Alternatives to C18 When Adsorption Occurs in Drug–Excipient Separations

Record: 617

Category: Column Selection
Product: ODP2 HP-4D
Sample: Excipient

Question
I am using a C18 column to separate a drug substance from excipients, but I am observing strong adsorption.
The molecular weight range of interest is approximately 500–2000 Da, and the mobile phase contains 80–100% acetonitrile.

Because of adsorption issues, I am considering size exclusion chromatography (SEC/GPC) instead of reversed-phase HPLC.
However, I am concerned that typical SEC pore sizes may be too large for this molecular weight range.
Do you have a suitable column recommendation?

Answer

When strong adsorption is observed on silica-based C18 columns, switching to a polymer-based stationary phase is often an effective way to reduce secondary interactions.

Although SEC/GPC is sometimes considered as an alternative, size exclusion chromatography is generally not effective for small molecules in the 500–2000 Da range due to limited size discrimination. Polymer SEC columns (e.g., SB series) are designed primarily for polymers and higher-molecular-weight oligomers and may not provide sufficient resolution for low-MW drug and excipient separations.

Shodex ODP2 HP-4D (4.6 × 150 mm) is a polymer-based reversed-phase column designed to minimize adsorption commonly encountered with silica-based C18 phases. It is well suited for small-molecule pharmaceuticals, supports high organic mobile phases, and provides improved recovery and peak shape for compounds that adsorb on conventional RP columns.

In specific cases—such as separating surfactant-type excipients from an active ingredient—a GF-4A column may be evaluated. However, for most small-molecule separations in this molecular weight range, SEC is unlikely to provide adequate resolution and should be considered only after RP alternatives are assessed.

Additional Comments

Adsorption issues are often due to silica surface interactions, not size effects. Polymer-based RP columns frequently provide a practical solution when C18 fails. If SEC must be evaluated, feasibility should be confirmed experimentally.

Shodex can support sample testing and demo columns depending on the application. Technical Support can help confirm the most appropriate approach based on analyte and excipient properties. 

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