Crystallization method for purification of calcipotriene
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsAnchel Schwartz, Asher Maimon
Life of this patent
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Abstract
Provided is a crystallization method for reducing the level of impurities in calcipotriene in which a solution of a starting calcipotriene in a first process solvent, for example THF, is combined with second process solvent, for example methyl formate, and, after cooling, calcipotriene is isolated. The method can include a slurry step for reducing the level of residual first process solvent.
Claims23
A method of crystallizing calcipotriene comprising the steps of:
- a) providing a solution of a starting calcipotriene in a first solvent selected from:
- lower alkyl alcohols, lower aliphatic ketones, alkyl esters of lower carboxylic acids, and cyclic ethers,
- b) combining, with agitation, the provided solution with from about 1 to about 100 volumes of a second solvent,
- c) cooling the combination to a temperature of less than about −10° C., and
- d) isolating calcipotriene from the resulting suspension, wherein when the first solvent is a cyclic ether the second solvent is methyl formate, when the first solvent is a lower alkyl alcohol the second solvent is a lower hydrocarbon, and when the first solvent is a lower dialkyl ketone, the second solvent is methyl formate.
A method of making calcipotriene having a reduced level of impurities comprising the steps of:
- a) providing a solution of starting calcipotriene in a first solvent selected from:
- lower alkyl alcohols, lower aliphatic ketones, alkyl esters of lower carboxylic acids, and cyclic ethers,
- b) combining the provided solution, with agitation, with from about 1 to about 100 volumes of a second solvent,
- c) cooling the combination to a temperature of less than about −10° C. at a cooling rate between about 10° and about 40° C. per hour, and
- d) isolating from the resulting suspension calcipotriene having a reduced level of impurities, wherein when the first solvent is a cyclic ether the second solvent is methyl formate, when the first solvent is a lower alkyl alcohol the second solvent is a lower hydrocarbon, and when the first solvent is a lower dialky ketone, the second solvent is methyl formate.
A method of making purified calcipotriene having a reduced level of impurities and a reduced level of residual first process solvent comprising the steps of:
- a) providing a solution of starting calcipotriene in a first solvent selected from:
- lower alkyl alcohols, lower aliphatic ketones, alkyl esters of lower carboxylic acids, and cyclic ethers,
- b) combining the provided solution, with agitation, with from about 1 to about 100 volumes of a second solvent,
- c) cooling the combination to a temperature of less than about −10° C. at a cooling rate between about 10° and about 40° C. per hour,
- d) isolating from the resulting suspension calcipotriene having a reduced level of impurities, wherein when the first solvent is a cyclic ether the second solvent is methyl formate, when the first solvent is a lower alkyl alcohol the second solvent is a lower hydrocarbon, and when the first solvent is a lower dialkyl ketone, the second solvent is methyl formate,
- e) suspending the isolated calcipotriene in a suspending volume of methyl formate at a temperature between about −10° and about 20° C. with agitation for a suspension time, and
- f) isolating from the suspension purified calcipotriene having a reduced level of impurities and a reduced level of first process solvent.
Dependencies are inferred from the claim text.