CPG’s loading capacity is limited by the density and distribution of surface silanol groups. Furthermore, surface area and number of anchoring silanol groups varies inversely with pore size. Thus, longer and/or bulkier oligos, which require minimum pore sizes of 1,000 Å or more, are made on CPGs with maximum nucleoside loadings below 50 µmoles/gram.
While low-level cross-linked PS supports can accommodate high ligand loadings on a dry weight basis, they expand when solvated, and column loadings must be limited to accommodate the swelling. Also, column backpressure can increase throughout the synthesis as the growing oligo causes further support expansion.
Finally, column heights are limited due to the compressibility of the polymer supports. These drawbacks can limit the utility of such supports, and add further complexity to scale-up operations.
To address these deficiencies, a hybrid support based on CPG has been developed. Through a very thin, highly functionalized polymer layer based on polystyrene, much higher ligand loadings (<2–5x) than conventional CPG can be achieved, removing the pore size/loading trade-off of conventional CPG, since the number of unhindered ligands no longer depends on surface silanol distributions.
Through careful design of the polymer structure, a uniform, sterically unhindered distribution of ligands is obtained. Since the polymer coating is very thin (~50 Å) and conformal, the well-defined, stable pore structure and low backpressure, typical of CPG, is retained (Figure 1).
As with conventional CPG, and unlike polystyrene supports, the pore size and pore volume of HybCPG may be specifically tailored for each application to maximize the product purity. The thin polymer layer avoids expansion of the bulk support in synthesis solvents and protects the underlying glass from attack by alkali or fluoroacid reagents.
The dimensional stability of the support also reduces the complexity of process scale-up as no accommodations are needed for swelling.