International Journal of Pharmaceutics 568 (2019) 118522

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International Journal of Pharmaceutics

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BET surface area measurement of commercial magnesium stearate by T

krypton adsorption in preference to nitrogen adsorption
⁎
Darren P. Lapham , Julie L. Lapham
MCA Services, Unit 1A Long Barn, North End, Meldreth, Cambridgeshire, UK

A R T I C LE I N FO A B S T R A C T

Chemical compound studied in the article: Magnesium stearate is an extremely common pharmaceutical excipient and the measurement of BET surface area
Magnesium stearate (PubChem CID: 11177) via nitrogen adsorption is undertaken during pharmaceutical formulation and manufacture. In this paper, four
commercial magnesium stearate materials in mono- and di-hydrated forms are analysed by nitrogen and krypton
Keywords: adsorption for the calculation of BET surface area. BET surface area via nitrogen adsorption is shown to be
Magnesium stearate erroneously high due to a structural swelling and adsorbate encapsulation effect occurring throughout the BET
Gas adsorption
range and which should preclude the use of BET theory. However, with krypton adsorption this effect com-
BET surface area
mences at higher adsorption pressures and it is possible to calculate BET surface area which better represents the
Nitrogen adsorption
Krypton adsorption true surface area of the material. The disparity between nitrogen and krypton adsorption is greater for the di-
Tablet formulation hydrate form: the mean average BET surface area of 10 samples from the same di-hydrate containing batch are
23.18 m2g−1 via nitrogen adsorption and 6.78 m2g−1 via krypton. It is also shown than the standard deviation of
BET surface area across 10 analyses of each of the four batches is considerably lower via krypton adsorption.
Finally, an analytical protocol for krypton adsorption onto magnesium stearate for BET surface area measure-
ment is established.

1. Introduction et al., 2006). Therefore, it is necessary to determine the optimum

Magnesium Stearate, MgSt, is one of the most common excipients
added to solid dosage pharmaceutical preparations. Added as a lu-
bricant, MgSt facilitates clean release of compacted powder blends from
the press die and also provides improved flowability and homogeneity
of the powder blend itself. A benefit of MgSt over alternative lubricants
is that desired lubricating effects are obtained with low proportions,
typically < 2 wt% of MgSt being required. For the plate-like form of
MgSt particles, the lubricating mechanism is understood and char-
acterised. On mixing, aggregated particles shear, forming smaller par-
ticles which cover the surfaces of the other powder constituents. The
effect is to reduce friction and increase flowability within the powder
blend (Hussain et al., 1992; Wang et al., 2010; Lakio et al., 2013; Morin
and Briens, 2013; Li and Wu, 2014; Mosig and Kleinebudde, 2014).
However, MgSt also has deleterious effects on finished tablets, such
as increased dissolution rate (Levy and Gumtow, 1963; Wang et al.,
2010; Uchimoto et al., 2011; Li and Wu, 2014), reduced tablet strength
(Shah and Mlodozeniec, 1977; Johansson, 1984; Vromans et al., 1988;
Zuurman et al., 1999; Wang et al., 2010), alteration of disintegration
characteristics (Johansson, 1984; Uchimoto et al., 2011) and the ag-
glomeration of other dry powder constituents (DesRosiers Lachiver
loading of MgSt in order to maximise the effects of lubrication whilst
minimising deleterious effects.
MgSt exists in a number of hydration states: mono-, di- and tri-hy-
drates as well as anhydrous and amorphous forms which exist in a ra-
ther complex, interchangeable, manner depending on the temperature
and humidity to which the materials are exposed (Ertel and Carstensen,
1988; Rajala and Laine, 1995). It has been shown that MgSt of higher
hydration state offers improved lubricity (Rajala and Laine, 1995) and,
specifically, MgSt di-hydrate with a plate-like crystal morphology offers
optimum lubricating qualities (Marwaha and Rubinstein, 1988; Miller
and York, 1985b; Li and Wu, 2014).
It is critical that the physical factors influencing the performance of
a drug are understood and controlled at all stages of formulation and
development. Furthermore, during production it is essential to monitor
and control physical characteristics which are subject to variability in
order to ensure intra-batch and inter-batch uniformity of the final do-
sage form. For MgSt, physical properties likely to influence both lu-
bricating efficiency and deleterious effects are subject to considerable
variability. Of the physical characteristics of a lubricant, particle size
and specific surface area are inextricably related and are thought to be
critical to the determination of lubricant surface coverage and thus

⁎
Corresponding author.
E-mail address: darren@mcaservices.co.uk (D.P. Lapham).

https://doi.org/10.1016/j.ijpharm.2019.118522
Received 5 April 2019; Received in revised form 18 June 2019; Accepted 13 July 2019
Available online 15 July 2019
0378-5173/ © 2019 Elsevier B.V. All rights reserved.
D.P. Lapham and J.L. Lapham
lubricating efficiency (Rajala and Laine, 1995; Haware et al., 2014; Li
and Wu, 2014). The measurement of particle size and surface area
should be made with reference to the primary particles as opposed to
agglomerated material since the former are responsible for lubricant
film formation. This may be of issue to particle size analysis, where the
tendency of MgSt to form agglomerates could pose problems for both
wet and dry analytical techniques. Wet particle sizing techniques have
additional problems posed by the combined hydrophilic and hydro-
phobic nature of MgSt and its solubility in common solvents. Samples in
the dried state are used for surface area measurement and therefore
solubility is of no issue and agglomeration is of less concern since ad-
sorbate species will permeate into agglomerates and internal pores of
the primary particles. The measurement of specific surface area (SSA) is
commonplace throughout the pharmaceutical industry. The most
common technique of measurement, described in various pharmaco-
poeia (US Pharmacopoeia, 2000; European Pharmacopoeia, 2005;
European Pharmacopoeia, 2009), is via volumetric gas adsorption. Ni-
trogen is the most common adsorbate, although alternatives such as
krypton are also detailed.
Essentially, an adsorption isotherm is collected over a certain re-
lative pressure (P/Po) range by the volumetric dosing of N2 onto the
sample at cryogenic temperature, usually liquid N2 (nominally 77 K).
Surface area is then calculated through application of the Brunauer-
Emmett-Teller (BET) Eq. (1) to the adsorption data within a certain P/
Po range. The most common form of the BET equation is:
P to allow excess adsorption: that is adsorbate-on-adsorbate as opposed to
Po 1 C−1 P
= + ⎛ ⎞
(
n 1−
P
Po ) nm C nm C ⎝ Po ⎠
(1)
where at a specific relative pressure (P/Po): n is the quantity of ad-
sorbate adsorbed, nm is the monolayer capacity and C is the BET C-
value. The BET C-value is a function of the exponential heat of ad-
sorption of the given adsorbate on the given adsorbent.
The BET equation is applied to the isotherm data to construct a BET
transform plot of P/Po against the BET function.
Specific BET surface area, SBET, is then calculated as:
nm . L. Am
s (BET ) =
VO. m (2)
where nm is the mono-layer capacity, L is the Avogadro constant, Am is
the molecular cross-sectional area of the adsorbate, VO is the molar gas
volume of the adsorbate at STP and m is the sample mass.
The BET transform plot should be inspected in order to assess re-
liability of the data: the correlation coefficient providing a good in-
dication of the suitability of the P/Po range applied and a value >
0.999 being expected for most sample materials. The BET C-value
provides an indication of the strength of adsorption, typically for N2
adsorption a value < 10 is considered to show weak interaction and
thus potential inapplicability of BET theory (Thommes et al., 2015).
According to BET theory (Brunauer et al., 1938), the ‘classic’ BET range
is 0.05–0.35 P/Po and within this region multi-layer absorption of the
adsorbate on the adsorbent occurs from which the statistical mono-
layer volume can be calculated. For the majority of pharmaceutical
materials it is possible to obtain a linear BET transform plot within part
of this region through adjustment of the P/Po range applied.
Problems regarding SBET measurement specifically of MgSt by gas
adsorption are recognised and the reliability of measurements has been
questioned (Koivisto et al., 2004; Kato et al., 2005; Wang et al., 2010).
The collection of erroneous N2 adsorption isotherms, particularly for
MgSt di-hydrate, has been recognised (Phadke and Collier, 1994;
Andres et al., 2001; Koivisto et al., 2004). Specifically, it has been
shown (Lapham and Lapham, 2017) that the low P/Po region of N2
adsorption isotherms, up to approximately 0.2 P/Po, of MgSt di-hydrate
is non-linear. Furthermore, the isotherm profile in this region is not in
agreement with any BDDT classification of isotherm types (Brunauer
et al., 1940; Thommes et al., 2015) in that it is not possible to determine
2
International Journal of Pharmaceutics 568 (2019) 118522
curvature relative to the P/Po axis due to non-linearity. BET theory is
applicable to isotherms showing convex curvature relative to the P/Po
axis: isotherms of types II and IV and, to a certain extent, type I. Con-
versely, BET theory is inapplicable to isotherms showing concave cur-
vature relative to the P/Po axis: i.e. isotherms of types III and V. Con-
sequently, it is not possible to determine the applicability of BET theory
to MgSt di-hydrate from inspection of the adsorption isotherm alone.
When the calculation of SBET includes data within this portion of the
isotherm, non-linearity is apparent within the resulting BET transform
plot. Given non-linearity of the adsorption isotherm, and thus the re-
sulting BET transform plot, SBET will be heavily dependent on the BET
range selected and the number of data points within it. Such non-lin-
earity was not observed for either MgSt mono-hydrate or the anhydrous
material and adsorption isotherms are of BDDT type II.
In addition to isotherm non-linearity within the BET range, two
additional atypical isotherm features outside of the BET range were also
identified (Lapham and Lapham, 2017): an unsual isotherm profile
above approximately 0.7 P/Po and low pressure hysteresis (LPH) be-
tween adsorption and desorption isotherms. These were significantly
more pronounced for MgSt di-hydrate than for the mono-hydrate and
were absent for anhydrous MgSt. A detailed investigation of MgSt gas
adsorption isotherms (Lapham and Lapham, 2019) found that the aty-
pical isotherm features are a result of an adsorbate swelling and en-
trapment effect. With increasing adsorption P/Po, adsorbate fills the
porous spaces between stearate chains, the chains then swell and distort
adsorbate-on-adsorbent interaction. Ultimately a limit of distortion is
reached, at which point the adsorbate between the chains becomes
entrapped. The effect on the adsorption isotherm of structural swelling
is apparent in the region of non-linearity within the BET range, ad-
sorbate entrapment then causing LPH which continues so long as the
sample is maintained at the cryogenic analysis temperature. The effects
on SBET not only include poor correlation coefficient but also a con-
siderable over-estimate due to an adsorption volume in excess of that of
the mono-layer.
Krypton adsorption is well established for the measurement of SBET.
Kr is usually applied to materials having SBET below that measurable by
N2 adsorption due to it having a considerably lower saturation vapour
pressure than N2 and therefore a lower sample tube free-space error. Kr
adsorption can be conveniently undertaken at the same cryogenic
temperature used for N2 adsorption but some modification of in-
strumentation is often required to allow for the generation and mea-
surement of the lower absolute pressures demanded by Kr adsorption. It
has been noted (Lapham and Lapham, 2019) that SBET of MgSt di-hy-
drate by Kr adsorption is significantly lower than that from N2 ad-
sorption on the same sample. Moreover, in contrast to N2 adsorption
isotherms, the portion of the isotherm at the lower end of the BET range
is linear, only becoming non-linear towards the top half of the ‘classic’
range. The significance to SBET calculation is that it is possible to obtain
a BET transform plot of good linearity towards the lower P/Po end of
the BET range for Kr adsorption without the over-estimation due to
excess adsorption seen with N2.
SBET measurement of MgSt is critical to the formulation process
when determining MgSt loading and to tablet production as part of the
quality control process. In addition to this, attempts have been made to
determine the relationship between MgSt SBET and lubricity (Marwaha
and Rubinstein,1988; Hussain et al., 1990; Hussain et al., 1992; Rajala
and Laine, 1995; Kato et al., 2005) and also between SBET and the de-
leterious physical properties noted above (Dansereau and Peck, 1987;
Kushner et al., 2011; Li and Wu, 2014). However, conclusions as to
these relationships are contradictory in the literature. SBET is invariably
calculated from N2 adsorption data but MgSt hydration state is often
not reported, neither are factors influencing SBET calculation or those
allowing for its assessment, such as the BET range applied, correlation
coefficient or BET C-value. Therefore, conclusions are difficult to assess
given the unreliability of N2 SBET data, particularly if the materials
D.P. Lapham and J.L. Lapham
analysed contain di-hydrated MgSt due to the swelling and encapsula-
tion effect.
Indeed, without the reliable measurement of MgSt SBET which re-
flects the true surface area of the material, the use of such data for
quality control purposes is likely to be erroneous. Furthermore, it is not
possible to determine whether relationships exist between this and lu-
bricating properties or deleterious effects, which would provide valu-
able information for the determination of optimum MgSt loading. The
requirement for reliable SBET measurement is of greater significance
given the preference of the di-hydrate due to its greater lubricating
efficiency. The possibility of applying Kr adsorption to the measure-
ment of MgSt SBET became apparent previously when used for in-
vestigations of isotherm LPH and adsorbate/adsorbent interaction
(Lapham and Lapham 2019) In this paper SBET from Kr adsorption is
assessed for mono-hydrated and di-hydrated MgSt. Emphasis is given to
the accuracy of SBET with respect to the P/Po range, the number of data
points applied and the repeatability of measurements over replicate
analyses of the same parent batch. Comparisons are made with analyses
of the same batches using N2 adsorption to highlight the error in SBET
caused by the swelling and encapsulation effect. Analysis of a re-
cognised standard material is also reported to illustrate the repeat-
ability and isotherm linearity achievable from Kr adsorption. The Kr
molecular cross-sectional area to be applied to SBET calculation is de-
termined through analysis of a range of stearic acid batches and a
protocol for both analytical parameters and SBET calculation from iso-
therm data is ultimately established.
2. Experimental
2.1. Materials and preparation
Four batches of vegetable derived MgSt from three suppliers:
Mallinckrodt Pharmaceuticals (USA), Peter Greven GmbH and Co
(Germany) and FACI S.p.a (Italy) were analysed and are the same
material batches as reported previously (Lapham and Lapham, 2017,
2019). Throughout this article the batches are designated MgSt A to D
in order of increasing SBET of the anhydrous form without reference to
specific supplier or batch number. In order to determine the appropriate
molecular cross-sectional diameter of Kr three batches of stearic acid in
flake form were analysed in triplicate. These were from three different
suppliers: 95+% purity from Sigma-Aldrich GmbH (Germany), 95%
purity from Prime Chemicals UK (UK) and 98+% purity from APC Pure
(UK). The batches are numbered 1 to 3 in order of increasing SBET
without reference to their specific supplier. In order to demonstrate
typical isotherm and BET transform properties, a certified reference
material was also analysed: BAM-PM-102 α-alumina issued by the
Federal Institute for Materials Research and Testing, (Germany).
2.2. Analytical
Gas adsorption was undertaken using a Micromeritics TriStar II Plus
instrument, having a molecular drag vacuum pump (Edwards T-Station
75). The instrument was enabled for Kr adsorption through provision of
an additional pressure transducer measuring the range 0–10 Torr to a
resolution of 0.0001 Torr. Adsorption was conducted using either N2
(99.999%, BOC, UK) or Kr (99.999% BOC, UK) each at liquid nitrogen
temperature (77.3 K, manually entered to the instrument software).
Free-space was measured using He (99.9995%, BOC, UK).
Micromeritics iso-thermal jackets were fitted to sample tubes for all
analyses to compensate for the fall in cryogen level over the period of
analysis. Adsorption isotherms of MgSt were measured over the range,
0.03–0.35 P/Po, at intervals of 0.01 P/Po. These were constructed
linearly and the abundance of points allowed for detailed construction
of BET transform data and calculation of SBET. Equilibration times were
10 s throughout and MgSt sample masses were 0.30 ± 0.01 g
throughout. With both adsorbates, ten replicates were analysed for each
3
International Journal of Pharmaceutics 568 (2019) 118522
MgSt batch. For stearic acid samples, 1.5 g ± 0.1 g of Prime Chemicals
and APC Pure batches and 1.0 g ± 0.05 g of the Sigma-Aldrich batch
were analysed. Isotherms of the α-alumina reference were measured in
triplicate over the same P/Po range with SBET calculated over the range
0.05–0.30 P/Po using 0.6 g ± 0.02 g sample mass as directed by ac-
companying instructions from the supplier.
All MgSt and stearic acid samples were degassed under vacuum to
constant mass at 35 °C using a Micromeritics VacPrep 061 degassing
station (Micromeritics Instrument Corp, Norcross, GA, USA) applying
an ultimate vacuum of 100 mTorr. The α-alumina reference material
was degassed according to the supplier specification: under dynamic
vacuum at 250 °C for 3 h, also using a Micromeritics VacPrep 061 de-
gassing station.
SBET was calculated through application of the BET equation. The P/
Po range applied to SBET calculation was selected to include the max-
imum number of data points whilst also ensuring that the correlation
coefficient was maximised. The critical adsorbate parameters applied
for N2 were: molecular cross sectional area (Am) of 0.162 nm2 with Po
being measured by the instrument for each adsorption point. For Kr, Po
was selected as 2.320 mmHg throughout which represents the satura-
tion vapour pressure of the vapour phase above the solid phase. Am was
determined using stearic acid as a model adsorbent as detailed below.
Scanning electron microscopy (SEM) images were recorded for each
of the MgSt batches in the as-received state using a Zeiss Supra 35UP
SEM at 3.60 kV with an Intens detector. Samples were mounted to
carbon tape on aluminium stubs and were sputter-coated with gold
before analysis.
Thermal Gravimetric Analysis (TGA) was undertaken at
Micromeritics Analytical Services (Norcross USA) using a TA
Instruments model Q5000 IR. Samples of 10–15 mg mass were equili-
brated at 25 °C for 5 min and heated in air in the range 25 °C to 130 °C at
a ramp rate of 5 °C/min on a platinum pan.
3. Results and discussion
3.1. Characterisation of batches
Fig. 1 shows SEM images of the four MgSt batches. MgSt A appears
to be somewhat different from the other three batches in that there is
little visual evidence agglomeration. Instead, the sample appears to be
of irregularly sized and shaped pieces, possibly broken from a larger
sheet of the material during the production process. Batches B, C and D
appear to be very similar: showing clear loose agglomeration of plate
like particles with inter-particulate void spacing between them and
fracture lines within them. From inspection of the SEM images, the
agglomerated particles of MgSt B are generally in excess of 20–30 µm,
formed from smaller particles of 2–10 µm. These are significantly larger
than those present within MgSt C and D, these having agglomer-
ates < 20 µm formed of particles up to approximately 2 µm. This re-
presents a significant difference when considering their application as a
lower mixing input would be expected for batches C and D in order to
achieve efficient lubrication through coverage of other batch con-
stituents according to the accepted lubrication mechanism.
Characterisation of MgSt hydration state by thermal analysis has
been extensively discussed (Miller and York, 1985a; Ertel and
Carstensen, 1988; Phadke and Collier, 1994; Rajala and Laine 1995;
Sharpe et al., 1997; Koivisto et al., 2004; Bracconi et al., 2005). Typi-
cally, thermal events occur with increasing temperature and are as-
cribed to: loss of unbound water (typically < 40 °C), loss of bound/
hydrated water (between 70 and 105 °) and melting (> 110 °C). For the
current batches the hydration states have been previously elucidated by
combination of TGA and mass loss on drying investigations (Lapham
and Lapham, 2017). However, given the importance of hydration state
to the current investigations of SBET and to the selection of the materials
for pharmaceutical applications, it is worth considering the character-
isation in some detail as hydration states of the batches are confirmed.
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

Fig. 1. SEM Images of four MgSt batches, A, B, C and D in the as received state.

Fig. 2. TGA plots of four MgSt batches: A, B, C and D.

TGA plots of the four MgSt batches are shown in Fig. 2. For MgSt A,
72% of the total mass loss by TGA occurs by 40 °C, whereas for MgSt B,
C and D this figure is 24%, 17% and 4% respectively. Expressed as wt%
of total sample mass, unbound water contents are then 2.3%, 0.7%,
0.6% and 0.2% for Batches A, B, C and D respectively. Theoretical
hydrated water contents by mass of the various MgSt
pseudopolymorphs are: 2.90% (monohydrate), 5.74% (di-hydrate) and
8.37% (tri-hydrate). It must be realised however that these are not
likely to be precisely observed for commercial MgSt due to inclusion of
magnesium palmitate to variable extents and the possible mixture of
hydration states present. Mass loss in the range 40–110 °C, in which de-
hydration occurs, expressed as a percentage of initial sample mass at

4
D.P. Lapham and J.L. Lapham
Table 1
SBET of three stearic acid batches in triplicate by N2 adsorption and corre-
sponding Kr Am required to obtain SBET parity via Kr adsorption.
Batch Triplicate SBET by N2 adsorption Kr Am required for SBET
Analysis (m2g−1) parity (nm2)
1 1 0.10 0.203
1 2 0.11 0.203
1 3 0.13 0.205
2 1 0.17 0.206
2 2 0.18 0.205
2 3 0.20 0.206
3 1 0.45 0.208
3 2 0.47 0.208
3 3 0.44 0.207
40 °C is 3.19%, 3.13%, 3.70% and 4.10% for MgSt A, B, C and D re-
spectively. This equates to a mol ratio of H2O: MgSt of 1:1 for both MgSt
A and B, 1:1.3 for MgSt C and 1:1.5 for MgSt D. It is concluded,
therefore, that MgSt A and B are comprised of MgSt mono-hydrate with
MgSt A having a considerably greater proportion of unbound water.
MgSt C and D contain both mono- and di-hydrated material with MgSt
D containing comparatively more di-hydrate than MgSt C. This is fur-
ther evidenced by the bi-modal TGA profile within this temperature
range, indicating water to be bound at inequivalent sites: this being in
agreement with data reported elsewhere (Phadke and Collier, 1994;
Sharpe et al., 1997; Haware et al., 2014).
3.2. Considerations of SBET calculation
Before considering Kr adsorption data it is necessary to determine
the critical parameters of Kr adsorption which influence SBET. From Eqs.
(1) and (2) it is clear that saturation vapour pressure (Po) and mole-
cular cross-sectional area of the adsorbate (Am) are critical to the cal-
culation of SBET. Appropriate values for these must be determined by
the user, for N2 adsorption the automatic measurement of Po by the
instrumentation is commonplace and applying an Am of 0.162 nm2 is
almost universally accepted. However, for Kr adsorption the choice of
Po and Am is not so clear.
The choice of saturation vapour pressure is generally between that
of the vapour above the liquid phase (2.138 mmHg) and the vapour
above the solid phase (2.320 mmHg). However, alteration of Po does
not have a large effect on SBET since it is of second order in the calcu-
lation. For example, applying each value to a sample of MgSt A de-
gassed at 100 °C provides SBET of 2.1 m2g−1 when Po is 2.320 mmHg
and 2.0 m2g−1 when Po is 2.138 mmHg (Lapham and Lapham, 2019).
Since the operating temperature of 77.3 K is below the triple point of
Kr, 115.775 K (Handbook of Chemistry and Physics 2011), it seems
reasonable that Po is better represented by that of the vapour above the
solid phase. Therefore, Po of 2.320 mmHg is applied to the calculation
of all SBET from Kr adsorption in the present work, the critical con-
sideration being that this is applied to all data derived from Kr ad-
sorption.
SBET is considerably more sensitive to changes in Am and therefore
the selection of Am is of particular importance. The selection of Am is
dependent on the specific adsorbent and a range of Kr Am values for a
variety of adsorbents is reported as 0.186–0.236 nm2 (McClellan and
Harnsberger, 1967; Deitz and Turner, 1970; Gregg and Sing, 1982). A
common approach for assessing Kr Am is by adjustment to obtain parity
with SBET measured by N2 adsorption, assuming N2 Am to be 0.162 nm2.
This has been undertaken for a range of adsorbents enabling Kr Am to be
universally applied to each adsorbent type. It should be noted however
that it is reasonable to expect a difference between SBET values from
different adsorbates due to differing affinities of adsorption to different
adsorbents. This, in turn, causes differences in the alignment and
packing of adsorbate on the adsorbent surface. No appropriate model
adsorbent for the comparison of N2 and Kr adsorption on MgSt can be
5
International Journal of Pharmaceutics 568 (2019) 118522
found in literature. Furthermore, given the atypical nature of gas ad-
sorption on MgSt within the BET region, MgSt itself is an inappropriate
model adsorbent from which to determine Kr Am. The large disparity
between MgSt SBET calculated from N2 and Kr adsorption, which is in
excess of that reasonably corrected by alteration of Kr Am, has pre-
viously been reported (Lapham and Lapham, 2019). In the current in-
stance, since the absolute SBET values from N2 and Kr are being com-
pared, it is necessary to first determine Kr Am.
Stearic acid was selected as a model adsorbent since adsorption
isotherms within the BET range were found to be regular, providing
linear BET transform plots over a wide P/Po range. Furthermore, SBET
was found to be low, indicating that the stearic acid batches were of
relatively low porosity, which is desirable when determining Am by
comparison with a reference adsorbate (N2). Despite low SBET, BET
transform plots from N2 adsorption were constructed with 8 data points
linearly in the range 0.10–0.24 P/Po, with correlation coefficients >
0.999 and BET C-values > 30, the latter being in agreement with an
established range for organic materials (Gregg and Sing, 1982). It is
therefore possible to calculate reliable SBET data from N2 isotherms. BET
transform plots from Kr adsorption were constructed with 7 data points
linearly in the range 0.05–0.16 P/Po with BET C-values 8–10 and
correlation coefficients > 0.999. Table 1 details SBET for each triplicate
analysis of the three stearic acid batches with Kr Am required to obtain
SBET parity with the N2 data. The mean average of the Kr Am values is
0.206 nm2 with a standard deviation of 0.002 nm2 and, given the close
agreement, this value has been applied to all MgSt SBET calculations
from Kr adsorption.
To illustrate the problems with fitting an appropriate BET P/Po
range to MgSt isotherm data and subsequent problems with SBET data, it
is best to consider MgSt D. This batch has the highest proportion of di-
hydrated MgSt and therefore the most pronounced atypical isotherm
character. Fig. 3 shows the BET transform and linear isotherm plots of
N2 and Kr adsorption to MgSt D. Below 0.20 P/Po the isotherm shows
neither an upward curvature nor a region of linearity as would usually
be expected, instead a slight double curvature with an inflection at
approximately 0.1 P/Po is present. On applying the BET equation to the
isotherm data the resulting BET transform plot shows a more pro-
nounced curvature over the same P/Po range. Obtaining a correlation
coefficient > 0.999 is only possible if the BET range is selected as
0.22–0.33 P/Po, SBET then being calculated as 21.9 m2g−1. The BET C-
value is however low, 3.8, indicating weak adsorption of N2 on the
MgSt surface. Given the low BET C-value and the lack of isotherm
conformity to types suitable for SBET calculation, the application of N2
adsorption data should be considered inappropriate. Full adsorption/
desorption isotherms for all four MgSt batches are shown in supple-
mentary data Fig. 1.
For Kr adsorption on MgSt D, the isotherm can be considered as
being opposite from that of N2 adsorption in that linearity is present
within a lower P/Po range which extends to 0.19 P/Po. At higher P/Po
a sudden and profound upward curvature with an inflection at 0.28 P/
Po is observed and so the onset of atypical isotherm behaviour can be
considered as occurring at 0.19 P/Po for this sample. The BET range can
be fitted over a lower range, 0.07–0.18 P/Po, again having a correlation
coefficient > 0.999. SBET of 6.7 m2g−1 is significantly lower than the
corresponding N2 adsorption value but the BET C-value, 10.1, is ap-
preciably higher. The BET transform plot above 0.2 P/Po becomes very
erratic and it is clear that these data points should not be included in
the calculation of SBET. Previous investigations (Lapham and Lapham,
2019) showed that atypical MgSt isotherm behaviour is due to struc-
tural swelling of MgSt and subsequent adsorbate encapsulation as dis-
cussed above. This commences at a lower relative pressure for N2 than
for Kr adsorption. For N2 adsorption a degree of structural swelling
occurs below the P/Po region from which a linear BET transform plot
can be constructed. Consequently the adsorption volume is in excess of
the mono-layer volume, causing artificially high SBET. Conversely, for
Kr adsorption a linear BET transform plot can be constructed within a
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

Fig. 3. BET transform plots with adsorption isotherm inset of MgSt D by N2 and Kr adsorption. BET transform plot: (o) fitted and (+) not fitted data points.

P/Po range below that at which structural swelling and multi-layer

adsorption becomes appreciable. Kr adsorption isotherms for all four
MgSt batches up to 0.5 P/Po are shown in supplementary data Fig. 2.
Curvature of the isotherm from the P/Po axis conforms to isotherm
types II and IV and, together with the BET C-value, application of BET
theory to Kr adsorption can be considered appropriate. Whilst it is not
unreasonable to expect some disparity between SBET calculated via
different adsorbates, the magnitude of the difference between the above
values is excessive. SBET from Kr adsorption can therefore be considered
to be a more reliable value, representing the true surface area of the
material.
Given the atypical nature of gas adsorption on MgSt and the large
disparity between SBET calculated from different adsorbates, it is worth
considering adsorption to a high purity, homogenous material showing
typical isotherm characteristics. BAM-PM-102 α-alumina, with SBET
specification for volumetric N2 adsorption 5.41 m2g−1 ± 0.04 m2g−1,
was selected due to SBET being reasonably close to that usually observed
for MgSt and because of its exacting SBET specification ( ± 0.74%).
Reference materials with a certified SBET specification for Kr adsorption Fig. 5. BAM-PM-102 SBET transform plot from N2 adsorption (o fitted and +
are very uncommon and, in the absence of specified parameters, Kr Am not fitted) and Kr adsorption (□ fitted and x not fitted).
of 0.210 nm2 was applied. Fig. 4 shows triplicate SBET values by N2 and
Kr adsorption. Fig. 5 shows BET transform plots for N2 and Kr ad-
plot is shown for each adsorbate as each triplicate set overlays very
sorption, the plots extending from 0.03 to 0.35 P/Po to show the full
closely. Adsorption isotherms for all analyses are provided in supple-
range of isotherm data collected but with the BET range fitted to
mentary data Fig. 3. According to the specification, SBET from N2 ad-
maximise correlation coefficient. For clarity, only one BET transform
sorption should be fitted in the range 0.05–0.30 P/Po. This obtains
correlation coefficients > 0.99995 and BET C-values > 70. SBET of the
respective analyses were: 5.39, 5.42 and 5.40 m2g−1, having a standard
deviation of 0.012 m2g−1. SBET from Kr adsorption was fitted to a
narrower P/Po range, 0.05–0.25 in order to obtain correlation coeffi-
cients > 0.9995. SBET of the respective analyses were: 5.31, 5.31 and
5.34 m2g−1, having a standard deviation of 0.014 m2g−1. The mean
averages of the triplicate analyses differ by 1.6% which is of the order
to be expected between the two adsorbates (Gregg and Sing, 1982).
These results illustrate the ease with which SBET can be reproducibly
determined, having high BET C-values and correlation coefficients of
the BET transform plot for reliable sample materials. Furthermore they
highlight that the atypical isotherm behaviour of MgSt and that the
resulting difficulty in calculating SBET is particular to MgSt itself.
Moreover, the reproducibility and analytical accuracy of the current
instrumentation is illustrated and confirms that atypical adsorption
data is due to MgSt and not the apparatus or analytical protocols em-
ployed.

Fig. 4. SBET of BAM-PM-102 analysed in triplicate by N2 (grey) and Kr (white)

adsorption with standard error bars.

6
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

Fig. 6. SBET of 10 replicate samples of MgSt batches A, B C and D by N2 and Kr adsorption including standard error bars.

7
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

Table 2 correlation coefficients > 0.9995. SBET is higher than for MgSt A, in the
Summary of SBET data for 10 replicates of MgSt batches A, B, C and D by N2 and range 5.45–5.93 m2g−1 with a difference of ± 4.4% from the median
Kr adsorption. average. BET C-values are lower, in the range 11–12 and the BET error
SBET Low SBET High SBET Mean SBET Difference slightly higher, ± 0.03 m2g−1 for all analyses. For Kr adsorption, BET
Value Value Average Standard from median transform plots can be constructed in the range 0.10–0.30 P/Po having
(m2g−1) (m2g−1) (m2g−1) Deviation average ( ± correlation coefficients > 0.9990 for all samples of MgSt B. BET C-va-
(m2g−1) %)
lues are higher than for MgSt A, in the range 8.0–9.1 with BET errors in
MgSt A, N2 2.36 2.61 2.51 0.09 5.5 the range ± 0.03–0.05 m2g−1. SBET values are again higher than for
MgSt A, Kr 2.20 2.28 2.25 0.02 1.8 MgSt A, being in the range 3.55–3.81 m2g−1 with a difference
MgSt B, N2 5.45 5.93 5.69 0.15 4.4 of ± 3.6% from the median average.
MgSt B, Kr 3.55 3.81 3.68 0.08 3.6
The ability to construct BET transform data over a wide P/Po range
MgSt C, N2 14.62 16.41 15.64 0.53 6.2
MgSt C, Kr 5.87 6.13 5.96 0.09 1.7
with correlation coefficients > 0.9990 indicates that both N2 and Kr are
MgSt D, N2 21.7 25.1 23.18 0.98 5.5 suitable adsorbates for the determination of SBET of mono-hydrated
MgSt D, Kr 6.61 6.94 6.78 0.11 2.9 MgSt. Furthermore, BET C-values for N2 are sufficiently high and iso-
therm curvature such that adsorption is of appreciable strength and
localisation to allow for the application of BET theory. Although BET C-
3.3. SBET of magnesium stearate values for Kr adsorption are < 10, the low BET error and isotherm
curvature suggests that BET theory is applicable. It is interesting to note
SBET of each of the MgSt batches was measured a total of ten times that, under N2 adsorption, BET C-value decreases as proportionately
by both N2 and Kr adsorption. Different sample aliquots were used for more hydrated MgSt is present, a trend that continues as di-hydrated
each analysis by a given adsorbate. SBET of all analyses are shown in MgSt is introduced. Conversely, BET C-values from Kr adsorption ap-
Fig. 6, with standard error bars included. The ordinate (SBET) axes are pear reasonably stable for mono-hydrated MgSt irrespective of the
scaled to the same proportion with respect to the highest SBET recorded proportion of hydrated and anhydrous material present in the sample.
for the given batch and adsorbate to enable visual comparison of the Furthermore, BET C-values increase with the introduction of di-hy-
spread of values for a given batch and adsorbate. Table 2 details SBET drated material.
values, mean average, standard deviation and difference from median Even-though SBET can be reliably calculated from both N2 and Kr
average for each batch and adsorbate. Factors influencing the fitting of isotherms for mono-hydrated MgSt, that from Kr adsorption shows less
BET transform data to the adsorption isotherms and those providing variability over the 10 analyses. SBET from Kr adsorption is however
measures of reliability will also be discussed. These include the BET P/ consistently lower than that from N2 adsorption. The SBET mean
Po range applied, the aim being to obtain the widest P/Po range pos- averages by Kr adsorption are 10.4% and 35.5% lower than by N2 ad-
sible, thus maximising the number of data points, whilst maintaining a sorption for MgSt A and B respectively. Although some disparity be-
correlation coefficient > 0.999 wherever possible. The range of BET C- tween adsorbates is to be expected, the difference for MgSt B appears
values is noted since these provide an indication of the strength of excessive. The 1.6% difference between mean averages of the triplicate
adsorption and the applicability of BET theory and ultimately the re- Kr and N2 analyses of the α-alumina reference material should again be
liability of SBET data. Finally, the range of BET errors for a given batch considered in this respect. Furthermore, it is suggested that without
and adsorbate is also considered. The BET error is automatically gen- calibration of Kr Am the disparity between SBET from N2 and Kr ad-
erated by the instrument software (Micromeritics Microactive) using sorption can be at least 20% (Gregg and Sing, 1982). Given that Kr Am
least squares regression for each analysis as Eq. (3) below: has been calibrated using stearic acid, the disparity for MgSt B is,
2 2 1 therefore, particularly high. It has been shown previously (Lapham and
SBET (Serr + YIerr )2
BETerr = Lapham, 2017) that, whilst it is possible to construct BET transform
YI + S (3)
data for MgSt mono-hydrate, other atypical isotherm features, specifi-
Where: cally low pressure hysteresis between adsorption and desorption iso-
S = slope of the BET transform plot therms, are present. Therefore, despite the seemingly applicable BET
Serr = error of the BET transform slope (g/cm3 at STP) transform data, covering a reasonable P/Po range and high correlation
YI = y-axis intercept of the BET transform plot (g/cm3 at STP) coefficients and BET C-values, a degree of structural swelling does
YIerr = error of the y-axis intercept (g/cm3 at STP) occur. Although this does not have a noticeable effect on the isotherm
For the two MgSt batches A and B, confined to the mono-hydrated in the P/Po range applied to SBET calculation, some excess N2 adsorp-
form, isotherms within the classical BET range can be considered ty- tion will most likely occur. This will be included in the calculation of
pical. The construction of BET transform data is, therefore, not pro- SBET through an artificially high mono-layer adsorption volume.
blematic. Fig. 7 shows BET transform and linear isotherm plots for N2 Therefore, SBET from N2 adsorption is over-estimated despite the ap-
and Kr adsorption to MgSt A. It is possible to construct BET transform parent reliability from consideration of the BET correlation coefficient
plots from N2 adsorption data over the range 0.06–0.30 P/Po for all 10 and C-value and isotherm type. The excess adsorption volume caused
analyses. Resulting BET transform plots are all with correlation coeffi- by structural swelling is not as apparent at low P/Po for Kr adsorption
cients > 0.9995 and BET C-values in the range 17–22. SBET is in the and, therefore, the resulting SBET is considered to be a more accurate
range 2.36–2.61 m2g−1 with a difference of ± 5.5% from the median representation of the true surface area.
average. The BET error is calculated as ± 0.01 m2g−1 for all 10 ana- Fig. 9 shows BET transform and linear isotherm plots for N2 and Kr
lyses. BET transform plots from Kr adsorption can be constructed over adsorption to MgSt C. Constructing BET transform data from N2 ad-
the range 0.09–0.30 P/Po for all samples of MgSt A, having correlation sorption on MgSt C, which comprises both mono- and di-hydrated
coefficients > 0.9994 and BET C-values in the range 8.3–8.9. SBET is in material, is more problematic. This is due to non-linearity of the ad-
the range 2.20–2.28 m2g−1. The spread of SBET values from Kr ad- sorption isotherm at the lower P/Po end of the classic BET range and
sorption is less than for N2 adsorption with a difference of ± 1.8%, subsequent curvature of the BET transform plot. Consequently, it is only
compared to ± 5.5% for N2. The BET error is similar to that of N2 ad- possible to obtain BET transform data having a reasonably high corre-
sorption, varying between ± 0.01 and 0.02 m2g−1. lation coefficient above the P/Po at which non-linearity ceases. This
Fig. 8 shows BET transform and linear isotherm plots for N2 and Kr itself is variable, occurring between 0.13 and 0.22 P/Po over the ten
adsorption to MgSt B. BET transform plots from N2 adsorption data can MgSt C samples analysed. From this point it is possible to extend the
be constructed over the same P/Po range as for MgSt A, again all having BET range to 0.30 P/Po for all samples, providing at least 9 P/Po data

8
D.P. Lapham and J.L. Lapham
Fig. 7. BET transform plots with adsorption isotherm inset of MgSt A by N2 and Kr adsorption.
points for application to the calculation of SBET with the adsorption
isotherm being collected at intervals of 0.01 P/Po. Correlation coeffi-
cients are then > 0.9991, but BET errors are significantly higher,
0.06–0.20 m2g−1, when compared to the two mono-hydrated batches
discussed above. However, BET C-values are low, 3.8–5.3 and classifi-
cation of isotherm type is difficult given the lack of apparent isotherm
curvature at low P/Po and ultimately the applicability of BET theory is
questionable. Nevertheless, SBET is calculated to be the range
14.62–16.41 m2g−1 across the ten samples, having a standard deviation
of 0.53 m2g−1 and difference of ± 6.2% from the median average. The
construction of BET transform data from Kr adsorption is also restricted
to a more limited P/Po range but, conversely to N2 adsorption, this
range occurs at lower P/Po. BET transform data can be constructed in
the range 0.08–0.18 or 0.08–0.19 P/Po, having correlation coeffi-
cients > 0.998. The BET range is therefore more consistent than for N2
adsorption. The lower correlation coefficients are due a slight, yet even,
curvature convex to the P/Po axis of the BET transform plot. BET C-
values are higher than for N2 adsorption, 9.3–11.9 and BET errors
lower, 0.09–0.13 m2g−1. SBET of the ten samples is in the range
5.9–6.2 m2g−1, having a standard deviation of 0.11 m2g−1 and differ-
ences of ± 1.7% from the median average. Importantly, BET C-values
are sufficiently high and isotherm curvature such that BET theory can
be considered applicable to Kr adsorption data on MgSt C.
MgSt D is similar to MgSt C in that it is comprised of both mono- and
Fig. 8. BET transform plots with adsorption isotherm inset of MgSt B by N2 and Kr adsorption.
9
International Journal of Pharmaceutics 568 (2019) 118522
di-hydrated material, although comparatively more di-hydrated mate-
rial is present. BET transform and linear isotherm plots were shown in
Fig. 3. The general trends in SBET data are the same as for MgSt C but
the atypical nature of the isotherms are of greater magnitude. SBET from
N2 adsorption is significantly higher, 21.7–25.1 m2g−1 with a higher
standard deviation of 0.98 m2g−1 and a difference from the median
average of ± 5.5%. The BET range is more restricted, the lowest ap-
plicable P/Po varying in the range 0.19–0.25 but again extending to
0.30 P/Po for all ten samples. Correlation coefficients are generally >
0.999, although three of the ten samples showed lower values of 0.995
due to slight non-linearity of the isotherm continuing to 0.30 P/Po. This
non-linearity is irregular with data points lying randomly each side of
the resulting BET transform best fit plot and considered to be a con-
tinuation of MgSt structural swelling to higher P/Po than the other
samples. BET C-values are again low, 3.2–6.1, and comparable to those
for MgSt C. However, the BET error is considerably higher,
0.20–0.72 m2g−1. The spread of SBET is also greater, ranging
21.7–25.1 m2g−1 with a standard deviation of 0.98 m2g−1. The differ-
ence from the median average is, however, quite consistent with SBET
from N2 adsorption on the other batches: ± 5.5%. BET transform data
from Kr adsorption can be constructed over the same P/Po range as
applied to MgSt C having similar correlation coefficients, > 0.995, BET
C-values, 9.2–11.6 and BET errors, 0.09–0.19 m2g−1. SBET is higher
than obtained for MgSt C and in the range 6.61–6.94 m2g−1 with a
D.P. Lapham and J.L. Lapham
Fig. 9. BET transform plots with adsorption isotherm inset of MgSt C by N2 and Kr adsorption. BET transform plot: (o) fitted and (+) not fitted data points.
standard deviation of 0.11 m2g−1 and a difference of ± 2.9% from the
median average. Ultimately, the same applicability of BET theory as for
MgSt C exists: consideration of BET C-values and isotherm type in-
dicates that applicability of BET theory is limited to Kr adsorption data
of MgSt D.
The difference between SBET calculated from N2 and Kr adsorption
isotherms becomes greater with the presence of MgSt di-hydrate: SBET
from Kr adsorption being 61.9% lower for MgSt C and 70.8% lower for
MgSt D. Furthermore, the increase in mean average SBET is dis-
proportionately larger for N2 adsorption than for Kr. Again, this is a
considerably greater disparity than would usually be expected between
the two adsorbates and beyond the scope of influence by the selection
of Am or Po. To illustrate this, altering Po to that of Kr vapour above the
liquid phase (2.138 mmHg) and applying this to MgSt D actually de-
creases the mean average SBET from 6.78 m2g−1 to 6.20 m2g−1, thus
causing a greater disparity between the two adsorbates. Alteration of Kr
Am to increase the mean average SBET from Kr adsorption to match that
from N2 adsorption can also be considered. For MgSt D, Kr Am must be
increased to 0.71 nm2 to achieve this, which is far in excess of the
highest reported value for other adsorbents, 0.24 nm2 (McClellan and
Harnsberger, 1967). This suggests that the disparity between MgSt SBET
calculated from Kr and N2 adsorption is due to the swelling and en-
trapment effect of MgSt itself. Furthermore, it is clear that the disparity
between the two adsorbates increases with both the amount of hydrated
material and the hydration state itself.
These results also enable consideration of the intra-batch variability
of MgSt SBET from N2 adsorption discussed above and for this the α-
alumina reference material results are useful for comparison. To re-cap,
α-alumina triplicate SBET from N2 adsorption have a standard deviation
of 0.012 m2g−1, a difference of ± 0.25% and BET errors of
0.010–0.012 m2g−1. Comparing this to the figures discussed above and
presented in Table 2, it would appear that over the ten analyses a
greater than expected spread of SBET exists of all four MgSt batches.
Proportionally, this is reasonably constant across the four batches,
ranging from ± 4.4% to ± 6.2%. However in terms of absolute values,
the spread of SBET increases through the series of MgSt batches with
increasing hydration state. Such a spread of values is indicative of in-
homogeneity within the MgSt batches with respect to hydration state,
which becomes more significant as the hydration state and the amount
of hydrated material increases. Even though the MgSt batches were
thoroughly mixed, SBET remains subject to sensitivity due to sampling.
It is noteworthy that the spread of SBET values from Kr adsorption is
significantly less than for N2 for corresponding MgSt batches. Although
variation remains in excess of that observed for the α-alumina, it would
10
International Journal of Pharmaceutics 568 (2019) 118522
appear that SBET via Kr adsorption is less sensitive to changes within
each batch and subsequent sampling.
3.4. Sensitivity of SBET calculation
3.4.1. Multi-point vs single point SBET
Kr adsorption provides a more accurate representation of the true
SBET of MgSt over N2 adsorption due to a significant reduction in the
adsorbate swelling and encapsulation effect. However, it appears that
the swelling and encapsulation effect may not be completely absent for
Kr adsorption on MgSt di-hydrate. If present, this will cause curvature
of the adsorption isotherm which will also be evident in the corre-
sponding BET transform plot. The consequence will then be greater
sensitivity of SBET to both the number of P/Po data points included and
their precise values than would otherwise be expected. Given this sce-
nario, stipulating that SBET should be calculated over a certain P/Po
range alone would be insufficient instruction: stipulation of the number
of P/Po measurements and their values would also be required to en-
sure comparability of measurements across different operators, loca-
tions and instruments.
Single-point SBET measurement should also be considered. The
single-point method is of historical significance when considering
manually operated instrumentation with high demands on operator
input. With the advent of automated instrumentation the single-point
method has largely been superseded by the preferred multi-point BET
method. However, provision is given within pharmacopoeia for SBET
determination by the single-point method even though its use should be
precluded due to MgSt BET C-values typically approaching unity. Also
of significance, as discussed previously (Lapham and Lapham, 2017,
2019), some literature discusses adverse considerations of MgSt SBET
derived using the single-point method. Understanding the reliability of
this method is therefore required in order to assess the parity between
multi-point and single-point methods and ultimately determine the
validity of the relationships between MgSt and tablet properties re-
ported in literature.
The single-point SBET method involves the measurement of adsorp-
tion volume at one predetermined P/Po. It is not, therefore, possible to
construct BET transform data to determine mono-layer capacity and
this is instead derived according to Eq. (4) below:
P
nm = VA ⎡1 − ⎛ ⎞ ⎤
⎜ ⎟
⎢ ⎝ PO ⎠ ⎥ (4)
⎣ ⎦
where VA is the adsorbate volume adsorbed at the single relative
pressure (P/Po).
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

This value of nm can then be substituted into Eq. (2) for the calcu-

S.D. of 10 analyses
lation of SBET detailed above.
Single-point SBET was calculated directly using Micromeritics
Microactive software for each of the four MgSt batches at two P/Po
0.98 values within the linear portion of the adsorption isotherm previously
1.26
1.13
0.11
0.06
0.07
applied to the calculation of multi-point SBET: 0.20 and 0.30 for N2
adsorption and 0.10 and 0.15 for Kr adsorption. Values are provided in
Table 3 and are median averaged over the 10 replicate analyses re-
SBET (m2g−1)

ported above. For comparison, the median average multi-point SBET is

also included. Fig. 10 shows the median average SBET of the four MgSt
MgSt D

23.18
11.97
14.99

batches calculated from N2 and Kr adsorption using the multi-point and

6.78
3.55
4.25

single-point conditions described above. Error bars showing the stan-

dard deviation are included together with results from triplicate ana-
lyses of BAM-PM-102 alumina under the same conditions of SBET cal-
culation.
S.D. of 10 analyses

It is well established that single-point SBET calculation will incur an

inherent error over the multi-point method, effectively due to the in-
creased slope of the BET transform plot caused by ignoring the intercept
and forcing it through the origin (Webb and Orr, 1997). This conse-
0.53
0.50
0.52
0.09
0.09
0.19

quently results in a lower SBET than the multi-point method for the same
sample. This can be demonstrated by the BAM-PM-102 alumina results
by comparing multi-point and single-point SBET values, the latter cal-
SBET (m2g−1)

culated at P/Po values at either end of the multi-point range. Multi-

point SBET by N2 adsorption was 5.40 m2g−1 whereas single-point va-
MgSt C

lues calculated at 0.30 and 0.10 P/Po were 5.23 and 4.99 m2g−1 re-
15.64

10.13
8.11

5.96
3.19
3.70

spectively, thus 3.2% and 7.6% lower than the multi-point value. Si-
milarly for Kr adsorption, the multi-point value was 5.32 m2g−1 and the
single-point values were 5.30 m2g−1 at both 0.30 and 0.10 P/Po, thus
S.D. of 10 analyses

0.4% lower than the multi-point value. Given adsorption isotherms

from which BET transform plots of high linearity can be plotted, such as
BAM-PM-102, a disparity of < 10% between single-point and multi-
point SBET can therefore be expected. The discrepancy between multi-
0.15
0.18
0.21
0.08
0.03
0.04

point and single-point SBET of MgSt is considerably greater than this for
all four batches and for both N2 and Kr adsorbates. For N2 adsorption on
mono-hydrated MgSt batches A and B, the single-point SBET at 0.20 P/
Single-point SBET averaged over 10 replicate analyses of four MgSt batches by N2 and Kr adsorption.

Po is 17% and 27% lower than the multi-point values respectively and
SBET (m2g−1)

13% and 20% respectively lower when calculated at 0.30 P/Po. The
discrepancy is greater for Kr adsorption: single-point SBET at 0.15 P/Po
MgSt B

being 56% lower than the multi-point value for MgSt A and 51% lower
5.69
4.15
4.57
3.68
1.81
2.16

for MgSt B. For di-hydrated MgSt these discrepancies are more similar
for N2 and Kr adsorbates and are minimised when the single-point value
is calculated at a P/Po towards the lower end of the multi-point SBET
S.D. of 10 analyses

range. Nevertheless, discrepancies remain high. Single-point SBET from

N2 adsorption calculated at 0.20 P/Po is 35% lower than the multi-
point value for both MgSt C and D. Similarly for Kr adsorption calcu-
lated at 0.10 P/Po, single-Point SBET is lower by 38% and 36% for
0.09
0.06
0.07
0.02
0.04
0.03

batches C and D respectively. In all cases of MgSt hydration state and

with both adsorbates, the application of single-point SBET measurement
should be excluded and reported values should be considered with
extreme caution given the likely disparity from the multi-point SBET
SBET (m2g−1)

value and the error they incur. Ultimately, comparison of single-point

and multi-point SBET data can in all likelihood not be undertaken.
MgSt A

2.51
2.08
2.20
2.25
0.97
1.20

3.4.2. Multi-point SBET range

Standard practice when fitting SBET data to measured adsorption
isotherms is to select a suitable number of P/Po data points within the
N2 Single-point SBET at 0.20 P/Po
N2 Single-point SBET at 0.30 P/Po

Kr Single-point SBET at 0.10 P/Po

Kr Single-point SBET at 0.15 P/Po

classic BET range whilst ensuring that the correlation coefficient re-
mains appreciably high. Furthermore, the y-intercept of the BET
transform plot must be positive, resulting in a positive BET C-value.
Such an approach can be undertaken for the majority of non-micro-
N2 Multi-point SBET

Kr Multi-point SBET

porous samples and a similar BET P/Po range can often be applied to
samples of the same chemical nature. Since correlation coefficients can
usually be expected to exceed 0.9995 the removal of P/Po data points
within the selected BET P/Po range can typically be undertaken with
Table 3

only a negligible effect on SBET. In the current study, adsorption iso-

therms were constructed with an abundance of P/Po data points and

11
D.P. Lapham and J.L. Lapham International Journal of Pharmaceutics 568 (2019) 118522

Fig. 10. Effects of single-point vs multi-point SBET calculation, error bars showing standard deviation of 10 replicate analyses by N2 (black) and Kr (white).
MP = multi-point SBET SP = single-point SBET at P/Po as indicated.

BET transform data could be constructed in the range 0.05–0.30 P/Po Table 4
with 21 data points at intervals of 0.01 P/Po. This allowed for the close SBET of mono-hydrated MgSt batches A and B with varying BET P/Po range and
inspection of the adsorption isotherm and resulting BET transform and number of P/Po data points.
SBET data. Such an abundance of isotherm data would usually be con- MgSt Batch BET Range BET Range BET Range 0.10–0.28
sidered excessive for the purposes of calculating multi-point SBET but in 0.10–0.30 0.10–0.30 P/Po × 7 points
this study it allows for investigation of the effect of reducing the P/Po × 21 points P/Po × 11 points
SBET (m2g−1) SBET (m2g−1) SBET (m2g−1)
number of data points included in the calculation of SBET.
As discussed above, Kr adsorption on mono-hydrated MgSt produces A 2.25 2.24 2.24
a linear isotherm throughout the P/Po range 0.08–0.30, resulting in a B 3.68 3.68 3.65
linear BET transform plot with a correlation coefficient > 0.999.
Unsurprisingly, alteration of the number of P/Po data points included in
the calculation of SBET has a negligible effect. Table 4 details the SBET points from 21 to 11 in the BET range 0.10–0.30 P/Po has virtually no
for MgSt batches A and B averaged over the 10 samples discussed above effect on SBET, for MgSt A SBET is reduced by 0.44% and is unchanged
and calculated with three different P/Po regimes of BET range and the for MgSt B. Further reduction to 7 data points in the BET range
number of P/Po data points: (a). 21 points at 0.01 P/Po intervals in the 0.10–0.28 P/Po reduces SBET by 0.44% for MgSt A and reduces SBET of
range 0.10–0.30 P/Po, (b). 11 points at 0.02 P/Po intervals in the range MgSt B by 0.82%. The calculation of mono-hydrated MgSt SBET via Kr
0.10–0.30 P/Po and (c). 7 points at 0.03 P/Po intervals in the range adsorption can therefore be expected to be applicable over an appre-
0.10–0.28 P/Po. It can be seen that reducing the number of P/Po data ciably wide P/Po range with negligible sensitivity to the number of P/
Po data points included.

12
D.P. Lapham and J.L. Lapham
Table 5
SBET of di-hydrated MgSt batches C and D with varying BET P/Po range and
number of P/Po data points.
MgSt BET Range BET Range BET Range BET Range
Batch 0.08–0.18 0.08–0.18 0.08–0.16 0.08–0.16
P/Po × 11 P/Po × 6 P/Po × 9 P/Po × 5 points
points points points
SBET (m2g−1) SBET (m2g−1) SBET (m2g−1) SBET (m2g−1)
C 5.96 5.95 5.77 5.75
D 6.78 6.82 6.35 6.37
The BET P/Po range for Kr adsorption on di-hydrated MgSt is lim-
ited to a maximum P/Po of approximately 0.18. The same operation as
undertaken for the mono-hydrated batches above has also been applied
to the two di-hydrated batches, with the calculation of SBET being un-
dertaken with four regimes of BET range and the number of P/Po data
points applied: (a). 11 points at 0.01 P/Po intervals in the range
0.08–0.18 P/Po, (b). 6 points at 0.02 P/Po intervals in the range
0.08–0.18 P/Po, (c). 9 points at 0.01 P/Po intervals in the range
0.08–0.16 P/Po and (d). 5 points at 0.02 P/Po intervals in the range
0.08–0.16 P/Po. Table 5 details the average SBET of ten samples of MgSt
batches C and D averaged under each of these regimes. Reducing the
number of P/Po data points applied to the calculation of SBET within a
given P/Po range again has a negligible effect. However, the slight
reduction in the BET P/Po range significantly reduces SBET. Maintaining
P/Po data points at intervals of 0.01 P/Po but reducing the maximum
P/Po applied to the calculation of SBET from 0.18 to 0.16 reduces SBET
by 3% for MgSt C and 6.8% for MgSt D. Given the BET range 0.08–0.16
P/Po, reducing the number of P/Po data points from 9 to 5 reduces SBET
of MgSt C by 0.35% and increases it by 0.15% for MgSt D.
When constructing SBET data for di-hydrated MgSt it is therefore
necessary to standardise the BET P/Po range applied in order to ensure
that measurements undertaken by different operators and using dif-
ferent instrumentation can be directly compared. Given that the BET
range should be restricted to the linear portion of the isotherm before
the onset of significant structural swelling, it would appear prudent to
limit the maximum P/Po applied to 0.16. Although the number of P/Po
data points included within this range would not appear to be influ-
ential on SBET, a sufficient number should be applied. Collecting the
adsorption isotherm at intervals of 0.01 P/Po within the BET range to
provide 9 P/Po data points for the calculation of SBET is not excessive.
4. Conclusions
For MgSt mono-hydrate, Kr adsorption provides lower SBET than N2
adsorption due to less multi-layer adsorption occurring within the BET
range through structural swelling. Isotherms are of good linearity and
ostensibly allow for reliable SBET calculation since application of BET
theory appears to be valid. SBET from N2 adsorption is over-estimated
due to the inclusion of multi-layer adsorption volumes caused by
structural swelling throughout the BET range. For MgSt di-hydrate the
large SBET disparity between the two adsorbates is caused by a con-
siderably higher multi-layer adsorption volume occurring with N2 ad-
sorption than with Kr adsorption. Essentially, this occurs at relative
pressures below the range providing linear BET transform data from N2
adsorption but above the corresponding range for Kr adsorption.
Consequently, a lower multi-layer adsorption volume is included in the
calculation of SBET via Kr adsorption than for N2 adsorption when re-
stricted to P/Po approximately 0.16. This is further supported by the
higher BET C-values obtained from Kr compared to N2 adsorption.
Overall, application of BET theory to Kr adsorption appears more valid
than N2 adsorption, Kr adsorption ultimately providing SBET data that
better represents the true surface area of MgSt.
It is necessary to establish a set of analytical protocols pertinent to
Kr adsorption on MgSt. For the calculation of SBET from N2 adsorption
13
International Journal of Pharmaceutics 568 (2019) 118522
data, Po is usually measured during analysis and Am is universally ac-
cepted. These values need to be selected for Kr adsorption and stan-
dardised to provide compatibility between analyses. It is suggested
from the above investigation that Po should be 2.320 mmHg and Am
should be 0.206 nm2. SBET calculation of di-hydrated MgSt is particu-
larly sensitive to the BET P/Po range applied and it is recommended
that adsorption isotherms be constructed so that the range 0.08–0.16 P/
Po can be applied to BET calculation with 9 data points at intervals of
0.01 P/Po. The multi-point BET method should be applied in preference
to the single-point method.
The preference of plate-like MgSt morphology and higher hydration
state for obtaining optimum lubricity has been discussed above. From
SEM and TGA data it appears that MgSt C and D would be most pro-
mising in this respect. Contradictory reports in literature concerning the
effects of MgSt on the physical properties of tablets, such as hardness,
strength and dissolution rate were stated above. However, the over-
estimate of SBET from N2 adsorption data, sensitivity to the BET P/Po
range applied and the apparent lack of standardisation of reported
measurements are likely to be a major influence on these disagree-
ments. Application of Kr adsorption to the calculation of SBET under the
analytical protocols established above would provide for considerably
improved reliability of measurements which may provide greater
clarity of the relationship between MgSt and tablet properties.
Furthermore, the issue of intra-batch and inter-batch variability of MgSt
SBET could also be investigated with greater certainty through Kr ad-
sorption, as suggested by the considerably lower standard deviation of
the ten SBET measurements discussed above.
Declaration of Competing Interest
None declared.
Acknowledgements
This research did not receive any specific grant from funding
agencies in the public commercial, or not-for-profit sectors.
The authors wish to thank Dr L F Jones of MCA Services Cambridge
LLP for his time and expertise in discussing and reviewing this work.
The authors also wish to sincerely thank Micromeritics Instrument
Corporation for their assistance with TGA analyses, the groups of
Professor J Silver and Dr G Fern at Brunel University, London for the
assistance with the SEM images and also FACI s.p.A, Mallinckrodt
Pharmaceuticals and Peter Greven GmbH for their assistance with the
sample materials.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ijpharm.2019.118522.
References
Andres, C., Bracconi, P., Pourcelot, Y., 2001. On the difficulty of assessing the specific
surface area of magnesium stearate. Int. J. Pharm. 218, 153–163.
Bracconi, P., Andres, C., N’diaye, A., Pourcelot, Y., 2005. Thermal analysis of commercial
magnesium stearate pseudopolymorphs. Thermochim. Acta 429, 43–51.
Brunauer, S., Emmett, P.H., Teller, E., 1938. Adsorption of gases in multimolecular layers.
J. Am. Chem. Soc. 60, 309–319.
Brunauer, S., Deming, I., Deming, W., Teller, E.J., 1940. On a theory of the van der waals
adsorption of gases. J. Am. Chem. Soc. 62, 1723–1732.
Dansereau, R., Peck, G.E., 1987. The effect of the variability in the physical and chemical
properties of magnesium stearate on the properties of compressed tablets. Drug Del.
Ind. Pharm. 13, 975–999.
Deitz, V.R., Turner, N.H., 1970. Cross-sectional area of adsorbed gases on pristine E-glass
fibre of known area. In: Proc. Int. Symposium 1969. Butterworths, London, pp.
43–54.
DesRosiers Lachiver, E., Abatzoglou, N., Cartilier, L., Simard, J.-S., 2006. Agglomeration
tendency in dry pharmaceutical granular systems. Eur. J. Pharm. Biopharm. 64,
193–199.
Ertel, K.D., Carstensen, J.T., 1988. An examination of the physical properties of pure
D.P. Lapham and J.L. Lapham
magnesium stearate. Int. J. Pharm. 42, 171–180.
Specific Surface Area by Gas Adsorption, 2005. European Pharmacopoeia 01/
2005:20926. Council of Europe, Strasbourg.
Magnesium Stearate, 2009. European Pharmacopoeia 07/2009:0229. Council of Europe,
Strasbourg.
Gregg, S.J., Sing, K.S.W., 1982. Adsorption, Surface Area and Porosity, second ed.
Academic Press, London.
Handbook of Chemistry and Physics, 2011, 92nd ed. CRC Press, Boca Raton, FL, USA, pp.
4–121.
Haware, R.V., Shivagari, Johnson, P.R., Staton, S., Stagner, W.C., Gupta, M.R., 2014.
Applications of multivariate methods to evaluate the functionality of bovine – and
vegetable – derived magnesium stearate. J. Pharm. Sci. 103, 1466–1477.
Hussain, M.S.H., York, P., Timmins, P., Humphrey, P., 1990. Secondary ion mass spec-
trometry (SIMS) evaluation of magnesium stearate distribution and its effects on the
physico-technical properties of sodium chloride tablets. Powder Technol. 60, 39–45.
Hussain, M.S.H., York, P., Timmins, P., 1992. Effect of commercial and high purity
magnesium stearates on in-vitro dissolution of paracetamol DC tablets. Int. J. Pharm.
78, 203–207.
Johansson, M.E., 1984. Granular magnesium stearate as a lubricant in tablet formations.
Int. J. Pharm. 21, 307–315.
Kato, H., Kimura, K., Izumi, S., Nakamichi, K., Danjo, K., Sunada, H., 2005. The effect of
magnesium stearate particle size on tablet properties and tabletting characteristics of
granules prepared with standard formulation. J. Drug Del. Sci. Technol. 15, 475–480.
Koivisto, M., Jalonen, H., Lehto, V.-S., 2004. Effect of temperature and humidity on ve-
getable grade magnesium stearate. Powder Technol. 147, 79–85.
Kushner, J.I.V., Langdon, B.A., Hiller, J.I., Carlson, J., 2011. Examining the impact of
excipient material property variation on drug quality attributes: a quality–by–design
study for a roller compacted, immediate release tablet. J. Pharma Sci. 100,
2222–2239.
Lakio, S., Vajna, B., Farkas, I., Salokangas, H., Marosi, G., Yliruusi, J., 2013. Challenges in
detecting magnesium stearate distribution in tablets. AAPS Pharm. Sci. Technol. 14
(1), 435–444.
Lapham, D.P., Lapham, J.L., 2017. Gas adsorption on commercial magnesium stearate:
Effects of degassing conditions on nitrogen BET surface area and isotherm char-
acteristics. Int. J. Pharm. 530, 364–376.
Lapham, D.P., Lapham, J.L., 2019. Gas adsorption on commercial magnesium stearate:
the origin of atypical isotherms and BET transform data. Powder Technol. 342,
676–689.
Levy, G., Gumtow, R.H., 1963. Effect of certain tablet formulation factors on dissolution
rate of the active ingredient III. J. Pharma Sci. 52 (12), 1139–1144.
Li, J., Wu, Y., 2014. Lubricants in pharmaceutical solid dosage forms. Lubricants 2,
21–43.
Marwaha, S.B., Rubinstein, M.H., 1988. Structure – lubricity evaluation of magnesium
14
International Journal of Pharmaceutics 568 (2019) 118522
stearate. Int. J. Pharm. 43, 249–255.
McClellan, A.L., Harnsberger, H.F., 1967. Cross-sectional areas of molecules adsorbed on
solid surfaces. J. Colloid Interface Sci. 23, 577–599.
Miller, T.A., York, P., 1985a. Physical and chemical characteristics of some high purity
magnesium stearate and palmitate powders. Int. J. Pharm. 23, 55–67.
Miller, T.A., York, P., 1985b. Frictional assessment of magnesium stearate and palmitate
lubricant powder. Powder Technol. 44, 219–226.
Morin, G., Briens, L., 2013. The effect of lubricants on powder flowability for pharma-
ceutical application. AAPS Pharm. Sci Technol. 14 (3), 1158–1168.
Mosig, J., Kleinebudde, P., 2014. Evaluation of lubrication methods: how to generate a
comparable lubrication for dry granules and powder material for tableting processes.
Powder Technol. 266, 156–166.
Phadke, D.S., Collier, J.L., 1994. Effect of degassing temperature on the specific surface
area and other physical properties of magnesium stearate. Drug Del. Ind. Pharm. 5,
853–858.
Rajala, R., Laine, E., 1995. The effect of moisture on the structure of magnesium stearate.
Thermochim. Acta 248, 177–188.
Shah, A.C., Mlodozeniec, A.R., 1977. Mechanism of surface lubrication: influence of
duration of lubricant – excipient mixing on processing characteristics of powders and
properties of compressed tablets. Pharma Sci. 66, 1377–1382.
Sharpe, S.A., Celik, M., Newman, A., Brittain, H.G., 1997. Physical characterisation of the
polymorphic variations of magnesium stearate and magnesium palmitate hydrate
species. Struct. Chem. 8 (1), 73–84.
Thommes, M., Kaneko, K., Neimark, A.V., Olivier, J.P., Rodriguez-Reinoso, F., Rouquerol,
J., Sing, K.S.W., 2015. Physisorption of gases, with special reference to the evaluation
of surface area and pore size distribution (IUPAC technical report). Pure Appl. Chem.
87, 1051–1069.
Uchimoto, T., Iwao, Y., Takahashi, K., Tanaka, S., Agata, Y., Iwamura, T., Miyagishima,
A., Itai, S., 2011. A comparative study of glycerine fatty acid ester and magnesium
stearate on the dissolution of acetaminophen tablets using the analysis of available
surface area. Eur. J. Pharm. Biopharm. 78, 492–498.
Specific Surface Area, 2000. U.S. Pharmacopoeia – National Formulary USP 24 NF 19.
Rockville, MD, 846.
Vromans, H., Bolhuis, G.K., Lerk, C.F., 1988. Magnesium stearate susceptibility of directly
compressible materials as an indication of fragmentation properties. Powder Technol.
54, 39–44.
Wang, J., Wen, H., Desai, D., 2010. Lubrication in tablet formulations. Eur. J. Pharm.
Biopharm. 75, 1–15.
Webb, P.A., Orr, C., 1997. Analytical Methods in Fine Particle Technology. Micromeritics
Instrument Corporation, USA.
Zuurman, K., van der Voort Maarschalk, K., Bolhuis, G.K., 1999. Effect of magnesium
stearate on bonding and porosity expansion of tablets produced from materials with
different consolidation properties. Int J. Pharm. 179, 107–115.