Poly(ethylene glycol) or Poly(ethylene oxide)?: Magnitude of end-group Contribution to the Partitioning of Ethylene Oxide Oligomers and Polymers between Water and Organic Phases

[摘要] Ethylene oxide oligomers and polymers (hereafter referred to as PEO) are amongst the most commonly used substances in pharmaceutical and other industrial formulations. Depending on the oligomer/polymer molar mass, they have been called poly(ethylene glycol)s or poly(ethylene oxide)s, the former applied to smaller ones to suggest a glycolic chemical nature attributed to significant contributions from their hydroxyl end-groups. Just for guidance, catalogues from some common chemical companies place this transition between molar mass of 3350 or 10 000 g mol-1.1 More than a nomenclature issue, this end-group contribution may have important implications, as already stressed in relation to PEO solubility2 and miscibility in blends.3 In general, it is assumed that end-group effects become less important, and, eventually, insignificant, as polymer molar mass increases, but no clear discrimination of this transition region for PEO has been presented yet. Most PEO applications depend on its high water solubility, a feature that has been related to a precise fitting of the ethylene oxide units into liquid water structure4 (for instance, poly(methylene oxide) and poly(propylene oxide) are considerably less soluble in water), in addition to favourable contributions from its hydroxyl end-groups. Despite this high aqueous solubility, there is a classical statement (found in Bailey´s textbook5) that PEO may be extracted from water to organic solvents, that has been ascribed to an entropy increase due to the loss of polymer chain helicity upon transfer from water to the apolar phase. Polymer partitioning is a key issue in the mechanism of formation of liquid biphasic systems (both aqueous and organic), as well as an important step in fractionation procedures. For PEO, it is of great importance when extended to biological systems, given its use, for instance, in cell fusion, where a key step has been proposed to be PEO interaction / partitioning at the biological membrane.6 In the last years, we have investigated PEO solution behaviour in both aqueous7 and organic8-10 biphasic systems, and shown that polymer solvation makes an important contribution to the driving forces controlling the formation of such systems.7, 10 Hence, continuing this line of investigation, we report in this communication partitioning studies in three water/organic biphase systems, as a function of PEO molar mass, aiming at factoring out the individual contributions of ethylene oxide and hydroxyl groups.  Results and Discussion Table 1 shows the partition coefficients (K) measured at 298 K for some PEO and PEO-dimethyl ethers in biphasic systems containing water and dichloromethane, chloroform or chlorobenzene.11 These data were obtained at ca. 8-10% total polymer concentrations, where polymer-polymer interactions or entanglements may be present, especially for PEO of higher molecular weights. Partition coefficients for PEO 3350 determined at different polymer contents (1, 5 and 10 %) led to essentially the same K values, suggesting that contribution from these interactions may be insignificant.   It is clear from these data that these organic solvents behave differently, since with chlorobenzene, PEO partitioning is always favoured into water, whereas for the other two, this preference shifts as PEO molar mass varies. The first behaviour may be ascribed to a less efficient PEO solvation by chlorobenzene, in comparison with water, which is not surprising considering the lower solubility of the polymer in this solvent. Such a more efficient PEO solvation by CH2Cl2 and CHCl3 may be attributed to their hydrogen bonding donating capability, which has already been stressed as an important feature related to PEO solubility.2 As for the behaviour observed in systems containing CH2Cl2 and CHCl3, the trend of increasing K values with the increase of PEO molar mass agrees with the proposition that end-group effects, which should act favouring its partitioning into water, become less important. A clearer picture of these trends, including data for more polymers, is presented in Figure 1. In general, the same tendency is observed for partitioning into both chloroform and dichloromethane/water systems, with increasing K values for increasing molar mass, until levelling off at ca. 3350 g mol-1. The only difference is the slightly higher partition coefficients with chloroform for lower molar mass, a sequence opposite to that observed for PEO solubility.10   The first striking point that arises from these data is that PEO begins to prefer the organic phase at quite low molar mass, 300 g mol-1 for chloroform and 400 g mol-1 for dichloromethane, indicating that its apolar nature (polyether) starts to prevail even for oligomers most commonly referred to as glycols. This fact may have important implications when analysing PEO partitioning in other systems. It is important, however, that this behaviour does not occur with chlorobenzene (preliminary investigations indicate that PEO also partitions predominantly into water in the presence of ethyl acetate and THF). At this point it is not clear which solvent property controls PEO partitioning, but it would be interesting to assess, for instance, the partitioning behaviour exhibited with solvents usually assumed to mimic biological membranes.14 Methylation of PEO end-groups produces a remarkable increase of K values, as shown in Table 1, which is well above any estimated increase due to the addition of two methyl groups (even if assumed as two extra EO units). Such an increase confirms that ¾OH groups still contribute significantly, favouring PEO partitioning into water even above the 300-400 g mol-1 range. Another interesting point revealed in Figure 1 is that, unlike the partitioning of homologous series between aqueous/organic phases, the increment (sometimes referred to as D DtG) in Gibbs energy of transfer (where DtG = - RT ln K) per EO subunit is not constant, but decreases as the polymer chain length increases, eventually vanishing, when the plateau is reached. For molar mass below 1000 g mol-1, this increment per ethylene oxide unit varies between ca. ¾1 and ¾0.4 kJ mol-1, much smaller than values for the transfer of one methylene unit between water and organic solvents (usually in the range of ¾ 3 kJ mol-1).15 The fact that a plateau is reached is also important since it reveals that, for polymers above the molar mass range of 3350-35 000 g mol-1, increase in PEO molar mass does not change significantly their solvation properties. Interestingly, a similar behaviour is displayed by other PEO properties, as its melting point and enthalpy of fusion, such as shown in Figure 1. Since all comparisons are made on a monomer basis, those findings suggest that, above this molar mass range, upon addition of more EO units to the polymer chain, the average contribution of its end-groups becomes insignificant, a feature associated with the polyglycol to polyether transition, as previously described. Sakellariou and co-workers2 also found a two-step variation for the hydrogen-bonding basicity contribution to PEO solvation, but with a change at molar mass around 1 000 g mol-1. Such changes in polymer properties would be felt not only in solution properties, like partitioning, but also in other physical properties related to polymer-polymer interaction, as in the

[学科分类] 化学（综合）