STABILIZED 1,25-DIHYDROXYVITAMIN D2 AND METHOD OF MAKING SAME
A stabilized 1,25-dihydroxyvitamin D 2 composition which is particularly well suited for pharmaceutical formulations, pharmaceutical formulations of the 1,25-dihydroxyvitamin D 2 composition, and a method of making the purified composition by purifying a crude 1,25-dihydroxyvitamin D 2 from acetone/water, are disclosed.
1 . A stabilized 1,25-dihydroxyvitamin D 2 composition, characterized by a purity of at least 97% based on total AUC by an HPLC assay and being free of methyl formate.
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3 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein the amount comprising 2.5% by weight or less of 1,25-dihydroxyprevitamin D 2 based on the total weight of the 1,25-dihydroxyvitamin D 2 .
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5 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein the amount of total residual solvent is 1.0% or less.
6 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , being free of acids and substantially free of at least one solvent selected from the group consisting of formate ester solvents, acetate ester solvents, lactate ester solvents, alcohol ester solvents, halogenated solvents, dimethylsulfoxide, dimethylformamide, and solvents capable of generating acid at elevated temperature or over time.
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12 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein the purity is at least 98% after the composition is stored at about 60° C. for a period of at least 24 hours.
13 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein at least about 97.5% of the initial amount of the 1,25-dihydroxyvitamin D 2 remains after the composition is stored at about 60° C. for a period of at least 24 hours.
14 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein the purity is at least about 98% after the composition is stored at about −20° C. under argon for a period of at least 6 months.
15 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein at least about 97% of the initial amount of the 1,25-dihydroxyvitamin D 2 remains after the composition is stored at about −20° C. under argon for a period of at least 6 months.
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18 . The stabilized 1,25-dihydroxyvitamin D 2 composition according to claim 1 , wherein the purity is at least about 98% after the composition is stored at about −20° C. under argon for a period of at least 12 months.
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20 . A pharmaceutical composition comprising an active component which is the stabilized 1,25-dihydroxyvitamin D 2 composition of claim 1 and a pharmaceutically acceptable excipient.
21 . The composition of claim 20 , which is selected from the group consisting of a tablet, a soft gelatin capsule, a non-aqueous solution, and a non-aqueous suspension.
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26 . The composition of claim 20 , in unit dosage form, having a content of active component of 0.1 μg to 25 μg.
27 . The composition of claim 21 , comprising a solution of an effective amount of the stabilized 1,25-dihydroxyvitamin D 2 in fractionated coconut oil, the solution contained in a soft gelatin capsule and further comprising an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin E, and combinations thereof.
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34 . The composition of claim 20 , comprising a solid pharmaceutical preparation of an effective amount of the stabilized 1,25-dihydroxyvitamin D 2 composition, wherein the solid pharmaceutical preparation is in the form of a tablet, a capsule, a granule or a powder.
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39 . A method for purifying crude 1,25-dihydroxyvitamin D 2 , comprising crystallizing 1,25-dihydroxyvitamin D 2 from a solvent system free of methyl formate.
40 . The method of claim 39 , wherein the solvent system is further free of at least one of the following solvents selected from the group consisting of formate ester solvents, acetate ester solvents, lactate ester solvents, alcohol ester solvents, halogenated solvents, dimethylsulfoxide, dimethylformamide, and solvents capable of generating acid.
41 . The method of claim 40 , wherein the solvent system is free of formate ester solvents, acetate ester solvents, lactate ester solvents, alcohol ester solvents, halogenated solvents, dimethylsulfoxide, dimethylformamide, and solvents capable of generating acid.
42 . The method of claim 39 , comprising performing said crystallization as the final crystallization stage in a multi-stage crystallization purification.
43 . The method of claim 39 , wherein the solvent system is an acetone/water mixture.
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47 . The method according to claim 43 , comprising
refluxing crude 1,25-dihydroxyvitamin D 2 with HPLC grade acetone;
filtering off solids;
adding a volume of 18.2 megaohm water to the acetone solution; and
reducing the temperature of the solution to crystallize 1,25-dihydroxyvitamin D 2 .
48 . The method according to claim 43 , further comprising washing the crystallized 1,25-dihydroxyvitamin D 2 with an acetone/water solution and drying the crystallized 1,25-dihydroxyvitamin D 2 to remove residual solvents.
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