WE CLAIM:
1. A composition comprising mixed salts of water-soluble polymer-active agent
conjugates, wherein the active agent in the conjugate has at least one basic amine group, and
wherein for each amine group within the active agent, the amine group is either protonated or
unprotonated, where any given protonated amine group is an acid salt form of an inorganic
acid or trifluoroacetic acid (TFA), wherein said water soluble polymer is a multi-armed
polyethylene glycol), wherein the active agent is irinotecan, wherein the inorganic acid is
hydrochloric acid, wherein at least 25 mole percent of the amine groups within the active
agent are protonated as the TFA salt, wherein 25-40 mole percent of the amine groups within
the active agent are protonated as the HCl salt, and 5-35 mole percent of the amine groups
within the active agent are non-protonated.
2. The composition as claimed in claim 1, wherein the water-soluble polymer-active
agent conjugate corresponds to structure (I)


and n is an integer ranging from 20 to 500, wherein at least 25 mole percent of the amine groups within the active agent are protonated as the TFA salt, wherein 25-40 mole percent of the amine groups within the active agent are protonated as the HCl salt, and wherein 5-35 mole percent of the amine groups within the active agent are non-protonated.
3. A trifluoroacetic acid / hydrochloric acid mixed salt of the following structure:

where n is an integer ranging from 40 to 500, wherein 25-40 mole percent of the amine groups within the active agent are protonated as the HCl salt, and 5-35 mole percent of the amine groups within the active agent are non-protonated.
4. A method for preparing a mixed salt of a water-soluble polymer-active agent
conjugate, comprising the steps of:
(i) deprotecting an inorganic acid salt of an amine-containing active agent in protected form by treatment with trifluoroacetic acid (TFA) to form a deprotected inorganic acid/TFA mixed salt,
(ii) determining the relative molar amounts of inorganic acid and TFA in the deprotected acid salt formed in step (i),

(iii) coupling the deprotected inorganic acid/TFA mixed salt of step (i) with a water soluble polymer reagent in the presence of a base to form a polymer-active agent conjugate, and
(iv) recovering said polymer active agent conjugate, said polymer-active agent conjugate characterized by having said one or more amino groups present in a combination of free base, inorganic acid salt, and TFA salt form,
wherein said water soluble polymer is a multi-armed poly(ethylene glycol), wherein the active agent is irinotecan, wherein the inorganic acid salt is HCl, wherein the water soluble polymer reagent is an activated polyethylene glycol ester, wherein at least 25 mole percent of the amine groups within the active agent are protonated as the TFA salt, wherein 25-40 mole percent of the amine groups within the active agent are protonated as the HCl salt, and 5-35 mole percent of the amine groups within the active agent amino groups are non-protonated.
5. The method as claimed in claim 4, wherein the polyethylene glycol reagent is a branched reagent having three, four, five, six, seven or eight polymer arms.
6. The method as claimed in claim 4, wherein the base in step (iii) is an amine.
7. The method as claimed in claim 6, wherein the base is selected from trimethyl amine, triethyl amine, and dimethylaminopyridine.
8. The method as claimed in claim 4, wherein the amount of base in step (ii) ranges from 1.00 - 2.00 (moles TFA + moles acid).
9. The method as claimed in claim 4, wherein the amine-containing active agent in protected form is t-boc-glycine irinotecan.
10. A method for preparing a mixed salt of a water-soluble polymer-active agent conjugate, comprising the steps of:
(i) deprotecting t-Boc glycine-irinotecan.HCl by treatment with trifluoroacetic acid (TFA) to form deprotected glycine-irinotecan HCl,

(ii) coupling the deprotected glycine-irinotecan HCl with 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl succinimide in the presence of a base under conditions effective to form a conjugate, 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl glycine-irinotecan, and
(iii) recovering the conjugate from step (ii), wherein the conjugate is a mixed salt comprising amino groups in a combination of free base, HCl, and TFA salt forms, wherein at least 25 mole percent of the amine groups of the irinotecan comprised in the conjugate are protonated as the TFA salt, wherein 25-40 mole percent of the amine groups of the irinotecan comprised in the conjugate are protonated as the HCl salt, and 5-35 mole percent of the amine groups of the irinotecan comprised in the conjugate are non-protonated.
11. The method as claimed in any one of claims 4-10, comprising purifying the conjugate from step (iii).
12. The method as claimed in claim 11, wherein said purifying comprises recrystallizing the conjugate to form a recrystallized conjugate.
13. The method as claimed in claim 12, wherein the recrystallized product is also a mixed acid salt comprising amino groups in a combination of free base, HCl, and TFA salt form.
14. The method as claimed in any one of claims 4-13, effective to reproducibly provide a mixed salt possessing relative molar amounts of inorganic acid addition salt, trifluoroacetic acid salt, and free base that vary by no more than fifteen percent in batch to batch consistency.
15. A mixed salt reproducibly prepared by the method as claimed in any one of claims 4-13, possessing relative molar amounts of inorganic acid addition salt, trifluoroacetic acid salt and free base that vary by no more than fifteen percent in consistency from batch to batch.

16. A pharmaceutically acceptable composition comprising (i) a mixed salt as claimed in any one of claims 1-3, 15 or prepared by the method as claimed in any one of claims 4-14 and (ii) lactate buffer, in lyophilized form.
17. A composition comprising mixed salts of four-arm polymer conjugates, wherein at least 90% of the four-arm conjugates in the composition:
(i) have a structure encompassed by the formula,
C-[CH2-O-(CH2CH2O)n-CH2-C(O)-Term]4,
wherein
n, in each instance, is an integer having a value from 5 to 150 and
Term, in each instance, is selected from the group consisting of -OH, -OCH3,
o


and -NH-CH2-C(O)-O-Irino (“GLY-Irino”), wherein Irino is a residue of irinotecan; and
(ii) for each Term in the at least 90% of the four-arm conjugates in the composition, at least 90% thereof are -NH-CH2-C(O)-O-Irino,
and wherein for each amino group within each Irino in the at least 90% of the four-arm conjugates in the composition, each amino group is either protonated or unprotonated, where any given protonated amino group is an acid salt form of an inorganic acid or trifluoroacetic acid, wherein the inorganic acid is hydrochloric acid, wherein at least 25 mole percent of amino groups are protonated as TFA salt, and wherein 25-40 mole percent of amino groups are protonated as HCl salt, and 5-35 mole percent of amino groups are non-protonated.