Synthesis and structure–property evaluation of cellulose ω-carboxyesters for amorphous solid dispersions

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.

► Novel class of cellulose ω-carboxyesters synthesized and fully characterized.
► No substitution regioselectivity found for the esterification reactions.
► CA suberate, sebacate very effective crystallization inhibitors for ritonavir.
► Derivatives promising for amorphous dispersion to enhance drug bioavailability.