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Details for Patent: 8,344,139

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Details for Patent: 8,344,139

Title:Process for preparing crystalline polymorphic forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride
Abstract: Crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, hydrates and solvates and processes for their preparation are provided. These crystal forms are either intermediates for the preparation of stable polymorphic form B or are suitable for solid formulations.
Inventor(s): Moser; Rudolf (Schaffhausen, CH), Groehn; Viola (Dachsen, CH), Egger; Thomas (Kempthal, CH), Blatter; Fritz (Reinach, CH)
Assignee: Merck Eprova AG (Schaffhausen, CH)
Filing Date:May 10, 2010
Application Number:12/776,551
Claims:1. A process for preparing 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 (.ANG.): 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 as exhibited in FIG. 1; 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 as exhibited in FIG. 6; or for form J, which is a crystalline polymorph: 14.6 (m), 3.29 (vs), and 3.21 (vs); or as exhibited in FIG. 10; 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 as exhibited in FIG. 11; 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 as exhibited in FIG. 3; 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 as exhibited in FIG. 4; 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 as exhibited in FIG. 5; 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 as exhibited in FIG. 8; 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 as exhibited in FIG. 15; 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 as exhibited in FIG. 7; 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 as exhibited in FIG. 9; or for form L, which is a crystalline mixed ethanol solvate/hydrate: 14.01 (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 as exhibited in FIG. 12; or for form M, which is a crystalline ethanol solvate: 18.9 (s), 6.4 (m), and 3.22 (vs); or as exhibited in FIG. 13; 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), or as exhibited in FIG. 14; for form A, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride at ambient temperatures in water, and (1) cooling the solution to a temperature sufficient to solidify the solution, and removing water under reduced pressure, or (2) removing water from said aqueous solution; or for form F, comprising dispersing particles of solid form A of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, which is methanol, ethanol, propanol or isopropanol, below room temperature, stirring the suspension for a time sufficient to produce polymorph form F; or for form J, comprising preparing form E and removing the water from form E by treating form E in a vacuum drier at a moderate temperature of about 25 to 70.degree. C.; or for form K, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and an alcohol containing water and ascorbic acid forming a solvent mixture, lowering the temperature to crystallise the dihydrochloride, thereby forming a precipitate, isolating the precipitate and drying the isolated precipitate optionally under vacuum; or for form C, comprising suspending (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a non-solvent, adding sufficient water to allow the formation of a monohydrate by stirring the suspension at or below ambient tempterature to form a monohydrate; or for form D, comprising adding at about room temperature a concentrated aqueous solutions of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to a non-solvent and stifling the resultant suspension at an ambient temperature; or for form E, comprising adding a concentrated aqueous solution of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to an excess of a non-solvent, determined by volume, cooled to a temperature of about 10 to -10.degree. C. and stifling the suspension at said temperature; or for form H, comprising dissolving at ambient temperatures (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and a less amount than that of acetic acid of water, determined by weight, adding a non-solvent, cooling the obtained suspension to a temperature of -10 to 10.degree. C., and stirring the suspension at said temperature; or for form O, comprising exposing polymorphic form F to a nitrogen atmosphere containing water vapour with a resulting relative humidity of about 52% for about 24 hours; or for form G, comprising dissolving at about room temperature to a temperature of 75.degree. C. (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water or in a mixture of water and ethanol, if the temperature is above room temperature, then first cooling the resultant heated solution to room temperature, and then down to 5 to 10.degree. C., adding optionally ethanol to complete precipitation, stirring the obtained suspension at a temperature of 20 to 5.degree. C., filtering off a white, crystalline solid and drying the solid under air or a protection gas or nitrogen at about room temperature; or for form I, comprising dissolving 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.degree. C., then warming up the formed suspension to about 15.degree. C., and then stirring the obtained suspension for a time sufficient for phase equilibration; or for form L, comprising suspending hydrate form E at room temperature in ethanol and stirring the suspension at a temperature of 0 to 10.degree. C. for a time sufficient for phase equilibration; or for form M, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in ethanol and evaporating the solution under nitrogen at ambient temperature or drying of form G under a flow of dry nitrogen at a rate of about 20 to 100 ml/min; or for form N, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of isopropanol and water, adding isopropanol, cooling the resulting suspension to about 0.degree. 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.

2. A process according to claim 1, wherein the crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.) 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 process according to claim 1, wherein the crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride 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. The process of claim 1, further comprising isolating crystalline form A, form F, form J, form C, form D, form E, form H, form O, form G, form I, form L, form M, or form N.

5. The process of claim 1, wherein for form F, the temperature below room temperature is down to 0.degree. C.; for form F, the non-aqueous solvent is methanol, ethanol, propanol or isopropanol; for form K, the amount of water in the final composition is 0.5 to 5 percent by weight based on the solvent mixture and the amount of ascorbic acid is 0.01 to 0.5 percent by weight based on the solvent mixture; for form K, the (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is dissolved at a temperature of 30.degree. C. to 100.degree. C., and the precipitate is dried at a temperature of 30.degree. C. to 50.degree. C.; for form C, D, E or H, the non-solvent is heptane, hexane, dichloromethane, acetone, methanol, ethanol, 1- or 2-propanol, ethyl acetate, acetonitrile, acetic acid, terahydrofuran, dioxane, tertiary-butyl methyl ether, or a binary or ternary mixture thereof; and/or for form C, the temperature for stirring the suspension is 0.degree. C. to 30.degree. C.

6. The process of claim 1, wherein for form K, the amount of water in the final composition is 0.5 to 5 percent by weight based on the solvent mixture and the amount of ascorbic acid is 0.01 to 0.5 percent by weight based on the solvent mixture.

7. The process of claim 1, wherein the solvent is methanol, or ethanol.

8. A process for preparing a crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin 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); or which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.): 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); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; the process comprising A) dispersing a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in methanol, ethanol, propanol or isopropanol, and stifling the obtained suspension; or B) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, cooling the solution, and optionally seeding the solution with a nucleating agent; or C) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, combining the obtained solution with a non-solvent thereby forming a suspension, and optionally stifling and/or cooling and/or seeding with a nucleating agent the solution; and thereafter isolating the formed crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride.

9. A process according to claim 8, wherein in C), the solvent is water.

10. A process according to claim 8, wherein the solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is amorphous.

11. A process according to claim 8, wherein the solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is 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 (.ANG.): 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).

12. A process for preparing a crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin 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); or which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.): 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); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; the process comprising A) dispersing a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent and stirring the obtained suspension; or B) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, cooling the solution, and optionally seeding the solution with a nucleating agent; or C) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, combining the obtained solution with a non-solvent thereby forming a suspension, and optionally stirring and/or cooling and/or seeding with a nucleating agent the solution; and thereafter isolating the formed crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, wherein in A), the solvent is selected from methanol, ethanol, C3 and C4 alcohols, acetic acid, acetonitrile, tetrahydrofuran, methyl-t-butyl ether, 1,4-dioxane, C3-C6 acetates, methyl ethyl ketone, methyl C3-05 alkyl ketones, and combinations thereof; or in B), the dissolving step is performed at a temperature of about 20.degree. Celsius to about 70.degree. Celsius; and/or the cooling step is performed at a temperature of about -40.degree. Celsius to about 0.degree. Celsius; and/or the suspension contains less than about 5% of water by weight based on the total weight of the suspension; and/or the solvent comprises a mixture of water, acetic acid, and tetrahydrofuran; and/or the solvent is a mixture by volume of water to acetic acid to tetrahydrofuran at a ratio of between 1:3:2 to 1:9:4; or in C), the cooling step is performed at a temperature of about -40.degree. Celsius to about 0.degree. Celsius; and/or the dissolving step is performed at a temperature of about 10.degree. Celsius to about 40.degree. Celsius; and/or the non-solvent is methanol, ethanol, acetic acid, or a combination thereof; and/or the concentration of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in the solvent is about 10% to about 80% by weight.

13. A process according to claim 12, wherein in B) the solvent is a mixture by volume of water to acetic acid to tetrahydrofuran of about 1:5:4; or in C), the dissolving step is performed at a temperature of about 23.degree. Celsius; and/or the concentration of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in the solvent is about 20% to about 60% by weight.

14. A process for preparing a pharmaceutical composition comprising preparing a crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride of form B 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); or which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (.ANG.): 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); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; the process comprising A) dispersing a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in methanol, ethanol, propanol or isopropanol, and stifling the obtained suspension; or B) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, cooling the solution, and optionally seeding the solution with a nucleating agent; or C) dissolving a solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, combining the obtained solution with a non-solvent thereby forming a suspension, and optionally stifling and/or cooling and/or seeding with a nucleating agent the solution; and thereafter isolating the formed crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride of form B, and mixing said crystalline polymorph with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

15. The process of claim 8, wherein the cooling is down to a temperature of -40.degree. C. to 0.degree. C. or to a temperature of 10.degree. C. to 30.degree. C.

16. The process of claim 8, wherein the solvent is methanol, or ethanol.

17. A process according to claim 16, wherein the solid form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is 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 (.ANG.) : 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).

18. A process for preparing 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 (.ANG.): 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 as exhibited in FIG. 1; 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 as exhibited in FIG. 6; or for form J, which is a crystalline polymorph: 14.6 (m), 3.29 (vs), and 3.21 (vs); or as exhibited in FIG. 10; 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 as exhibited in FIG. 11; 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 as exhibited in FIG. 3; 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 as exhibited in FIG. 4; 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 as exhibited in FIG. 5; 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 as exhibited in FIG. 8; 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 as exhibited in FIG. 15; 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 as exhibited in FIG. 7; 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 as exhibited in FIG. 9; 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 as exhibited in FIG. 12; or for form M, which is a crystalline ethanol solvate: 18.9 (s), 6.4 (m), and 3.22 (vs); or as exhibited in FIG. 13; 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), or as exhibited in FIG. 14; for form A, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride at ambient temperatures in water, and (1) cooling the solution to a temperature sufficient to solidify the solution, and removing water under reduced pressure, or (2) removing water from said aqueous solution; or for form F, comprising dispersing particles of solid form A of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, which is methanol, ethanol, propanol or isopropanol, below room temperature, stirring the suspension to produce polymorph form F; or for form J, comprising preparing form E and removing the water from form E by treating form E in a vacuum drier at a moderate temperature of about 25 to 70.degree. C.; or for form K, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and an alcohol containing a 0.5 to 5 percent by weight of water and 0.01 to 0.5 percent by weight of ascorbic acid forming a solvent mixture, lowering the temperature to crystallise the dihydrochloride thereby forming a precipitate, isolating the precipitate and drying the isolated precipitate optionally under vacuum; or for form C, comprising suspending (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a non-solvent, adding 1 to 10 percent by weight of water to allow the formation of a monohydrate by stirring the suspension at or below ambient temperature to form a monohydrate; or for form D, comprising adding at about room temperature a concentrated aqueous solutions of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to a non-solvent and stifling the resultant suspension at an ambient temperature of 20 to 30.degree. C.; or for form E, comprising adding a concentrated aqueous solution of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to an excess of a non-solvent, determined by volume, cooled to a temperature of about 10 to -10.degree. C. and stifling the suspension at said temperature; or for form H, comprising dissolving at ambient temperatures (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and a less amount than that of acetic acid of water, determined by weight, adding a non-solvent, cooling the obtained suspension to a temperature of -10 to 10.degree. C., and stirring the suspension at said temperature; or for form O, comprising exposing polymorphic form F to a nitrogen atmosphere containing water vapour with a resulting relative humidity of about 52% for about 24 hours; or for form G, comprising dissolving at about room temperature to a temperature of 75.degree. C. (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water or in a mixture of water and ethanol, if the temperature is above room temperature, then first cooling the resultant heated solution to room temperature, and then down to 5 to 10.degree. C., adding optionally ethanol to complete precipitation, stirring the obtained suspension at a temperature of 20 to 5.degree. C., filtering off a white, crystalline solid and drying the solid under air or a protection gas or nitrogen at about room temperature; or for form I, comprising dissolving 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.degree. C., then warming up the formed suspension to about 15.degree. C., and then stirring the obtained suspension for a time sufficient for phase equilibration; or for form L, comprising suspending hydrate form E at room temperature in ethanol and stirring the suspension at a temperature of 0 to 10.degree. C. for a time sufficient for phase equilibration; or for form M, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in ethanol and evaporating the solution under nitrogen at ambient temperature or drying of form G under a flow of dry nitrogen at a rate of about 20 to 100 ml/min; or for form N, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of isopropanol and water, adding isopropanol, cooling the resulting suspension to about 0.degree. 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.

19. A process according to claim 8, wherein the nucleating agent is polymorph form B from another batch or crystals having identical morphology to crystalline form B.
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