**Concentration Dependent Single Chain Properties of Poly(sodium 4-styrenesulfonate) Subjected to Aromatic Interactions with Chlorpheniramine Maleate Studied by Diafiltration and Synchrotron-SAXS**

**Felipe Orozco <sup>1</sup> , Thomas Hoffmann <sup>2</sup> , Mario E. Flores <sup>2</sup> , Judit G. Lisoni <sup>3</sup> , José Roberto Vega-Baudrit <sup>1</sup> and Ignacio Moreno-Villoslada 2,\***


**Citation:** Orozco, F.; Hoffmann, T.; Flores, M.E.; Lisoni, J.G.; Vega-Baudrit, J.R.; Moreno-Villoslada, I. Concentration Dependent Single Chain Properties of Poly(sodium 4-styrenesulfonate) Subjected to Aromatic Interactions with Chlorpheniramine Maleate Studied by Diafiltration and Synchrotron-SAXS. *Polymers* **2021**, *13*, 3563. https://doi.org/10.3390/ polym13203563

Academic Editor: Bramasta Nugraha

Received: 31 August 2021 Accepted: 1 October 2021 Published: 15 October 2021

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**Abstract:** The polyelectrolyte poly(sodium 4-styrenesulfonate) undergoes aromatic–aromatic interaction with the drug chlorpheniramine, which acts as an aromatic counterion. In this work, we show that an increase in the concentration in the dilute and semidilute regimes of a complex polyelectrolyte/drug 2:1 produces the increasing confinement of the drug in hydrophobic domains, with implications in single chain thermodynamic behavior. Diafiltration analysis at polymer concentrations between 0.5 and 2.5 mM show an increase in the fraction of the aromatic counterion irreversibly bound to the polyelectrolyte, as well as a decrease in the electrostatic reversible interaction forces with the remaining fraction of drug molecules as the total concentration of the system increases. Synchrotron-SAXS results performed in the semidilute regimes show a fractal chain conformation pattern with a fractal dimension of 1.7, similar to uncharged polymers. Interestingly, static and fractal correlation lengths increase with increasing complex concentration, due to the increase in the amount of the confined drug. Nanoprecipitates are found in the range of 30–40 mM, and macroprecipitates are found at a higher system concentration. A model of molecular complexation between the two species is proposed as the total concentration increases, which involves ion pair formation and aggregation, producing increasingly confined aromatic counterions in hydrophobic domains, as well as a decreasing number of charged polymer segments at the hydrophobic/hydrophilic interphase. All of these features are of pivotal importance to the general knowledge of polyelectrolytes, with implications both in fundamental knowledge and potential technological applications considering aromatic-aromatic binding between aromatic polyelectrolytes and aromatic counterions, such as in the production of pharmaceutical formulations.

**Keywords:** diafiltration; SAXS; aromatic interactions; poly(sodium 4-styrenesulfonate); chlorpheniramine; polyelectrolyte; aggregation
