A simplified approach to determine effective surface area and porosity of low bulk density active pharmaceutical ingredients in early development

• Guideline to enhance accuracy of true density measurements.
• Surface roughness parameter to access the spherical morphology and shape.
• Assess the effective surface area of SDDs with a theoretical factor of 2.28.

It can be difficult to accurately measure true density of low bulk density materials, which are frequently used in drug products. This was demonstrated on a crystalline model API. Uncertainty was related to insufficient sample volume. The error function was theoretically described by assuming an inverse relation to the sample volume. Hence, an easy to implement guideline to increase accuracy was established. Verification was performed using spray dried dispersions, SDDs. Practically, bulk density rather than sample volume was used for risk evaluation. Procedures such as compacting a sample into a pellet or using a low volume instrumental calibration mode were implemented. Risk assessment of morphology or crystal form change was included in the guideline.Furthermore, a simplified approach using true density as a central parameter was developed to assess surface area and porosity. For spherically shaped SDDs, surface area can be estimated from true density and particle size, and porosity can be estimated from true and bulk densities. A surface roughness parameter, theoretically derived, leads to a surface area scale factor of 2.28, which provides results in good agreement with the experimentally obtained surface areas. Also, SDD porosities follow a trend similar to those obtained by mercury porosimetry.

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