*Article* **Accelerating Payload Release from Complex Coacervates through Mechanical Stimulation**

**Wesam A. Hatem and Yakov Lapitsky \***

Department of Chemical Engineering, University of Toledo, Toledo, OH 43606, USA

**\*** Correspondence: yakov.lapitsky@utoledo.edu; Tel.: +1-419-530-8254

**Abstract:** Complex coacervates formed through the association of charged polymers with oppositely charged species are often investigated for controlled release applications and can provide highly sustained (multi-day, -week or -month) release of both small-molecule and macromolecular actives. This release, however, can sometimes be too slow to deliver the active molecules in the doses needed to achieve the desired effect. Here, we explore how the slow release of small molecules from coacervate matrices can be accelerated through mechanical stimulation. Using coacervates formed through the association of poly(allylamine hydrochloride) (PAH) with pentavalent tripolyphosphate (TPP) ions and Rhodamine B dye as the model coacervate and payload, we demonstrate that slow payload release from complex coacervates can be accelerated severalfold through mechanical stimulation (akin to flavor release from a chewed piece of gum). The stimulation leading to this effect can be readily achieved through either perforation (with needles) or compression of the coacervates and, besides accelerating the release, can result in a deswelling of the coacervate phases. The mechanical activation effect evidently reflects the rupture and collapse of solvent-filled pores, which form due to osmotic swelling of the solute-charged coacervate pellets and is most pronounced in release media that favor swelling. This stimulation effect is therefore strong in deionized water (where the swelling is substantial) and only subtle and shorter-lived in phosphate buffered saline (where the PAH/TPP coacervate swelling is inhibited). Taken together, these findings suggest that mechanical activation could be useful in extending the complex coacervate matrix efficacy in highly sustained release applications where the slowly releasing coacervate-based sustained release vehicles undergo significant osmotic swelling.

**Keywords:** polyelectrolyte; complex coacervate; polyamine; stimulus-responsive materials; controlled release

## **1. Introduction**

Complex coacervation is a liquid-liquid phase separation that occurs through the complexation of colloidal (or macromolecular) solutes with other solute species [1–3]. This phase separation generates a solute-rich coacervate phase, which is rich in both the associating solution species and in equilibrium with a dilute, solvent-rich supernatant phase. The colloid-rich coacervate phase typically has viscoelastic fluid- or gel-like properties [4–6], and offers numerous benefits: easy formation under mild, aqueous conditions [7,8]; low toxicity [9,10]; and an ability to form, transform their properties, and dissolve in response to external stimuli [1,11–13]. Among their many potential applications (which range from drug delivery [8,14,15] to separation processes [16,17], foods [18], and adhesives [11,19,20]), complex coacervates are frequently used in the controlled release of various active compounds [8,14,15,21–23].

One aspect of complex coacervates that makes them potentially effective for sustained release applications is their polymer-rich composition, which—in contrast to most hydrogels [24]—makes them highly effective diffusion barriers [9,15,25,26]. This barrier property enables them to sustain the release of small water-soluble molecules (which tend to elute

**Citation:** Hatem, W.A.; Lapitsky, Y. Accelerating Payload Release from Complex Coacervates through Mechanical Stimulation. *Polymers* **2023**, *15*, 586. https://doi.org/ 10.3390/polym15030586

Academic Editors: Lorenzo Antonio Picos Corrales, Angel Licea-Claverie and Grégorio Crini

Received: 5 January 2023 Revised: 17 January 2023 Accepted: 17 January 2023 Published: 23 January 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

rapidly from gels) over highly extended timescales. Complex coacervates formed from poly(allylamine hydrochloride) (PAH) complexed with the multivalent anion tripolyphosphate (TPP), for instance, have recently been shown to sustain the release of diverse small molecules (including drugs and disinfectants) over multiple months [9,15,21,27].

While the highly sustained release enabled by these viscoelastic materials could be useful in an array of biomedical, household, and industrial technologies, the duration of the benefits derived from such release can sometimes be limited by the payload delivery ultimately becoming too slow to be efficacious (once the most-accessible portion of their payload closest to the surface is released) [21,27]. A recent study, for instance, revealed that, while the long-term bactericide release from PAH/TPP coacervates can provide antibacterial benefits over multiple weeks, this activity is ultimately lost (even though only a fraction of the bactericidal payload is released) [21]. The evident reason for this ultimate activity loss is that the release rate declines with time and, after a few weeks, becomes too slow to be effective. Indeed, with certain coacervate/payload molecule combinations, the slower-than-desired release can impose even greater limitations on the coacervate's applicability (e.g., to situations/applications where the volumes of the release media relative to the coacervate are very low, such that the released actives are not diluted below the minimal concentration needed for their efficacious use) [27].

To overcome these limitations of insufficient release rates or early activity loss, here we explore the use of mechanical stimulation—namely, periodic perforation and compression as a method for stimulating or reactivating small molecule release from coacervate matrices. Mechanical crushing of coacervate-based microcapsules (e.g., in ink, fragrance, or food formulations) is a well-known approach to achieving rapid stimulus-responsive release of hydrophobic payloads such as oil droplets [28–31]. However, we are not aware of any reports demonstrating mechanical stimulus use for controlling (1) long-term (multiday) release from complex coacervates, (2) the release of hydrophilic/water-soluble actives from complex coacervates, or (3) the release from continuous coacervate phases (i.e., macroscopic matrices) rather than dispersed coacervate microcapsules. To this end, using macroscopic PAH/TPP coacervates and the Rhodamine B (RhB) dye as a model complex coacervate and small, hydrophilic payload system, we analyze the effect of mechanical stimulation (using UV-vis spectroscopy) on long-term small molecule release. To gain further insight into these effects, the impacts of mechanical stimulation on coacervate swelling are also analyzed (through gravimetry and digital photography) and related to changes in the release profiles. Finally, we discuss the opportunities offered by (and limitations of) this approach in potential applications of complex coacervates.

#### **2. Materials and Methods**
