(M1430-03-21) In Vitro Evaluation of Polyvinyl Alcohol (PVA) Cryogels for Sustained Release of Anionic and Cationic Drugs

Purpose: Cryogel-based drug delivery systems represent an innovative platform for sustained therapeutic release, offering advantages such as biocompatibility, mechanical robustness, tunable porosity, and tailored drug release profiles [1,2]. These supermacroporous scaffolds are formed under sub-zero conditions via cryogelation, which creates interconnected pores ideal for regulating matrix–drug interactions [1,2]. Cryogels are particularly valuable for gastrointestinal and other site-specific drug delivery applications, where sustained release can reduce dosage frequency, improve patient compliance, and minimize side effects associated with fluctuating drug levels [1–4]. Incorporating oppositely charged drugs cationic and anionic into a neutral PVA matrix allows modulation of release kinetics via electrostatic interactions, pH responsiveness, and the drug’s physicochemical properties [1,2,5,6,8]. This study evaluates the in vitro drug release behavior of two ionically distinct model drugs diclofenac sodium (DIC, anionic) and dextromethorphan hydrobromide (DXM, cationic) from 5% PVA cryogels in an acidic environment (pH 1.2), with emphasis on swelling dynamics and matrix–drug interactions for sustained release.

Objective:  To investigate the swelling behavior and release kinetics of 5% PVA cryogels loaded with oppositely charged drugs (DIC and DXM) at pH 1.2, and to assess their utility as sustained release drug delivery platforms.

Methods: Cryogel Fabrication: PVA (MW 146,000–186,000 Da, ≥99% hydrolyzed) was dissolved at 5% w/w in isotonic saline via continuous magnetic stirring to form two drug-loaded batches (125 mg DIC + 5% PVA & 125 mg DXM + 5% PVA). The solutions were mixed until homogeneous and stored at room temperature overnight. Aliquots (0.3 mL) were transferred into molds and subjected to freeze–thaw cycles: (−20°C for 24 hours, thawed at 10°C, then refrozen at −20°C for 2 hours and thawed at 10°C ). Swelling Ratio (SR%): The percent change in gel weight after immersion, indicating water uptake or loss. Cryogels were weighed prior to immersion (W₀) and again after 14 days (W_t) of exposure to 900ml of simulated gastric fluid (SGF) (pH 1.2, 37 ± 0.5°C, 50 rpm) using USP Apparatus II (paddle method). All experiments were conducted in triplicate. The swelling ratio (SR) and percent swelling ratio (SR%) were calculated using: SR=W_t-W₀/W₀, where SR% = SR X 100. Drug Release (%): Cumulative release of DXM or DIC over time were quantified via spectrophotometry at wavelengths 278 nm for DXM and 276 nm for DIC. Cryogels were immersed in 900ml SGF (pH 1.2, 37 ± 0.5°C) and agitated at 50 rpm for 14 days. At predefined time points, 1 mL samples were withdrawn and analyzed using a UV-Vis spectrophotometer. Calibration curves were prepared for both DXM and DIC to quantify drug concentration over time. Each test was performed in triplicate.

Results: Negative SR values were received for both PVA cryogels DXM (−46.09% SR%) and DIC (−50.10% SR%), suggesting net weight loss, likely due to dehydration or matrix degradation in acidic conditions. The greater shrinkage observed in DXM-loaded cryogels indicates stronger PVA–PVA hydrogen bonding at low pH, possibly reducing drug diffusion pathways.  The acidic environment thus not only affects the drug’s ionization but also enhances matrix–matrix interactions, compounding the release differences. Both diclofenac sodium (DIC) and dextromethorphan hydrobromide (DXM) exhibited sustained release from PVA cryogels over 14 days. However, DIC demonstrated a consistently higher cumulative release (96.4%) compared to DXM (88.2%). This difference is strongly influenced by the drugs’ ionization states and their resulting interactions with the neutral PVA matrix under acidic conditions (pH 1.2). At this low pH, DIC, a weak acid, exists predominantly in its unionized (protonated) form, reducing its electrostatic affinity for the PVA network and thereby facilitating faster diffusion and higher release. Conversely, DXM, a weak base, remains largely ionized (protonated and cationic) at pH 1.2, which may promote stronger ion–dipole or hydrogen bonding interactions with the hydroxyl groups of PVA or any residual negatively charged sites within the matrix, leading to a slower diffusion of DXM from the cryogel network.

Conclusion: This study demonstrates that drug ionization plays a critical role in governing release kinetics from PVA cryogels under acidic conditions. At pH 1.2, diclofenac sodium (DIC), a weak acid, remains largely in its unionized form, reducing its interaction with the neutral PVA matrix and enabling higher cumulative release (96.4%). In contrast, dextromethorphan hydrobromide (DXM), a weak base, is predominantly ionized (cationic) at this pH, which promotes stronger interactions with PVA via hydrogen bonding or ion–dipole forces, leading to lower release (88.2%). Furthermore, cryogel shrinkage due to hydrogen bonding among PVA chains was more pronounced in DXM-loaded formulations (−50.10% SR) than in DIC-loaded ones (−46.09% SR), further impeding DXM diffusion. These findings highlight the interplay between drug ionization, polymer–drug interactions, and matrix swelling behavior in modulating sustained release.

References: 1. Omidian H, Wilson RL. Advances in cryogels for drug delivery and biomedical engineering. Journal of Bioactive and Compatible Polymers. 2025;40(3):282-300. doi:10.1177/08839115251320652
2. Saylan, Y., & Denizli, A. (2019). Supermacroporous Composite Cryogels in Biomedical Applications. Gels (Basel, Switzerland), 5(2), 20. https://doi.org/10.3390/gels5020020
3. Razavi M, Qiao Y, Thakor AS. Three-dimensional cryogels for biomedical applications. J Biomed Mater Res A. 2019 Dec;107(12):2736-2755. doi: 10.1002/jbm.a.36777. Epub 2019 Aug 27. PMID: 31408265; PMCID: PMC7929089.
4. Shi Y, Lu A, Wang X, Belhadj Z, Wang J, Zhang Q. A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives. Acta Pharm Sin B. 2021 Aug;11(8):2396-2415. doi: 10.1016/j.apsb.2021.05.002. Epub 2021 Jun 17. PMID: 34522592; PMCID: PMC8424287.
5. Parhi R. Cross-Linked Hydrogel for Pharmaceutical Applications: A Review. Adv Pharm Bull. 2017 Dec;7(4):515-530. doi: 10.15171/apb.2017.064. Epub 2017 Dec 31. PMID: 29399542; PMCID: PMC5788207.
6. Cai, Y.P., et al., Effect of glycerol on sustained insulin release from PVA hydrogels and its application in diabetes therapy. Experimental and Therapeutic Medicine, 2016. 12(4): p. 2039-2044.
7. de Lima, G. G., Barbosa, R. R. C., de Andrade Santos, M. P., Chee, B. S., Esteves Magalhães, W. L., Devine, D. M., & Nugent, M. J. D. (2020). Effect of unidirectional freezing using a thermal camera on polyvinyl (alcohol) for aligned porous cryogels. Quantitative InfraRed Thermography Journal, 18(3), 177–186. https://doi.org/10.1080/17686733.2020.1732735
8. Omidian, H.; Dey Chowdhury, S.; Babanejad, N. Cryogels: Advancing Biomaterials for Transformative Biomedical Applications. Pharmaceutics 2023, 15, 1836

Acknowledgements: Affiliation: All authors are associated with the College of Pharmacy at Nova Southeastern University in Fort Lauderdale, Florida. We acknowledge Nova Southeastern University facilities for the implementation of the research. RLW designed, analyzed, wrote the manuscript, and conducted experiments. RLW and HO reviewed, revised and edited the content. Disclaimer: - The statements, opinions and data contained in this abstract are solely those of the individual author(s) and contributor(s) and not of the AAPS, or the reviewer/editor. AAPS and/or the reviewer/editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Funding: - This research received no external funding. Disclosure or conflict of interest statements: - The authors declare no conflicts of interest.

Figure 1. Showing the PVA cryogel formulations and dissolution apparatus test set-up using USP Apparatus II (paddle method). (A) i) 5% PVA Cryogel + 125 mg Dextromethorphan Hydrobromide ii) 5% PVA Cryogel + 125 mg Sodium Diclofenac. (B) Represents PVA Cryogels immersed in simulated gastric fluid (pH 1.2, 37 ± 0.5°C, 50 rpm) using USP Apparatus II (paddle method).

Table showing the mean weights (n=3) and swelling ratios for 5% PVA Cryogels with DIC & DXM.