ASSOCIATION REACTIONS OF POLYETHYLENE GLYCOLS 209 products cannot be applied with confidence to the more complex formula- tions of commerce. COMPLEX FORMATION WITH ORGANIC ACIDS An excellent demonstration of the "reactivity" of organic carboxylic acids with polyethylene oxide products is afforded by the mixture of aqueous solutions of Polyox resins and polyacrylic acid. Smith, Winslow and Peterson of our research department (8) have reported that water insoluble precipitates result when aqueous solutions of these reactants are mixed over a wide composition range. The strength of this complex is indicated by the fact that only about 10 to 15 per cent of the precipitated product made from equal weights of the reactants can be solubilized by exhaustive extraction with boiling water. While this strong insoluble complex forms under ideal conditions, a number of competitive reactions are known which completely inhibit the insolubilization. It is of interest to consider these competitive reactions from the standpoint that similar equilibria may be involved in many other mixtures of polyethylene oxide products with simple phenolic and monomeric carboxylic acid derivatives. Of primary interest is the observation that the formation of the insoluble complex of polyacrylic acid and Polyox resin is pH dependent and that no insolubilization occurs above a pH of 3.5. This is consistent with the view that complexation occurs by hydrogen bonding between the carboxyl hydrogen atom and the ether oxygen atoms and that such complexation would be maximal if acid ionization is suppressed. It is significant that aqueous solutions of ammonium polyacrylate and Polyox resin are com- patible but that complex precipitation occurs when ammonia is driven from the solution by heating. A further observation of interest is that acetone and other organic solvents prevent insolubilization. The authors propose that such nu- cleophilic solvents compete successfull? with the polyether oxygen atoms in associating with the carboxylic acid groups, thereby preventing the formation of the insoluble interpolymer complex. Evaporation of the inhibiting solvent allows the normal insolubilization reaction to proceed. In considering the numerous reported instances of complex formation between toohomeric organic acids and polyethylene oxide derivatives, a zipper analogy is appropriate. Taken singly, the interlocking pairs of prongs on the zipper may be easily separated when the locking device functions improperly. The intact zipper, however, offers amazing strength. So, too, we would expect the complexes formed between polyethers and polycarboxylic acids to be quite strong, as a result of the multiplicity of weak linkages. Where the organic acid has only a single point of at- tachment to the polyether chain, we would expect a lower order of strength. Since the strong complexes derived from polyethers and polyacids are

210 JOURNAl. OF THE SOCIETY OF COSMETIC CHEMISTS subject to drastic equilibria shifts under the influence of pH and various solvents, it is to be expected that the equilibria of those complexes re- sulting from single hydrogen bond attachments would be subject to the same influences. It should be pointed out, however, that the strength of any single hydrogen bond attachment can be greatly influenced by the structure of the molecule to which the carboxylic acid group is attached. Thus, the single hydrogen bond attachment of an aromatic monocarboxylic acid, due to structural influences, may be many times stronger than its aliphatic counterpart. Chakravarty, Lach and Baug (9) investigated the complexes formed be- tween polyethenoxy 40 stearate (Myrj 52 Atlas Chemical Industries, Inc. and a number of organic acids. The consequence of complex formation with each of the following acids was an increase in the solubility of the acid in the aqueous phase in direct proportion to the amount of the surfactant present: p-hydroxybenzoic acid p-aminobenzoic acid m-hydroxybenzoic acid benzoic acid acetylsalicylic acid This increased solubility of the acid-polyethylene oxide complex in water is in contrast to the decrease in solubility that occurs when phenol or re- sorcinol is mixed with this surface active agent. Another consequence of the interaction of acetylsalicylic acid with polyethylene oxide products was reported by Marcus (10). It was noted that the addition of aspirin to suppositories based on Carbowax © polyeth- ylene glycols produced a notable softening of the wax base. In addition, the rate of absorption of the complexed aspirin was drastically reduced. While complex formation--with its changes in solubility of the com- ponents and concomitant changes in the potency of preservatives or phar- maceuticals-has been reported for a number of organic acids, it is par- ticular]y noteworthy that no convincing evidence of complex formation between sorbic acid and polyethylene oxide products has come forth. Extensive studies by Tice and Bart (11) in which 5 per cent aqueous solutions of polyoxyethylene 20 sorbitan monostearate (Tween 60 Atlas Chemical Industries, Inc.) were inoculated with various microiSrganisms showed that 0.2 per cent sorbic acid was completely effective in preserving the formulation. The parabens (p-hydroxybenzoate esters) were, on the other hand, completely ineffective at all concentrations tested. More recent studies by Charles and Carter (7) attest to the efficacy of sorbic acid as a preservative in a wide variety of more complex commercial cosmetic preparations.