Process for controlling crystal structure of risedronate
View Patent ↗The present invention relates to a process for controlling the crystal form of 3-pyridyl-1-hydroxy-ethylidene-1,1-bisphosphonic acid salt (Risedronate). The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
1. A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid and an inorganic base in sufficient amount to provide a pH of 6, to form a solution;
b) heating the solution from about 50° C. to about 60° C. to form a heated solution;
c) filtering said heated solution to form a filtered solution;
d) adjusting the pH of said filtered solution with an inorganic acid to a pH range of from 4.7 to 5 while maintaining the temperature at the level oblained in step (b) to form a neutralized solution;
e) cooling the neutralized solution to a temperature of about 20° C. to about 40° C. to form a nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt;
f) adding to said slurry isopropyl alcohol and sufficient inorganic acid to provide a pH of from 4.7 to 5.2 to form a ripened slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form; and
g) isolating 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate.
2. A process according to claim 1 wherein the ratio of isopropyl alcohol to water in step (a) is 1:6.7.
3. A process according to claim 1 wherein rhc ratio of isopropyl alcohol to water in step (a) is from 1:5.9 to 1:9.1.
4. A process according to claim 1 wherein said inorganic base is step (a) is selected from the group consisting of NaOH, NaOCH 3 , and NaOC(O)CH 3 .
5. A process according to claim 4 wherein said inorganic base is NaOH.
6. A process according to claim 1 wherein said temperature in step (b) is from 52° C. to 58° C.
7. A process according to claim 6 wherein said temperature is 55° C.
8. A process according to claim 1 wherein said filtered solution formed in step (c) has the same temperature as the heated solution formed in step (b).
9. A process according to claim 1 wherein said inorganic acid in step (d) is selected from the group consisting of HCl, H 2 SO 4 , and H 3 PO 4 .
10. A process according to claim 9 wherein said inorganic acid is HCl.
11. A process according to claim 1 wherein said temperature in step (e) is from 20° C. to 40° C.
12. A process according to claim 11 wherein said temperature is from 20° C. to 30° C.
13. A process according to claim 12 wherein said temperature is 25° C.
14. A process according to claim 1 wherein said inorganic acid in step (f) is selected from the group consisting of HCl, H 2 SO 4, and H 3 PO 4 .
15. A process according to claim 14 wherein said inorganic acid is HCl.
16. A process according to claim 1 wherein said isopropyl alcohol and inorganic acid used to form said ripened slurry in step (f) is added as an admixture.
17. A process according to claim 1 wherein said isopropyl alcohol added in step (f) is added separately from said and inorganic acid.
18. A process according to claim 17 wherein said isopropyl alcohol and said inorganic acid are added separately but concurrently.
19. A process according to claim 17 wherein said isopropyl alcohol and said inorganic arid are added in alternating portions.
20. A process according to claim 1 wherein said product isolated in step (g) is isolated by filtration.
21. A process according to claim 1 wherein said product isolated in step (g) is isolated by decanting the solvent.
22. A process according to claim 1 wherein said product isolated in step (g) is isolated by centrifugation.
23. A process according to claim 1 having the optional step (c) (i), said step comprising:
c) (i) adding to said filtered solution 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate seed crystals.
24. A process according to claim 1 wherein said product formed in step (f) is in the platelet crystal form.
25. A process according to claim 1 wherein when said nucleating slurry formed in step (e) comprises an admixture of monahydrate and hemipentahydrate crystal forms, said process having further
c) (i) holding said nucleating slurry to a temperature from about 20° C. to about 30°C. and holding said slurry at said temperature until said monohydrate form is converted to said hemipentahydrate form;
e) (ii) repeating step (e).
26. A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and an inorganic base in sufficient amount to provide a pH of 6, to form a solution;
b) heating the solution from about 50° C. to about 60° C. to form a heated solution;
c) filtering said heated solution to form a filtered solution;
d) adjusting the pH of said filtered solution with an inorganic acid to a pH range of from 4.7 to 5 while maintaining the temperature at the level obtained in step (b) to form a neutralized solution;
e) cooling the neutralized solution to a temperature of about 20° C. to about 40° C. to form a nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt; and
f) isolating 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate.
27. A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid arid NaOH in sufficient amount to provide a pH of 6, to form a solution;
b) heating the solution to 55° C. to form a heated solution;
c) filtering said heated solution to form a filtered solution, while maintaining a temperature of 55° C.;
d) adjusting the pH of said filtered solution with HCl to a pH range of from 4.7 to 5, while maintaining a temperature of 55° C., to form a neutralized solution;
e) cooling the neutralized solution to 25° C. to form nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt; and
f) adding to said slurry isopropyl alcohol and sufficient HCl to provide a pH of from 4.7 to 5.2 to form a ripened slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form.