(T1130-08-49) Excipient Characterization: Solid Density and Surface Area

Purpose: Physical properties such as tapped and skeletal density and specific surface area of excipients such as milled lactose (ML), sieved lactose (SL), methylcellulose (MC), and magnesium stearate (MS) have been analyzed and the results correlated to their properties such as purity, flowability, compatibility, and compressibility.

Methods: Tapped density measurements were performed according to USP < 616 > method 1 at nominally 250 taps per minute and a drop height of 3 mm. Skeletal densities were measured by gas pycnometry using helium gas at ambient temperature. Surface area measurements were determined by nitrogen gas adsorption at 77 K on a vacuum volumetric gas sorption analyzer after a period of degassing under vacuum to remove surface moisture. Surface area was calculated by applying the BET method according to USP < 846 >¹.

Results: : Milled lactose (ML), sieved lactose (SL) Methylcellulose (MC), and magnesium stearate (MS), were studied for flowability. ML, SL, MC were prepared in 5 ways: (1) raw, as received; (2) conditioned to 45% RH and (3) 85% RH; samples previously conditioned at 85% RH were then dried at (4) 40^oC and (5) 80 ^oC for 30 minutes. Figure 1 shows the values obtained for tapped density, and the Hausner Ratio² and Carr Index³ were calculated from the tapped density data. ML, SL, MC, and MS were also studied for purity by comparing measured skeletal density to theoretical values. Only the raw (unconditioned) materials were studied. To examine repeatability of results, MS was run three times using helium pycnometry and a repeatability of 0.09% was found. Percent purity calculations were performed using the following theoretical density values: MS 1.08 g/cm³, ML & SL: 1.546 g/cm³, MC 1.33 g/cm³. Results are given in Figure 2, which shows a significant difference between the sugars and the non-sugars. The specific surface area of any solid relates to its particle morphology and can be indicative of its manufacturing and thermal history, as well as its suitability in a specific application. Specific surface area, the dominant parameter affecting solubility (see dissolution rate equation), of ML SL, MC, and MS was measured. It was determined that MS has the highest surface area, followed by ML, SL, and MC. The physical form of lactose has a significant impact; the BET area of milled lactose is almost 3 times that of sieved lactose. Figure 2 summarizes the results.

Conclusion: This work shows that density and surface area values provide comprehensive characterization and differentiation of various common excipients. The measured characteristics provide vital morphological and particle interaction information from which the most appropriate excipients can be selected. The MS and MC materials were the least pure (95%) as determined by comparing the measured skeletal density to the theoretical values; in terms of MS presumably from a chemical perspective which usually contains some of the salt from palmitic acid, and MC in terms of its crystallinity. Both of the lactose samples (ML and SL) – as determined in the same manner – indicated they were 99% pure. The sieved lactose shows the highest tapped density of the materials studied. The flow properties of the two low surface area samples, MC and SL as determined by the Hausner ratio, show slight susceptibility to humidity conditions and drying, suggesting predictable behavior over a range of ambient conditions during processing. The higher area milled lactose (ML), however, did show significant differences over the same range of conditions which would require greater attention to controlling process conditions for predictable and reproducible behavior. Significant differences between the surface areas of SL and MS suggests that dissolution rates between the two would be similarly affected. The relatively low surface area of sample MS compared to the typically used grades supports the notion that magnesium stearate should be formulated by surface area and not by weight so as to not adversely affect tablet hardness or disintegration time at the expense of injection force. The BET area is strongly correlated to flowability, as the extent of measurable surface area corresponds to excess surface free energy available for particle-particle bonding – and, perhaps surprisingly, it is largely independent of surface chemistry. Parameters such as surface area, bulk density, and skeletal density can be measured accurately using reliable instrumentation, and knowing these characteristics provides vital information about the most appropriate excipients to use in order to avoid defects which can cause the discharge of the batch at the end of manufacturing. Combining the results of several measurements can play a significant role in advancing excipient science and quality.

References: 1) https://doi.usp.org/USPNF/USPNF_M99635_01_01.html
2) Carr R.L. (1965) Chem. Eng. 72, 163.
3) Hausner H.H. (1967) Int. J Powder Mettall. 3, 7.

Figure 1: Tapped density, Carr Index, and Hausner Ratio data.

Figure 2: Summary statistics of skeletal density and BET surface area.