(M0930-11-64) Low Surface Area Measurements of Excipients, Replacing Krypton with Nitrogen

Purpose: For low surface area material analysis per USP 846¹ and other standard methods, krypton (77 K) is typically recommended as the analysis gas, but due to the cost associated with krypton gas and instrumentation requirements, it would be desirable to determine the same material properties using an inexpensive alternative such as nitrogen (77 K). The ability to analyze low surface excipients commonly used in formulation with nitrogen for BET multi-point surface area measurements is demonstrated. If nitrogen provides a satisfactory correlation coefficient (good BET linearity) of the BET surface area plot, there is a lower cost and more readily available alternative gas for these analyses.

Methods: Lactose monohydrate is an excipient used in the pharma industry and its surface area characterization is relevant as part of multiple formulations. Depending on the grade it, surface areas that are less than or equal to 1m²/g. Per USP it is recommended, but not required, to evaluate surface area with krypton due to the low surface area. For this study two aliquots from the same batch of lactose monohydrate were prepared and analyzed in triplicate on an Anton Paar Nova 800 surface area analyzer to determine repeatability between runs and reproducibility between analytical stations using N₂ (77 K).  Two aliquots of a mixture of an international standard BCR-169 for ultra-low range BET analysis were also prepared and analyzed in the same way. As there are no reference materials in this ultra-low range, a sample with ~0.01 m²/g surface area was created by diluting BCR-169 (nominal surface area of 0.10 m²/g) with copper beads. The BET surface area was determined in the range of 0.05 - 0.3 p/p_o.

Results: The lactose monohydrate results are shown in Figure 1. About 3.6 grams of material was used and, even with under 2 m² of total surface area in the sample cell, the data show excellent linearity ( > 0.999 correlation coefficient) and repeatability of the surface area of < 2% was achieved, showing the good sensitivity of the instrument to lower surface area materials. The ultra-low mixed sample of BCR 169 and copper beads results are shown in Figure 2. ~0.37 m² total surface area of sample was used for the measurements. All measurements gave a correlation coefficient for the BET plot of > 0.999. Repeatability of the BET surface area values is 3.5-4%. BET surface area values for all three measurements only varied by 0.001 m²/g, but because of the low overall surface area, even a difference that small leads to the 3-4% repeatability. Nova mode (helium free) allows the user to save analysis time and helium expenses by operating strictly with nitrogen. Analysis time of nitrogen in Nova mode took 25.35 min (blue line) vs. 250 min with krypton in helium measure mode (brown line), as shown in Figure 3.

Conclusion: Based on the performance observed on repeatability and reproducibility with the surface area analyzers with less than 2 m² in the cell present, it is possible to perform characterization on ultra-low surface area materials with nitrogen while obtaining good linear BET plots and valid data. There are several advantages for analyzing low surface area material with the BET method using nitrogen in place of krypton due to nitrogen being more readily available and less expensive.  Additionally, in order to perform nitrogen analyses, a turbomolecular vacuum pump and low-resolution pressure transducers are not needed.

References: 1) USP 846: Specific Surface Area
https://www.usp.org/harmonization-standards/pdg/general-chapters/specific-surface-area

Acknowledgements: The authors have no conflicts of interest to declare.


Figure 1: BET Surface area measurements of lactose monohydrate at 77K.


Figure 2: Ultra low BET surface area measurements of BCR 169 with copper beads.


Figure 3: Comparison of lactose monohydrate analysis with nitrogen (blue line) to krypton (brown line), showing good correlation for both samples, with a faster analysis time for nitrogen (26 minutes) compared to krypton (250 minutes).