title: Synthesis and structure-property evaluation of cellulose ω-carboxyesters for amorphous solid dispersions.
abstract: The use of amorphous solid dispersions (ASDs) is an effective and increasingly widely used approach for solubility enhancement of drugs and drug candidates with poor aqueous solubility. Successful molecular dispersion of drugs in polymer matrices requires new polymers that are designed to meet all ASD requirements, including drug release and prevention of drug recrystallization in storage or from solution. We describe herein design and synthesis of a new series of cellulose ω-carboxyalkanoates for ASDs, by reaction of cellulose with long-chain diacids that have been monoprotected as benzyl esters at one end, and monoactivated as acid chlorides at the other. Glass transition temperatures (Tg) of these cellulose ω-carboxyesters exceed ambient temperature by at least 50 °C, providing a sufficient ΔT to prevent drug mobility and crystallization. Cellulose acetate suberates and sebacates prepared in this way are extraordinary solution crystal growth inhibitors for the poorly soluble anti-HIV drug ritonavir. These new cellulose ω-carboxyesters have strong potential as ASD polymers for enhancement of drug solubility and bioavailability.
authors.affiliation: Macromolecules and Interfaces Institute, Virginia Tech, Blacksburg, VA 24061, United States; Department of Sustainable Biomaterials, College of Natural Resources and Environment, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Liu
authors.forename: Grace A
authors.initials: GA
authors.lastname: Ilevbare
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Cherniawski
authors.forename: Earl T
authors.initials: ET
authors.lastname: Ritchie
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Edgar
mesh_terms: D002482:Cellulose / Q000138:chemical synthesis* / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry*; D004952:Esters; D019438:Ritonavir / Q000737:chemistry; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004337:Drug Carriers; D004952:Esters; D002482:Cellulose; D019438:Ritonavir
keywords: Amorphous solid dispersion; Cellulose acylation; Cellulose esters; Cellulose ω-carboxyalkanoates; Crystal growth inhibition; Oral drug delivery