Design and synthesis of cellulose ω-carboxythioalkyl alkanoate derivatives for amorphous solid dispersion of hydrophobic compounds
Year: 2025
Type: article
Abstract: Many drugs, marketed and developmental, are crystalline, hydrophobic, and hence have poor water solubility. Oral drug delivery by amorphous solid dispersion (ASD) enhances solubility by molecular dispersion of drug molecules in a polymeric matrix. Commercial ASD polymers may effectively increase drug bioavailability, but they sometimes fail, as none were designed specifically for ASD. Herein we design, synthesize, and initially evaluate in vitro novel ω-carboxy-thioalkyl cellulose ester derivatives as ASD polymers. We hypothesized that incorporating hydrophobic side chains and hydrophilic carboxylate groups by regioselective thiol displacement of bromide on 6-bromo-6-deoxy cellulose acetate would afford polymers meeting essential ASD physicochemical requirements. CA derivatives with different tether chain lengths and functionalities were synthesized through regioselective C6 bromination of CA, then displacement with functional thiols. ω-Carboxy-thioalkyl ASD performance was evaluated as similar to the best commercial ASD polymers using model drugs. For basic drugs, CA-based polymers appeared more sensitive to drug-polymer interactions that reduce ASD release, but synthesis of more hydrophilic derivatives rescued release. Drug-polymer complexation with acidic polymers was observed for basic drugs; however, polymer salt formation with a bulky counterion inhibited complexation and improved release. Generally, thioacid-based polymers released more slowly but appeared less sensitive to drug loading effects than commercial polymers.
Source: Carbohydrate Polymers
Authors: Sara Yazdi, Emily Benson, Lynne S. Taylor, Kevin J. Edgar
Institutions: Virginia Tech, Purdue University West Lafayette
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,340
OpenAlex ID: W4416097266