(196f) Influence of Phosphate Salts and Solution pH on Aqueous-Phase NVP Free-Radical Polymerization

Poly(N-vinylamides), such as N-vinyl pyrrolidone (NVP), have been extensively used as monomers in the synthesis of crosslinked hydrogels. NVP has been systematically used as an accelerator and co-monomer during free-radical polymerization of poly(ethylene) glycol diacrylate (PEGDA) hydrogels for biomedical applications. Our research has focused on the design and fabrication of monophosphate (Pi) and hexametaphosphate (PPi) loaded hydrogel nanoparticles copolymerized with PEGDA and NVP using inverse phase miniemulsion polymerization for applications in drug delivery. (1,2) Specifically, Pi- and PPi- loaded nanoparticles are utilized for sustained delivery of phosphates to the intestinal tract in an effort to suppress bacterial transition to virulence. (1) Even though aqueous-phase polymerization of NVP has been previously investigated, little is known regarding the effect of salts on the free-radical polymerization kinetics of NVP. NVP monomer and its radicals are believed to stabilize in aqueous solution by aggregating water molecules. Santanakrishnan et al (3) showed that the NVP propagation constant is dependent on monomer concentration in solution. The more dilute the monomer solution the higher the polymerization rate due to more favorable monomer/solvent(water) interactions as compared to monomer/monomer interactions. The addition of salts, including phosphates, to the monomer solution may also influence NVP polymerization kinetics as salts have a similar tendency to aggregate water molecules and to hydrate in aqueous solution. This phenomenon could cause a decrease in the number of water molecules available for interaction with NVP molecules resulting in increased monomer/monomer interactions and decreases in the propagation rate constant and the rate of polymerization. In theory, it would be possible to calculate an “effective” concentration of NVP that would match the concentration-dependent rate constant proposed by Santanakrishnan et al (3) to describe the system with the addition of salts.

Additionally, the pH of the precursor is also known to affect the rate of polymerization in these systems. NVP monomers have been previously shown to readily react under alkaline conditions. Furthermore, solution pH should have a significant impact on initiator dissociation kinetics. Many aqueous-phase free-radical initiators present a strong dependence on solution pH, being able to operate under a limited pH range. Thus, in selecting an initiator to polymerize NVP it is important to consider the pH effect on the dissociation of the specific initiator.

The goal of this study is to investigate the influence of two different phosphate salts (Pi and PPi), as well as variations in pH, on the kinetics of free-radical aqueous-phase NVP polymerization. These studies will provide insight to optimize the nanoparticle production process for targeted drug delivery of phosphates to the gut.

Methods:

In this study, potassium monophosphate and sodium hexametaphosphate were used. Potassium persulfate (KPS) and 2,2'-Azobis(2-methylpropionamidine) dihydrochloride (V-50) were used as free-radical initiators. Varying amounts of HCl and NaOH solutions were used to adjust the solution pH. The influence in the rate of polymerization by both the salts and the pH was measured over time by following conversion of NVP to poly-NVP.

Fixed amounts of salt and NVP were added to DI water in separate test tubes. After mixing and solubilization of the salt, each type of initiator was separately added to the solution. Samples were bubbled with nitrogen to prevent oxygen inhibition before the polymerization reaction proceeded in a water bath at constant 60ºC. At pre-determined times, the tubes were removed from the water bath, methyl hydroquinone was added to stop the polymerization reaction and the tubes stored at -80ºC until the samples were completely frozen. Samples were then lyophilized to remove water and unreacted NVP. The final mass of poly-NVP was then obtained and monomer conversion calculated as a function of time.

Results:

Initial experiments were conducted using the initiator KPS and revealed interesting interactions at both acidic and alkaline pH. The experiments showed no formation of poly-NVP. This was attributed to the fact that KPS tends to make the solution very acidic, along with the fact that NVP does not react under acidic conditions. With that in mind, pH adjustments were made to bring the pH back to neutral after the addition of KPS. Even with these adjustments no polymerization of NVP was observed. This was most likely attributed to the fact that KPS does not dissociate under neutral to basic conditions. We therefore identified a different initiator, V-50 as being ideal for aqueous phase polymerization of NVP.

Preliminary results for the aqueous NVP polymerization initiated by V-50 were obtained over a range of pH (3-13). These experiments indicated a clear correlation between the solution pH and the rate of reaction. Our data indicate that there is an optimum pH for the aqueous polymerization of NVP with the V-50 initiator. As in the case of KPS, the V-50 dissociation rate was also dependent on pH, with increases in pH decreasing the initiator dissociation constant and subsequently affecting the overall polymerization reaction rate.

Results on the kinetics of the monomer solution in the presence of the monophosphate salt indicate a slight decrease in reaction rate (on average 9.6% slower as compared to pure NVP kinetics). This effect was more pronounced initially being about 26% slower in the first 15 minutes of reaction. In the case of NVP kinetics in the presence of sodium hexametaphosphate (PPi) a similar but accentuated trend is observed. In the presence of PPi, there is an even greater decrease in reaction rate (~ 15.3% compared to the kinetics of the pure NVP) with ~ 47% slower kinetics in the first 15 minutes. These preliminary results confirm our hypothesis that the addition of salts influences the kinetics of the aqueous-phase NVP polymerization.

The polymerization model reported by Santanakrishnan et al was used as a reference for comparison. The model was shown to fit our experimental data and used to obtain the initiator efficiency.

Additional studies are being conducted to determine an “effective” NVP concentration after the addition of the salts and the optimum pH for NVP homopolymerization and to extend these findings to synthesize a stable emulsion using V-50 as the initiator to create Pi and PPi loaded nanoparticles.

References:

(1) Yin, Y. et al, “De Novo Synthesis and Functional Analysis of Polyphosphate-Loaded Poly(Ethylene) Glycol Hydrogel Nanoparticles Targeting Pyocyanin and Pyoverdin Production in Pseudomonas aeruginosa as a Model Intestinal Pathogen”, Annals of Biomedical Engineering, 45 (4), pp. 1058-1068 (Apr. 2017)

(2) Vadlamudi, S. et al., “Inverse miniemulsion polymerization of phosphate-loaded hydrogel nanoparticles for sepsis prevention”, Unpublished master dissertation, Illinois Institute of Technology, Chicago, Illinois (2014)

(3) Santanakrishnan, S., et al, “Kinetics and Modeling of Batch and Semibatch Aqueous-Phase NVP Free-Radical Polymerization”, Macromol. React. Eng., 4, pp. 499–509 (2010)