Crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride

1. A crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):

for form A, which is a crystalline polymorph:

15.5 (vs), 12.0 (m), 4.89 (m), 3.70 (s), 3.33 (s), 3.26 (s), and 3.18 (m); or

for form F, which is a crystalline polymorph:

17.1 (vs), 4.92 (m), 4.68 (m), 3.49 (s), 3.46 (vs), 3.39 (s), 3.21 (m), and 3.19 (m); or

for form J, which is a crystalline polymorph:

14.6 (m), 3.29 (vs), and 3.21 (vs); or

for form K, which is a crystalline polymorph:

14.0 (s), 6.6 (w), 4.73 (m), 4.64 (m), 3.54 (m), 3.49 (vs), 3.39 (m), 3.33 (vs), 3.13 (s), 3.10 (m), 3.05 (m), 3.01 (m), 2.99 (m), and 2.90 (m); or

for form C, which is a crystalline hydrate:

13.9 (vs), 8.8 (m), 6.8 (m), 6.05 (m), 4.25 (m), 4.00 (m), 3.88 (m), 3.80 (m), 3.59 (s), 3.50 (m), 3.44 (m), 3.26 (s), 3.19 (vs), 3.17 (s), 3.11 (m), 2.97 (m), and 2.93 (vs); or

for form D, which is a crystalline hydrate:

8.6 (s), 5.56 (m), 4.99 (m), 4.67 (s), 4.32 (m), 3.93 (vs), 3.17 (m), 3.05 (s), 2.88 (m), and 2.79 (m); or

for form E, which is a crystalline hydrate:

15.4 (s), 4.87 (w), 3.69 (m), 3.33 (s), 3.26 (vs), 3.08 (m), 2.95 (m), and 2.87 (m); or

for form H, which is a crystalline hydrate:

15.8 (vs), 3.87 (m), 3.60 (m), 3.27 (m), 3.21 (m), 2.96 (m), 2.89 (m), and 2.67 (m); or

for form O, which is a crystalline hydrate:

8.8 (m), 6.3 (m), 5.65 (m), 5.06 (m), 4.00 (m), 3.88 (m), 3.69 (s), 3.64 (s), 3.52 (vs), 3.49 (s), 3.46 (s), 3.42 (s), 3.32 (m), 3.27 (m), 3.23 (s), 3.18 (s), 3.15 (vs), 3.12 (m), and 3.04 (vs); or

for form G, which is a crystalline ethanol solvate:

14.5 (vs), 7.0 (w), 4.41 (w), 3.63 (m), 3.57 (m), 3.49 (w), 3.41 (m), 3.26 (m), 3.17 (m), 3.07 (m), 2.97 (m), 2.95 (m), 2.87 (w), and 2.61 (w); or

for form I, which is a crystalline acetic acid solvate:

14.5 (m), 3.67 (vs), 3.61 (m), 3.44 (m), 3.11 (s), and 3.00 (m); or

for form L, which is a crystalline mixed ethanol solvate/hydrate:

14.1 (vs), 10.4 (w), 6.9 (w), 6.5 (w), 6.1 (w), 4.71 (w), 3.46 (m), 3.36 (m), and 2.82 (w); or

for form M, which is a crystalline ethanol solvate:

18.9 (s), 6.4 (m), and 3.22 (vs); or

for form N, which is a crystalline polymorph:

19.5 (m), 6.7 (w), 3.56 (m), and 3.33 (vs), 3.15 (w).

2. A crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride according to claim 1 , which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å)

for form A:

15.5 (vs), 12.0 (m), 6.7 (m), 6.5 (m), 6.3 (w), 6.1 (w), 5.96 (w), 5.49 (m), 4.89 (m), 3.79 (m), 3.70 (s), 3.48 (m), 3.45 (m), 3.33 (s), 3.26 (s), 3.22 (m), 3.18 (m), 3.08 (m), 3.02 (w), 2.95 (w), 2.87 (m), 2.79 (w), 2.70 (w); or

for form F:

17.1 (vs), 12.1 (w), 8.6 (w), 7.0 (w), 6.5 (w), 6.4 (w), 5.92 (w), 5.72 (w), 5.11 (w), 4.92 (m), 4.86 (w), 4.68 (m), 4.41 (w), 4.12 (w), 3.88 (w), 3.83 (w), 3.70 (m), 3.64 (w), 3.55 (m), 3.49 (s), 3.46 (vs), 3.39 (s), 3.33 (m), 3.31 (m), 3.27 (m), 3.21 (m), 3.19 (m), 3.09 (m), 3.02 (m), and 2.96 (m); or

for form J:

14.6 (m), 6.6 (w), 6.4 (w), 5.47 (w), 4.84 (w), 3.29 (vs), and 3.21 (vs); or

for form K:

14.0 (s), 9.4 (w), 6.6 (w), 6.4 (w), 6.3 (w), 6.1 (w), 6.0 (w), 5.66 (w), 5.33 (w), 5.13 (vw), 4.73 (m), 4.64 (m), 4.48 (w), 4.32 (vw), 4.22 (w), 4.08 (w), 3.88 (w), 3.79 (w), 3.54 (m), 3.49 (vs), 3.39 (m), 3.33 (vs), 3.13 (s), 3.10 (m), 3.05 (m), 3.01 (m), 2.99 (m), and 2.90 (m); or

for form C:

18.2 (m), 15.4 (w), 13.9 (vs), 10.4 (w), 9.6 (w), 9.1 (w), 8.8 (m), 8.2 (w), 8.0 (w), 6.8 (m), 6.5 (w), 6.05 (m), 5.77 (w), 5.64 (w), 5.44 (w), 5.19 (w), 4.89 (w), 4.76 (w), 4.70 (w), 4.41 (w), 4.25 (m), 4.00 (m), 3.88 (m), 3.80 (m), 3.59 (s), 3.50 (m), 3.44 (m), 3.37 (m), 3.26 (s), 3.19 (vs), 3.17 (s), 3.11 (m), 3.06 (m), 3.02 (m), 2.97 (vs), 2.93 (m), 2.89 (m), 2.83 (m), and 2.43 (m); or

for form D:

8.6 (s), 6.8 (w), 5.56 (m), 4.99 (m), 4.67 (s), 4.32 (m), 3.93 (vs), 3.88 (w), 3.64 (w), 3.41 (w), 3.25 (w), 3.17 (m), 3.05 (s), 2.94 (w), 2.92 (w), 2.88 (m), 2.85 (w), 2.80 (w), 2.79 (m), 2.68 (w), 2.65 (w), 2.52 (vw), 2.35 (w), 2.34 (w), 2.30 (w), and 2.29 (w); or

for form E:

15.4 (s), 6.6 (w), 6.5 (w), 5.95 (vw), 5.61 (vw), 5.48 (w), 5.24 (w), 4.87 (w), 4.50 (vw), 4.27 (w), 3.94 (w), 3.78 (w), 3.69 (m), 3.60 (w), 3.33 (s), 3.26 (vs), 3.16 (w), 3.08 (m), 2.98 (w), 2.95 (m), 2.91 (w), 2.87 (m), 2.79 (w), 2.74 (w), 2.69 (w), and 2.62 (w); or

for form H:

15.8 (vs), 10.3 (w), 8.0 (w), 6.6 (w), 6.07 (w), 4.81 (w), 4.30 (w), 3.87 (m), 3.60 (m), 3.27 (m), 3.21 (m), 3.13 (w), 3.05 (w), 2.96 (m), 2.89 (m), 2.82 (w), and 2.67 (m); or

for form O:

15.9 (w), 14.0 (w), 12.0 (w), 8.8 (m), 7.0 (w), 6.5 (w), 6.3 (m), 6.00 (w), 5.75 (w), 5.65 (m), 5.06 (m), 4.98 (m), 4.92 (m), 4.84 (w), 4.77 (w), 4.42 (w), 4.33 (w), 4.00 (m), 3.88 (m), 3.78 (w), 3.69 (s), 3.64 (s), 3.52 (vs), 3.49 (s), 3.46 (s), 3.42 (s), 3.32 (m), 3.27 (m), 3.23 (s), 3.18 (s), 3.15 (vs), 3.12 (m), 3.04 (vs), 2.95 (m), 2.81 (s), 2.72 (m), 2.67 (m), and 2.61 (m); or

for form G:

14.5 (vs), 10.9 (w), 9.8 (w), 7.0 (w), 6.3 (w), 5.74 (w), 5.24 (vw), 5.04 (vw), 4.79 (w), 4.41 (w), 4.02 (w), 3.86 (w), 3.77 (w), 3.69 (w), 3.63 (m), 3.57 (m), 3.49 (m), 3.41 (m), 3.26 (m), 3.17 (m), 3.07 (m), 2.97 (m), 2.95 (m), 2.87 (w), and 2.61 (w); or

for form I:

14.5 (m), 14.0 (w), 11.0 (w), 7.0 (vw), 6.9 (vw), 6.2 (vw), 5.30 (w), 4.79 (w), 4.44 (w), 4.29 (w), 4.20 (vw), 4.02 (w), 3.84 (w), 3.80 (w), 3.67 (vs), 3.61 (m), 3.56 (w), 3.44 (m), 3.27 (w), 3.19 (w), 3.11 (s), 3.00 (m), 2.94 (w), 2.87 (w), and 2.80 (w); or

for form L:

14.1 (vs), 10.4 (w), 9.5 (w), 9.0 (vw), 6.9 (w), 6.5 (w), 6.1 (w), 5.75 (w), 5.61 (w), 5.08 (w), 4.71 (w), 3.86 (w), 3.78 (w), 3.46 (m), 3.36 (m), 3.06 (w), 2.90 (w), and 2.82 (w); or

for form M:

18.9 (s), 6.4 (m), 6.06 (w), 5.66 (w), 5.28 (w), 4.50 (w), 4.23 (w), and 3.22 (vs); or

for form N:

19.5 (m), 9.9 (w), 6.7 (w), 5.15 (w), 4.83 (w), 3.91 (w), 3.56 (m), 3.33 (vs), 3.15 (w), 2.89 (w), 2.81 (w), 2.56 (w), and 2.36 (w).

3. A crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern

for form A as exhibited in FIG. 1 ; or

for form F as exhibited in FIG. 6 ; or

for form J as exhibited in FIG. 10 ; or

for form K as exhibited in FIG. 11 ; or

for form C as exhibited in FIG. 3 ; or

for form D as exhibited in FIG. 4 ; or

for form E as exhibited in FIG. 5 ; or

for form H as exhibited in FIG. 8 ; or

for form O as exhibited in FIG. 15 ; or

for form G as exhibited in FIG. 7 ; or

for form I as exhibited in FIG. 9 ; or

for form L as exhibited in FIG. 12 ; or

for form M as exhibited in FIG. 13 ; or

for form N as exhibited in FIG. 14 .

4. A pharmaceutical composition comprising a purified crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride according to claim 1 of at least about 98% purity by high performance liquid chromatography or a combination of more than one of the purified crystalline forms, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

5. A pharmaceutical composition according to claim 4 , further comprising folate, alone or together with arginine.

6. A pharmaceutical composition according to claim 5 , wherein the folate is folic acid or a tetrahydrofolate selected from tetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5-formyltetrahydrofolic acid or 5-methyltetrahydrofolic acid, or a polyglutamate thereof or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition according to claim 5 , wherein the folate is present as an optically pure diastereoisomer, a mixture of diastereoisomers, or a racemic mixture, and/or the pharmaceutically acceptable salt is a salt of sodium, potassium, calcium or ammonium.

8. A pharmaceutical composition according to claim 4 , wherein the crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is of at least about 98% purity by high performance liquid chromatography.

9. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2 ; and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

10. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w); and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

11. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2 ; and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

12. A pharmaceutical tablet comprising only one active ingredient, wherein said active ingredient consists essentially of purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs); or

which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w); or

which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2 ;

and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

13. A pharmaceutical tablet according to claim 12 , wherein the purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is of at least about 98% purity by high performance liquid chromatography.

14. A process for preparing a pharmaceutical tablet according to claim 9 comprising

(a) providing a purified crystalline polymorph of form B of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride of at least about 98% purity by high performance liquid chromatography, and

(b) mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.

15. A pharmaceutical tablet prepared by the process of claim 14 .

16. A pharmaceutical tablet according to claim 9 , further comprising folate alone or together with arginine.

17. A pharmaceutical tablet according to claim 9 , further comprising a lubricant, a vitamin and a sugar.

18. A pharmaceutical tablet according to claim 10 , further comprising a lubricant, a vitamin and a sugar.

19. A pharmaceutical tablet according to claim 11 , further comprising a lubricant, a vitamin and a sugar.

20. A pharmaceutical tablet according to claim 12 , further comprising a lubricant, a vitamin and a sugar.