The following article has been authored by Chris Lewis.
At times during dissolution testing, particularly with USP Apparatus 2 (paddle), a ‘cone’ can form in the bottom of a dissolution vessel. This ‘cone’ is the result of the accumulation of undissolved material, such as excipients or drug particles, directly beneath the stirring paddle. This occurs because the center of the vessel's hemispherical bottom is a hydrodynamic "dead zone" where hydrodynamic shear forces are too low to lift the particles which allow gravity to settle them in a cone shape.
Key Causes of Coning
• Low Hydrodynamic Activity (Dead Zone): The primary cause is the lack of sufficient agitation in the exact center of the vessel bottom.
• Formulation Characteristics:
· High Density Excipients: Dense insoluble ingredients (e.g., calcium phosphate) tend to settle quickly.
· Brittle Fillers: The type of filler used in the tablet formulation can significantly impact the extent of coning.
· Disintegrating/Beaded Forms: Rapidly disintegrating tablets or products containing beads often lead to accumulation.
• Low Stirring Speeds: Operating at low RPMs (e.g., 50 RPM) is less effective at breaking up the mound compared to 75 or 100 RPM.
• Poorly Aligned Apparatus: An off-center or non-vertical shaft, or a paddle that is too close to the bottom, can exacerbate the creation of these calm, non-stirred areas.
• Low Medium Volume: Using a low volume of dissolution medium (e.g., 500 mL) can reduce overall agitation, making coning more likely.
Consequences and Mitigation
When a cone forms, it may affect dissolution results. Having particles in the center of this cone may prevent the media from interacting with the drug particles, leading to low results.
• Remedy: To break up the cone, it is recommended to increase the RPM to 75 or 100, ensure proper instrument alignment, or use a non-compendial Apex vessel, which has a small pyramid structure at the bottom to eliminate the dead zone.