Patent ID: 8568705

Claim:
A method of preparing a multiarm polymer, comprising: (a) to a pentaerythritol bearing four hydroxyl groups, attaching a water-soluble and non-peptidic polymer, wherein the water-soluble and non-peptidic polymer is poly(ethylene glycol), to the pentaerythritol at the site of three of the hydroxyl groups; (b) reacting the pentaerythritol, in one or more reaction steps, with one or more functionalizing reagents to effect substitution of a protected carboxylic acid, —Y, to form a mixture comprising (i) unsubstituted pentaerythritol containing no —Y groups; (ii) a monosubstituted pentaerythritol comprising a single —Y group, and (iii) a multisubstituted pentaerythritol comprising at least two —Y groups; (c) hydrolyzing said protected carboxylic acid to thereby form a carboxylic acid; (d) purifying the mixture to separate the monosubstituted pentaerythritol from the unsubstituted and multisubstituted pentaerythritol species, wherein said purifying step comprises (i) passing the mixture through a first ion exchange column to provide an eluate, wherein said passing the mixture step is carried out under conditions effective to adsorb substantially all of said multisubstituted pentaerythritol onto the first column, (ii) passing the eluate through a second ion exchange column under conditions effective to adsorb substantially all of the monosubstituted pentaerythritol onto said second column, (iii) washing the second column with a water or a solution having low ionic strength to remove unsubstituted pentaerythritol, and (iv) passing a solution having high ionic strength through the second column to desorb the monosubstituted pentaerythritol, wherein the multiarm polymer has the following structure HO(O)C-L′-O—CH 2 —C—[CH 2 —O-L-(CH 2 CH 2 O) m H] 3 wherein L and L′ are spacers, and m is defined so as to provide a total molecular weight of the water-soluble and non-peptidic polymer portion of the multiarm polymer of from about 2,000 Da to about 40,000 Da.