Amphiphilic Cellulose Ethers Designed for Amorphous Solid Dispersion via Olefin Cross-Metathesis

The design of cellulose ether-based amphiphiles has been difficult and limited because of the harsh conditions typically required for appending ether moieties to cellulose. Olefin cross-metathesis recently has been shown to be a valuable approach for appending a variety of functional groups to cellulose ethers and esters, provided that an olefin handle for metathesis can be attached. This synthetic pathway gives access to these functional derivatives under very mild conditions and at high efficiency. Modification of ethyl cellulose by metathesis to prepare useful derivatives, for example, for solubility and bioavailability enhancement of drugs by amorphous solid dispersion (ASD), has been limited by the low DS(OH) of commercial ethyl cellulose derivatives. This is problematic because ethyl cellulose is otherwise a very attractive substrate for synthesis of amphiphilic derivatives by olefin metathesis. Herein we explore two methods for opening up this design space for ether-based amphiphiles, for example, permitting synthesis of more hydrophilic derivatives. One approach is to start with the more hydrophilic commercial methyl cellulose, which contains much higher DS(OH) and therefore is better suited for introduction of high DS of olefin metathesis "handles". In another approach, we explored a homogeneous one-pot synthesis methodology from cellulose, where controlled DS of ethyl groups was introduced at the same time as the ω-unsaturated alkyl groups, thereby permitting complete control of DS(OH), DS(Et), and ultimately DS of the functional group added by metathesis. We describe the functionalized derivatives available by these successful approaches. In addition, we explore new methods for reduction of the unsaturation in initial metathesis products to provide robust methods for enhancing product stability against further radical-catalyzed reactions. We demonstrate initial evidence that the products show strong promise as amphiphilic matrix polymers for amorphous solid dispersion and other applications.