Ascomycin and pimecrolimus having reduced levels of desmethylascomycin and 32-deoxy-32-epichloro-desmethylascomycin respectively, and methods for preparation thereof
Provided is ascomycin that has a low level of an FK523 impurity, and pimecrolimus that has a low level of a 32-deoxy-32-epichloro-FK523 impurity, methods of preparing them, and the use of such pimecrolimus for preparing a pharmaceutical composition.
1 . Ascomycin having less than 0.36% area of FK523 (desmethyl ascomycin).
2 . The ascomycin of claim 1 , having less than 0.2% area of FK523.
3 . The ascomycin of claim 2 , having about 0.15% area to about 0.2% area of FK523.
4 . Ascomycin that having a purity of at least about 99.2% area.
5 . Ascomycin of claim 4 , having a purity of at least about 99.5% area.
6 . Ascomycin of claim 1 , having a purity of at least about 99.2% area.
7 . A process for preparing ascomycin comprising providing a preliminary purified ascomycin, and crystallizing the ascomycin from a mixture of an alcohol as a solvent and water as an anti-solvent at a temperature of at least about 45° C.
8 . The process of claim 7 , wherein the temperature is at least about 60° C.
9 . The process of claim 7 , wherein crystallization comprises, dissolving the preliminary purified ascomycin in an alcohol and adding water to the solution to obtain a suspension comprising of precipitated ascomycin; wherein the dissolution and precipitation are done at a temperature of at least about 60° C.
10 . The process of claim 7 wherein the alcohol is a C 1-4 alcohol,
11 . The process of claim 10 , wherein the alcohol is methanol, ethanol, isopropyl alcohol, n-propyl alcohol, or n-butyl alcohol.
12 . The process of claim 11 , wherein the alcohol is methanol.
13 . The process of claim 7 , wherein the addition of water is done over a period of about 10 to about 600 minutes.
14 . The process of claim 7 , further comprising recovering the ascomycin.
15 . The process of claim 7 , further comprising repeating the crystallization.
16 . The process of claim 7 , wherein the obtained ascomycin has a purity of at least about 99.2% area.
17 . The process of claim 7 , wherein the obtained ascomycin has a purity of at least about 99.5% area.
18 . The process of claim 7 , wherein the obtained ascomycin has less than 0.36% area of FK523 (desmethyl ascomycin).
19 . The process of claim 18 , wherein the obtained ascomycin has less than 0.2% area of FK523 (desmethyl ascomycin).
20 . The process of claim 19 , wherein the obtained ascomycin has about 0.15% area to about 0.2% area of FK523 (desmethyl ascomycin).
21 . A process for preparing pimecrolimus comprising converting ascomycin of claim 1 to ascomycin.
22 . A process for preparing pimecrolimus, further comprising converting the obtained ascomycin of claim 7 of to pimecrolimus.
23 . The process of claim 22 , wherein the obtained pimecrolimus has a purity of at least 99.4% area.
24 . The process of claim 22 , wherein the obtained pimecrolimus has less than 0.45% area of 32-deoxy-32-epichloro-FK523 (desmethyl ascomycin).
25 . A process for preparing pimecrolimus having less than 0.45% area of 32-deoxy-32-epichloro-FK523 (desmethyl ascomycin) comprising a) measuring the purity of the ascomycin in at least one batch of ascomycin; b) selecting a batch of ascomycin having less than 0.36% area of FK523, and c) preparing pimecrolimus with less than 0.45% area of 32-deoxy-32-epichloro-FK523 from the selected batch.
26 . Pimecrolimus with less than 0.45% area of 32-deoxy-32-epichloro-FK523.
27 . Pimecrolimus of claim 26 having a purity of at least 99.4% area.
28 . A pharmaceutical composition comprising the Pimecrolimus of claim 26 and at least one pharmaceutically acceptable excipient.
29 . A method of treating atopic dermatitis in a human comprising administering the pharmaceutical composition of claim 28 to a human.