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at 60℃; under 600.0 Torr; for 16h;Product distribution / selectivity;
EXAMPLE 2 Conversion of Trihydrate to Monohydrate by Drying 1 g of zoledronic acid trihydrate was taken in a clean Petri dish. The compound was then dried in a vacuum oven at 60 C. under a vacuum of 600 mm Hg for 16 hours to obtain zoledronic acid monohydrate.
In water; acetone; at 28 - 99℃; for 3.66667h;Product distribution / selectivity;
30 ml of water was placed into a round bottom flask along with 1 g of zoledronic acid trihydrate. The mixture was stirred for about 10 minutes at 28 C. followed by heating to 99 C. and was maintained at 99 C. for another 30 minutes. The mixture was then allowed to cool by radiation to 57 C. At this temperature, 10 ml of acetone was added to precipitate the product. The mixture was then stirred until it had cooled to 28 C. The mass was maintained at 28 C. for 3 hours. The separated solid was then filtered under a vacuum of 600 mm Hg. The solid was suction dried for 45 minutes and finally dried under vacuum of 600 mm Hg at 60 C. for about 3 hours to afford the crystalline monohydrate of zoledronic acid.
In methanol; water; at 28 - 99℃; for 0.416667 - 0.583333h;Product distribution / selectivity;
EXAMPLE 4 Conversion of Trihydrate to Monohydrate Using Solvent-Antisolvent Technique 30 ml of water was placed into a round bottomed flask along with 1 g of zoledronic acid trihydrate. The mixture was stirred for about 10 to 20 minutes at 28 C. followed by heating to 99 C. and was maintained at 99 C. for another 15 minutes. The mass was then allowed to cool by radiation to 67 C. At this temperature 10 ml of methanol was added to precipitate the product, and the mass was then stirred until it had cooled to 28 C. The separated solid was filtered under vacuum and was washed with 10 ml of water. The solid was than suction dried under a vacuum of 600 mm Hg for 30 minutes at 28 C. and finally dried at 59 C. under a vacuum of 600 mm Hg for 12 hours to afford the crystalline monohydrate of zoledronic acid.
In acetone; at 28℃; for 0.5h;Product distribution / selectivity;
5 ml of acetone was placed into a round bottom flask along with 0.5 g of zoledronic acid trihydrate. The mixture was then stirred at 28 C. for 30 minutes. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at 28 C. to give the monohydrate of zoledronic acid.
at 60℃; under 600.0 Torr; for 16h;drying in a vacuum;Product distribution / selectivity;
EXAMPLE 2; CONVERSION OF MIXTURE OF TRIHYDRATE AND MONOHYDRATE TO MONOHYDRATE BY DRYING 1 g of zoledronic acid trihydrate was taken in a clean Petri dish. The compound was then dried in a vacuum oven at 60 C under a vacuum of 600 mm Hg for 16 hours to obtain zoledronic acid monohydrate.
EXAMPLE 4; CONVERSION OF TRIHYDRATE TO MONOHYDRATE USING SOLVENT- ANTISOLVENT TECHNIQUE30 ml of water was placed into a round bottomed flask along with 1g of zoledronic acid trihydrate The mixture was stirred for about 10 to 20 minutes at EPO <DP n="17"/>28 C followed by heating to 99 C and was maintained at 99 C for another 15 minutes. The mass was then allowed to cool by radiation to 67 C. At this temperature 10 ml of methanol was added to precipitate the product, and the mass was then stirred until it had cooled to 28 C. The separated solid was filtered under vacuum and was washed with 10 ml of water. The solid was than suction dried under a vacuum of 600 mm Hg for 30 minutes at 28 C and finally dried at 59 C under a vacuum of 600 mm Hg for 12 hours to afford the crystalline monohydrate of zoledronic acid.
EXAMPLE 5; CONVERSION OF TRIHYDRATE TO MONOHYDRATE USING SOLVENT- ANTISOLVENT TECHNIQUE30 ml of water was placed into a round bottom flask along with 1 g of zoledronic acid trihydrate The mixture was stirred for about 10 minutes at 28 C followed by heating to 99 C and was maintained at 99 C for another 30 minutes. The mixture was then allowed to cool by radiation to 57 C. At this temperature, 10 ml of acetone was added to precipitate the product. The mixture was then stirred until it had cooled to 28 C. The mass was maintained at 28 C for 3 hours. The separated solid was then filtered under a vacuum of 600 mm Hg. The solid was suction dried for 45 minutes and finally dried under vacuum of 600 mm Hg at 60 C for about 3 hours to afford the crystalline monohydrate of zoledronic acid.
In acetone; at 28℃; for 0.5h;Product distribution / selectivity;
EXAMPLE 3; CONVERSION OF A MIXTURE OF MONOHYDRATE AND TRIHYDRATE TQ MONOHYDRATE BY SLURRYING5 ml of acetone was placed into a round bottom flask along with 0.5 g of zoledronic acid trihydrate. The mixture was then stirred at 28 C for 30 minutes. The mixture was filtered under a vacuum of 600 mm Hg and the solid was finally dried under vacuum at 28 C to give the monohydrate of zoledronic acid.
Example 3 - Zoledronic Acid Monohydrate; The raw humid zoledronic acid (equivalent to 90.3 g raw product), obtained according to Example 1, is suspended in water (3050 ml). The suspension is heated at reflux, with agitation. EPO <DP n="9"/>Water is added up to a total volume of 3750 ml, by which a total dissolution is obtained.The heating is then interrupted and the agitation, allowing it to slowly cool down to ambient temperature.Once the inside temperature is around 70 - 800C a frank crystallization starts.Once the ambient temperature is reached, it is cooled down to 2 - 5 0C, maintained at that temperature during 1 'Lambda hours, filtered and the precipitate is washed with ice water.It is dried in a stove with air flow at 5C - 60 0C.169.3 g (89 %) colorless crystals are obtained.The loss through dissection (6.8%) confirms that this is a monohydrate.This substance, by diffraction with X-rays, dust method, presents peaks at the following values of 20 12.1; 12.8; 15.7; 18.9 +/- 0.2, coincident with those described for the form I (US 2005/0054616).Figure I A shows its diffractogram of dust X-rays and figure IV A the lay-out of the atoms in the unitary cell of the crystalline network for this form.
With water; In ethanol; at 60℃; for 2h;
Example 5: Process for Making the Crystalline Form of the Monohydrate of the Free Acid of Zoledronic Acid About 300 mg of the anhydrous form of zoledronic acid is suspended in about 1 mL of 96% ethanol. The suspension is equilibrated for about 2 hours at about 60C. The solid precipitate is then isolated by filtration.
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