cocrystal in a mixture of water and one or more water-immiscible organic solvent and subsequent separation of the phases of the biphasic mixture.

18. The process according to claim 17 , wherein the water-immiscible organic solvent is selected from the group consisting of (C 1 -C 9 )alkane, (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl and mixtures thereof.

19. The process according to claim 17 , wherein the water-immiscible organic solvent is (C 1 -C 9 )alkane.

20. The process according to claim 17 , wherein the water-immiscible organic solvent is one or more (C 1 -C 9 )alkanes selected from the group consisting of heptane, cyclohexane, pentane and mixtures thereof.