ALKOXYLATION METHODS
Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.
1 - 50 . (canceled)
51 . A method comprising the step of alkoxylating in a suitable solvent a previously isolated alkoxylatable oligomer to form an alkoxylated polymeric material, wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 300 Daltons.
52 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 500 Daltons.
53 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product are soluble in the suitable solvent.
54 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer is prepared by (a) alkoxylating a precursor molecule having a molecular weight of less than 300 Daltons to form a reaction mixture comprising an alkoxylatable oligomer, and (b) isolating the alkoxylatable oligomer from the reaction mixture.
55 . The method of claim 51 where the alkoxylation utilizes ethylene oxide as an alkoxylation agent.
56 . The method of claim 54 , wherein the precursor molecule is selected from the group consisting of glycerol, diglycerol, triglycerol, hexaglycerol, mannitol, sorbitol, pentaerythritol, dipentaerthitol, and tripentaerythritol.
57 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has from one to eight primary hydroxyl groups.
58 . The method of claim 57 , wherein each of the one to eight primary hydroxyl groups is the result of an alkoxylation reaction.
59 . The method of claim 57 , wherein the neither the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product has a hydroxyl group of the precursor molecule.
60 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has a branched structure.
61 . The method of claim 60 , wherein the branched structure is a 4- to 8-arm branched structure.
62 . The method of claim 61 , wherein the branched structure is a 4-arm branched structure.
63 . The method of claim 61 , wherein the branched structure is a 5-arm branched structure.
64 . The method of claim 61 , wherein the branched structure is a 6-arm branched structure.
65 . The method of claim 61 , wherein the branched structure is an 8-arm branched structure.
66 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:
wherein the average value of n within the structure is from 2 to 50.
67 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:
wherein the average value of all the instances of n within the structure is from 10 to 1000.
68 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:
wherein the average value of all instances of the value of n within the structure is from 2 to 35.
69 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:
wherein the average value of all instances of the value of n within the structure is from 10 to 750.
70 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:
wherein the average value of all instances of the value of n within the structure is 2 to 35.
71 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:
wherein the average value of all instances of the value of n within the structure is 10 to 600.
72 . The method claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 400.
73 . The method claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 300.
74 . The method of claim 66 , wherein all values of n are within three standard deviations of each other.
75 . The method of claim 66 , wherein all values of n are within two standard deviations of each other.
76 . The method claim 66 , wherein all values of n are within one standard deviation of each other.
77 . The method of claim 51 , wherein the suitable solvent include organic solvents selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), toluene, benzene, xylenes, mesitylene, tetrachloroethylene, anisole, and mixtures of the foregoing.
78 . The method of claim 51 , wherein the suitable solvent is selected from the group consisting of toluene, xylene, mesitylene, tetrahydrofuran (THF), and mixtures of foregoing.
79 . The method of claim 51 , wherein the suitable solvent is toluene used in quantities that after ethoxylation the solvent consists more than 25 wt % and less than 75 wt % of the reaction mixture.
80 . The method of claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions, wherein the alkoxylation conditions include the presence of a strong base.
81 . The method of claim 80 , wherein the strong base is selected from the group consisting of one or more alkali metals.
82 . The method of claim 80 , wherein the strong base is selected from the group consisting of metallic potassium, metallic sodium, sodium-potassium alloys, and a hydroxide.
83 . The method of claim 82 , wherein the hydroxide is NaOH, KOH and mixtures thereof.
84 . The method of claim 82 , wherein the strong base is a sodium-potassium alloy.
85 . The method of claim 80 , wherein the strong base is an alkoxide of a previously isolated alkoxylatable oligomer.
86 . The method of claim 80 , wherein the strong base is present in a catalytic amount.
87 . The method of claim 86 , wherein the catalytic amount is from 0.001 to 10.0 weight percent strong base based upon the weight of the total reaction mixture.
88 . The method of claim 86 , wherein the catalytic amount is from 0.01 to about 6.0 weight percent strong base based upon the weight of the total reaction mixture.
89 . The method of claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 20 ppm.
90 . The method of claim 89 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 14 ppm.
91 . The method of claim 90 , wherein the alkoxylating step is carried out under alkoxylating conditions wherein the amount of water present is less than 8 ppm.
92 . The method of claim 1 , wherein the alkoxylating step is carried out at a temperature between 80° C. and 140° C.
93 . A composition comprising the alkoxylated polymeric product prepared in accordance with the method claim 51 .
94 . The composition of claim 93 , wherein the purity of the alkoxylated polymeric product is greater than 92 wt % and the total content of high molecular weight impurities and diols is less than 8 wt %.
95 . The composition of claim 94 , wherein the purity is greater than 98 wt % and the total content of high molecular weight impurities and diols is less than 2 wt %.
96 . The method of claim 51 , further comprising the step of modifying the alkoxylated polymeric material to bear a reactive group to thereby form a water-soluble polymer reagent.
97 . The method of claim 96 , wherein the water-soluble polymer reagent has the following structure:
wherein each n is from about 40 to about 500.
98 - 100 . (canceled)