CA2545968A1 - Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride - Google Patents
Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, hydrates and solvates and processes for their preparation are provided. These crystal forms are either intermedi~ates for the preparation of stable polymorphic form B or are suitable for solid formulations.
Claims (64)
1. A crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhi-bits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
15.5 (vs), 12.0 (m), 4.89 (m), 3.70 (s), 3.33 (s), 3.26 (s), and 3.18 (m);
hereinafter designated as form A.
15.5 (vs), 12.0 (m), 4.89 (m), 3.70 (s), 3.33 (s), 3.26 (s), and 3.18 (m);
hereinafter designated as form A.
2. A crystalline polymorph according to claim 1, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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),
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).
3. A crystalline polymorph according to claim 1, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 1.
3. A crystalline polymorph according to claim 1, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 1.
4. A process for the preparation of polymorph form A according to claims 1, 2 or 3, compri-sing dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride at ambient temperatures in water, (1 ) cooling the solution to low temperatures for solidifying the solution, and removing water under reduced pressure, or (2) removing water from said aqueous solution.
5. A process for the preparation of a crystalline polymorph of (6R)-L-erythro-tetrahydrobio-pterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs), preferably 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), 2.44 (w); and which more preferably exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 2, and hereinafter designated as form B;
comprising dispersion of particles of a solid form other than form B of (6R)-L-erythro-tetra-hydrobiopterin dihydrochloride in a solvent that scarcely dissolves said (6R)-L-erythro-tet-rahydrobiopterin dihydrochloride at room temperature, stirring the suspension at ambient temperatures for a time sufficient to produce polymorh form B, thereafter isolating crystalline form B and removing the solvent from the isolated form B.
8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs), preferably 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), 2.44 (w); and which more preferably exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 2, and hereinafter designated as form B;
comprising dispersion of particles of a solid form other than form B of (6R)-L-erythro-tetra-hydrobiopterin dihydrochloride in a solvent that scarcely dissolves said (6R)-L-erythro-tet-rahydrobiopterin dihydrochloride at room temperature, stirring the suspension at ambient temperatures for a time sufficient to produce polymorh form B, thereafter isolating crystalline form B and removing the solvent from the isolated form B.
6. A process for the preparation of polymorph form B as defined according to claim 5, com-prising dissolution, optionally at elevated temperatures, of a solid form, preferably other than form B, of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent mixture comprising acetone, acetic acid and water, addition of seeds to the solution, cooling the obtained sus-pension and isolation of the formed crystals of form B.
7. A process for the preparation of polymorph form B according to claim 5, comprising dis-solution of a solid form, preferably other than form B, of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water at ambient temperatures, adding the aqueous solution to sufficient amount of a non-solvent to form a suspension, optionally stirring the suspension for a certain time, and thereafter isolation of the formed crystals.
8. A crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhi-bits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form F.
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), hereinafter designated as form F.
9. A crystalline polymorph according to claim 8, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form F.
10. A crystalline polymorph F according to claim 8, which exhibits a characteristic X-ray pow-der diffraction pattern as exhibited in Figure 6.
11. A process for the preparation of polymorph form F according to claims 8, 9 or 10, com-prising dispersion of particles of solid form A of (6R)-L-erythro-tetrahydrobiopterin dihydro-chloride in a non-aqueous solvent that scarcely dissolves said (6R)-L-erythro-tetrahydrobio-pterin dihydrochloride below room temperature, stirring the suspension at said temperatures for a time sufficient to produce polymorph form F, thereafter isolating crystalline form F and removing the solvent from the isolated form F.
12. A crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhi-bits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
14.6 (m), 3.29 (vs), and 3.21 (vs), hereinafter designated as form J.
14.6 (m), 3.29 (vs), and 3.21 (vs), hereinafter designated as form J.
13. A crystalline polymorph according to claim 12, which exhibits a characteristic X-ray pow-der diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
14.6 (m), 6.6 (w), 6.4 (w), 5.47 (w), 4.84 (w), 3.29 (vs), and 3.21 (vs), hereinafter designated as form J.
14. In A crystalline polymorph according to claim 12, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 10.
14. In A crystalline polymorph according to claim 12, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 10.
15. A process for the preparation of polymorph form J according to claims 12, 13 or 14, com-prising preparation of form E and removing the water from form E by treating form E in a va-cuum drier at moderate temperatures, preferably at a temperature in the range of 25 to 70 °C.
16. A crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhi-bits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form K.
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), hereinafter designated as form K.
17. A crystalline polymorph according to claim 16, which exhibits a characteristic X-ray pow-der diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form K.
18. A crystalline polymorph according to claim 16, which exhibits a characteristic X-ray pow-der diffraction pattern as exhibited in Figure 11.
19. A process for the preparation of polymorph form K according to claims 16, 17 or 18, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of ace-tic acid and an alcohol containing small amounts of water and a small amount of ascorbic acid at elevated temperatures, lowering temperature to crystallise said dihydrochloride, iso-lating the precipitate and drying the isolated precipitate at elevated temperature optionally under vacuum.
20. A crystalline hydrate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-va-lues (.ANG.):
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), hereinafter designated as form C.
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), hereinafter designated as form C.
21. A crystalline hydrate according to claim 20, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form C.
22. A crystalline hydrate according to claim 20, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 3
23. A process for the preparation of hydrate form C according to claims 20, 21 or 22, compri-sing suspending (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a non-solvent, adding sufficient water to form a monohydrate, and stirring the suspension at or below ambient tem-peratures, preferably 0 to 30 °C, for a time sufficient to form a monohydrate.
24. A crystalline hydrate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form D.
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), hereinafter designated as form D.
25. A crystalline hydrate according to claim 24, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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) hereinafter designated as 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) hereinafter designated as form D.
26. A crystalline hydrate according to claim 24, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 4.
27. A process for the preparation of hydrate form D according to claims 24, 25 or 26, compri-sing adding at about room temperature a concentrated aqueous solutions of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to an excess of a non-solvent and stirring the suspension at ambient temperatures.
28. A crystalline hydrate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-va-lues (.ANG.):
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), hereinafter designated as form E.
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), hereinafter designated as form E.
29. A crystalline hydrate E according to claim 28, which exhibits a characteristic X-ray pow-der diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form E.
30. A crystalline hydrate E according to claim 28, which exhibits a characteristic X-ray pow-der diffraction pattern as exhibited in Figure 5.
31. A process for the preparation of hydrate form E according to claims 28, 29 or 30, which comprises adding concentrated aqueous solutions of (6R)-L-erythro-tetrahydrobiopterin di-hydrochloride to an excess of a non-solvent cooled to temperatures from about 10 to -10 °C
and stirring the suspension at said temperatures.
and stirring the suspension at said temperatures.
32. A crystalline hydrate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form H.
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), hereinafter designated as form H.
33. A crystalline hydrate of according to claim 32, which exhibits a characteristic X-ray pow-der diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form H.
34. A crystalline hydrate of according to claim 32, which exhibits a characteristic X-ray pow-der diffraction pattern as exhibited in Figure 8.
35. A process for the preparation of hydrate form H of (6R)-L-erythro-tetrahydrobiopterin di-hydrochloride, comprising dissolving at ambient temperatures (6R)-L-erythro-tetrahydrobio-pterin dihydrochloride in a mixture of acetic acid and a less amount than that of acetic acid of water, adding a non-solvent, cooling the obtained suspension to temperatures in the range of -10 to 10 °C, and stirring the suspension at said temperature for a certain time.
36. A crystalline hydrate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-va-lues (.ANG.):
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), hereinafter designated as form O.
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), hereinafter designated as form O.
37. A crystalline hydrate according to claim 36, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form O.
38. A crystalline hydrate according to claim 36, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 15.
39. A process for the preparation of a crystalline hydrate O according to claims 36, 37 or 38, which comprises to expose polymorphic form F to a nitrogen atmosphere containing water vapour with a resulting relative humidity of about 52% for about 24 hours.
40. A crystalline ethanol solvate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form G.
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), hereinafter designated as form G.
41. A crystalline solvate according to claim 40, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form G.
42. A crystalline solvate G according to claim 40, which exhibits a characteristic X-ray pow-der diffraction pattern as exhibited in Figure 7.
43. A process for the preparation of an ethanol solvate form G according to claims 40, 41 or 42, comprising dissolving at about room temperature to temperatures of 75 °C (6R)-L-ery-thro-tetrahydrobiopterin dihydrochloride in water or in a mixture of water and ethanol, cooling a heated solution to room temperature and then down to 5 to 10 °C, adding optionally etha-nol to complete precipitation, stirring the obtained suspension at temperatures of 20 to 5 °C, filtering off the white, crystalline solid and drying the solid under air or a protection gas such as nitrogen at temperatures about room temperature.
44. A crystalline acetic acid solvate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
14.5 (m), 3.67 (vs), 3.61 (m), 3.44 (m), 3.11 (s), and 3.00 (m), hereinafter designated as form I.
14.5 (m), 3.67 (vs), 3.61 (m), 3.44 (m), 3.11 (s), and 3.00 (m), hereinafter designated as form I.
45. A crystalline acetic acid solvate according to claim 44, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form I.
46. A crystalline acetic acid solvate according to claim 44, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 9.
47. A process for the preparation of a crystalline acetic acid solvate according to claims 44, 45 or 46, which comprises dissolution of L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and water at elevated temperature, adding further acetic acid to the solution, cooling down to a temperature of about 10 °C, then warming up the formed sus-pension to about 15 °C, and then stirring the obtained suspension for a time sufficient for phase equilibration.
48. A crystalline mixed ethanol solvate / hydrate of (6R)-L-erythro-tetrahydrobiopterin dihy-drochloride, which exhibits a characteristic X-ray powder diffraction pattern with characte-ristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as form L.
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), hereinafter designated as form L.
49. A crystalline mixed ethanol solvate / hydrate according to claim 48, which exhibits a cha-racteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form L.
50. A crystalline mixed ethanol solvate / hydrate form L according to claim 48, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 12.
51. A process for the preparation of a mixed ethanol solvate / hydrate L
according to claims 48, 49 or 50, which comprises suspending hydrate form E according to claim 28 at room temperature in ethanol and stirring the suspension at temperatures from 0 to 10 °C for a ti-me sufficient for phase equilibration.
according to claims 48, 49 or 50, which comprises suspending hydrate form E according to claim 28 at room temperature in ethanol and stirring the suspension at temperatures from 0 to 10 °C for a ti-me sufficient for phase equilibration.
52. A crystalline ethanol solvate of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
18.9 (s), 6.4 (m), and 3.22 (vs), hereinafter designated as form M.
18.9 (s), 6.4 (m), and 3.22 (vs), hereinafter designated as form M.
53. A crystalline ethanol solvate according to claim 52, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form M.
54. A crystalline ethanol solvate form M according to claim 52, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 13.
55. A process for the preparation of a solvate form M according to claims 52, 53 or 54, which comprises dissolution of L-erythro-tetrahydrobiopterin dihydrochloride in ethanol and evapo-ration of the solution under nitrogen at ambient temperature or drying of form G according to claim 40 under a slight flow of dry nitrogen at a rate of about 20 to 100 ml/min.
56. A crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhi-bits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
19.5 (m), 6.7 (w), 3.56 (m), and 3.33 (vs), 3.15 (w), hereinafter designated as form N.
19.5 (m), 6.7 (w), 3.56 (m), and 3.33 (vs), 3.15 (w), hereinafter designated as form N.
57. A crystalline polymorph according to claim 56, which exhibits a characteristic X-ray pow-der diffraction pattern with characteristic peaks expressed in d-values (.ANG.):
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), hereinafter designated as 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), hereinafter designated as form N.
58. A crystalline polymorph N according to claim 56, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in Figure 14.
59. A process for the preparation of a solvate form N according to claims 56, 57 or 58, which comprises dissolution of L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of isopro-panol and water, slowly adding isopropanol, cooling the resulting suspension to 0°C, stirring for several hours at this temperature, filtering the suspension, washing the solid residue with isopropanol at room temperature and drying the obtained crystalline material at ambient temperature and reduced pressure for several hours.
60. A pharmaceutical composition comprising solid crystal forms of (6R)-L-erythro-tetrahy-drobiopterin dihydrochloride selected from the group consisting of forms A, B, D, E, F, J, K, L
and O or a combination thereof, and a pharmaceutically acceptable carrier or diluent.
and O or a combination thereof, and a pharmaceutically acceptable carrier or diluent.
61. A composition according to claim 60, comprising additionally a folate, alone or together with arginine.
62. A composition according to claim 61, whereas as folate folic acid, or tetrahydrofolates, selected from tetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5-formyltetrahydrofolic acid or 5-methyltetrahydrofolic acid, their polyglutamates, their optically pure diastereoisomers, mixtures of diastereoisomers, especially the racemic mixture, pharmaceutically acceptable salts such as sodium, potassium, calcium or ammonium salts, each alone, or in combination with an other folate or additionally with arginine is used.
63. A method of delivering crystal forms A, B, D, E, F, J, K, L and O of (6R)-L-erythro-tetra-hydrobiopterin dihydrochloride to a host, comprising administering to a host an effective amount of a crystal forms A, B, D, E, F, J, K, L and O.
64. Use of polymorph crystal forms A, B, D, E, F, J, K, L and O of (6R)-L-erythro-tetrahydro-biopterin dihydrochloride for the manufacture of a medicament useful in the treatment of neurological disorders.
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CA2678165A CA2678165C (en) | 2003-11-17 | 2004-11-17 | Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride |
CA2678124A CA2678124C (en) | 2003-11-17 | 2004-11-17 | Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride |
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CA2678165A Division CA2678165C (en) | 2003-11-17 | 2004-11-17 | Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride |
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CA2678125C (en) * | 2003-11-17 | 2014-10-14 | Merck Eprova Ag | Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride |
PL3138566T3 (en) | 2003-11-17 | 2022-03-07 | Biomarin Pharmaceutical Inc. | Treatment of phenylketonuria with bh4 |
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KR102561697B1 (en) | 2016-11-29 | 2023-07-28 | 피티씨 테라퓨틱스 엠피, 인크. | Polymorphs of sepiapterin and salts thereof |
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JP2021525729A (en) | 2018-05-30 | 2021-09-27 | ピーティーシー セラピューティクス エムピー,インコーポレイテッド | Sepiapterin Methods for Increasing Plasma Exposure |
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EP1687308B1 (en) | 2019-06-12 |
CA2678125C (en) | 2014-10-14 |
CN1894251B (en) | 2011-06-29 |
CA2678124A1 (en) | 2005-07-21 |
AU2004311544A1 (en) | 2005-07-21 |
US20060035900A1 (en) | 2006-02-16 |
WO2005065018A3 (en) | 2005-10-20 |
CA2678165C (en) | 2013-11-05 |
ES2755334T3 (en) | 2020-04-22 |
CA2678125A1 (en) | 2005-07-21 |
CA2678124C (en) | 2014-10-07 |
CN1894251A (en) | 2007-01-10 |
CA2678165A1 (en) | 2005-07-21 |
EP1687308A2 (en) | 2006-08-09 |
US7727987B2 (en) | 2010-06-01 |
JP2011162568A (en) | 2011-08-25 |
US20100099685A1 (en) | 2010-04-22 |
RU2006121341A (en) | 2008-01-10 |
JP2007536210A (en) | 2007-12-13 |
RU2434870C2 (en) | 2011-11-27 |
WO2005065018A2 (en) | 2005-07-21 |
HK1103294A1 (en) | 2007-12-14 |
US8318745B2 (en) | 2012-11-27 |
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US20100240667A1 (en) | 2010-09-23 |
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