Specific Surface Area Measurement of Intact Lyophilized Cakes

The increasing significance of the physical characterization of pharmaceuticals necessitates the need to have analytical techniques capable of providing representative data of the materials of interest.

The robustness of formulas, products, and processes is ensured by companies through implementation of Process Analytical Technologies (PAT) and Quality by Design (QbD) initiatives. These initiatives can be effective in the key areas of lyophilized products for product and process knowledge.

Significance of Surface Area Measurement

Key data regarding product consistency and process capability can be obtained from the surface area measurement of lyophilized cakes. In BET surface area analysis, these cakes need to be manipulated before analysis in order to feed them into the instrument sample tubes. This may lead to erroneous measurements, affecting the repeatability and robustness of the experiment and misrepresenting the actual surface area of the sample. In addition, it is not possible to perform further analysis due to this type of destructive sample preparation technique.

Instrumentation and Experimental Procedure

Possible differences originating from non-standardized extraction methods used for removing cake from the vials may provide less reliable information about the surface area of the material being analyzed. Micromeritics has designed a special prototype lyophilization vial holder apparatus (Figure 1), which, when attached to the Micromeritics ASAP 2420 Surface Area and Porosity Tester, facilitates surface area measurement of intact lyophilized cakes in a non-destructive manner.

Micromeritics’ special prototype lyophilization vial holder apparatus

Figure 1. Micromeritics’ special prototype lyophilization vial holder apparatus

A 48-square-foot lyophilizer was used to process full chamber loads of model product in 20cc tubing vials under a GMP aseptic environment. Amorphous sucrose was chosen as the sample for this preliminary BET surface area analysis. A standard freezing technique or a controlled nucleation approach was employed by lyophilization cycles, utilizing rapid depressurization of the product chamber.

Although various techniques may control the temperature and repeatable performance can be provided by commercial temperature controllers, this preliminary study focuses on the subject of vacuum versus flowing degas instead of temperature control.

After placing the vial onto the sample holder, the combination of sample holder/vial is then attached to the analysis port of the ASAP 2420 by means of a ferrule, frit and O-ring.

Each sample is subjected to a step-wise manual evacuation. The samples are retained in the analysis port under evacuation without any additional external heat for around 16 hours to ensure the removal of any contaminants before beginning the analysis.

Sample analysis begins at liquid nitrogen temperature without backfill at the onset of the experiment. Krypton is used for sample analysis over a relative pressure range of 0.045-0.24 P/P0.

Experimental Results

The following table summarizes the results for five separate analyses, reporting Specific Surface Area (SSA) for both intact cakes and manipulated cakes.

Sample Type SSA (m2/g) Manipulated Cakes SSA (m2/g) Intact Cakes % Difference
1 Sucrose 0.8663 0.5481 -36.7
2 Sucrose 0.8030 0.5167 -35.7
3 Sucrose 0.4384 0.2060 -53.0
4 Sucrose 0.3704 0.1868 -49.6
5 Sucrose 0.8854 0.4609 -47.9

The results reveal that surface area of the intact lyophilized cakes is roughly 35 – 55% less than that of manipulated cakes. Further development of this product improvement will bring about an invaluable characterization method for lyophilized products in stages of product development and scale-up. Furthermore, this characterization technique can be used as an implementable PAT tool to control this key process parameter.


The study results show that the specific surface area of intact lyophilized cakes varies significantly from that of manipulated cakes, demonstrating key and meaningful developments being made for surface area testing of lyophilized products.

Micromeritics continues to work on the development of this technology by iterations of the sample vial holder and analysis conditions. If successful, this technology will not only enable a simple, direct and effective approach in performing surface area measurements of intact lyophilized cakes, but also allow for further physical characterization analysis using the same sample of intact cakes.

This information has been sourced, reviewed and adapted from materials provided by Micromeritics Instrument Corporation.

For more information on this source, please visit Micromeritics Instrument Corporation


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