Method: Igc Sea Technical Note 804

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iGC SEA

Influence of the Sample Mass on the Results Technical


obtained by Inverse Gas Chromatography
Note 804
Majid Naderi
Surface Measurement Systems Ltd.

In this study the effect of the sample mass on the surface and free energy of different pharmaceutical
ingredients has been investigated.

Introduction Method
Paracetamol (Sigma Aldrich, UK with a purity of
Inverse Gas Chromatography (IGC) is typically minimum 99.0%) and microcrystalline cellulose
carried out at infinite dilution (low concentration Prosolv 50 (Penwest Co., USA) have been used as
of vapour). In this regime only few vapour probe model substances for an active pharmaceutical
molecules interact with the high energy sites on ingredient and an excipient, respectively.
the surface of the solid material under Different masses of each powder were packed
investigation. If the concentration (partial into a silanised standard column (SMS standard
pressure) of the vapour probe is increased (“finite columns, 2mm ID for Paracetamol and 4 mm ID
dilution”) less active sites on the surface are also for microcrystalline cellulose) using the SMS
involved in the interaction and energetic sample-packing device. All columns were
parameters measured usually decrease in prepared using the same frequency and duration
comparison to infinite dilution conditions. of tapping during packing.
Whether a pulse experiment is carried out at Five columns containing different sample masses
infinite or finite concentration depends on the (ranging between 80 mg and 480 mg) of
ratio between amount of sample (= mass) and paracetamol and six columns of microcrystalline
amount of probe vapour (= concentration cellulose (between 8 mg and 271 mg) were
/volume) due to its discontinuous nature. packed and analysed. All analyses were carried
Given the above, it becomes obvious that the out using the SMS-iGC SEA instrument and the
results of an IGC-SEA pulse experiment are SMS-iGC v1.3 analysis suite of macros. All
dependent on the concentration regime and columns were initially conditioned at 30oC for 2h
conditions must therefore be carefully controlled. and 0% relative humidity (RH) and experiments
were carried out at 30°C and 0% RH with
injections of 0.03 P/P0 elutant vapour
concentrations for all elutants. A flame ionisation
detector was used to record the chromatogram
and resulting retention times.

P-SCI-320 v1.0 12NOV2013


The analysis of the dispersive component of the All values used to plot Figures 1 & 2 are average
surface energy was performed by measuring the values over all the runs measured on each sample
net retention volume VN (measured retention mass.
volume – dead volume) for a series of alkane
elutants (for Paracetamol: undecane, decane,
nonane, octane, heptane and for Prosolv: decane,
nonane, octane, heptane, hexane). The dead
volume was determined by injecting methane, a
probe molecule that does not interact
significantly with low energy materials. By
plotting RTln(VN) versus a(γLD)1/2 , where a is the
molecular area of the probe molecule and γLD is
the dispersive component of the surface energy
of the liquid elutant (surface tension), a straight
line is produced. Its slope equals to 2NA(γSD)1/2
from which γSD, the dispersive component of the Figure 1. Dispersive surface energy of
solid surface energy, can easily be deduced [1]. Paracetamol as a function of sample mass
The specific free energies of desorption were
obtained by measuring the retention volume of
polar probe molecules (toluene, 1,4-dioxane,
ethyl acetate and ethanol for Paracetamol and
acetone, ethyl acetate and ethanol for Prosolv).
Points representing a polar probe are located
above the alkane straight line in the plot. The
distance to the straight line is equal to the
specific free energy.
All columns have been analysed twice in a row
(i.e. using the same column) while performing
another conditioning of 2h at 30oC between each
run to check for irreversible sorption effects and
make sure the 2h conditioning was long enough
to reach equilibrium. In the case of Paracetamol, Figure 2. Specific free energy of Paracetamol as a
two columns have been analysed for each sample function of sample mass
mass in order to check for sample-to-sample
The dispersive component of the surface energy
variation.
for all Prosolv columns is illustrated in Figure 3.
The specific free energies for acetone, ethyl
acetate and ethanol are illustrated in Figure 4
Results (values grouped by probe molecule). All values
The results for Paracetamol and for the used to plot Figures 3 & 4 are average values over
microcrystalline cellulose were calculated. all the runs measured on each sample mass

The dispersive component of the surface energy


for all Paracetamol columns is illustrated in Figure
1. The specific free energies for toluene, 1,4-
dioxane, ethyl acetate and ethanol are illustrated
in Figure 2 (values grouped by probe molecule).
As illustrated in Figures 1 - 4, the values for the
dispersive surface energy as well as for the
specific free energy seem to increase with
increasing sample mass until they reach a plateau
at higher masses. This is surprising, because one
would expect the surface and free energy to be
mass independent when at infinite dilution
conditions. Since this is not the case suggests
either inaccurate measurements or that infinite
dilution conditions were not present with lower
sample masses. The former can be excluded
Figure 3. Dispersive surface energy of Prosolv as a
based on the good experiment-to-experiment
function of sample mass
reproducibilities. For this reason, the vapour
concentration to sample mass ratio should be
examined in more detail based on the
microcrystalline cellulose measurements.
There is a relationship between concentration
regime and peak shape. At infinite dilution peaks
are supposed to be Gaussian, meaning fully
symmetrical. At higher concentrations (“finite
dilution”) a tailing is typically observed for vapour
probes that interact preferentially with the
surface rather than with themselves. A more
detailed description of the impact of the
adsorption mechanisms on the overall
Figure 4. Specific free energy of desorption of interactions and on the peak shape can be found
Prosolv as a function of sample mass in ref. [4] and [5] respectively. Unfortunately, it
For each column, the experiment-to-experiment has been found in practice that the symmetry
reproducibility for the dispersive component of criterion is too inaccurate to ensure that infinite
the surface energy and the specific free energies dilution conditions are present as peaks can be
is within the typical error margin (standard also distorted due to other effects such as gas
deviation <3-4%) [2, 3] with the exception of the phase diffusion and are therefore almost never
very small masses for Paracetamol. It could be totally Gaussian. A better and quantitative way of
concluded that the two-hour preconditioning at checking for the concentration regime is the
30ºC allowed all columns to reach equilibrium calculation of the sorption isotherm. As
and the sorption mechanism exclusively involves mentioned above the peak shape changes with
reversible physisorption. The bigger variation for concentration. This suggests that this effect is
small masses of Paracetmaol can be explained by also related to the shape of the adsorption
insufficient retention. isotherm. Indeed, the isotherm can be directly
computed from the retention volume and partial
The sample-to-sample variation is also overall low pressure [4]. At infinite dilution a linear isotherm
which suggests that there are no sampling issues results and can be described by Henry’s law. At
and the sample has a low heterogeneity. Again, elevated concentration a deviation from the
bigger variations can be observed for small linear behaviour is observed. For a peak with
masses of Paracetmol due to insufficient tailing a curved sorption isotherm (type II) results
retention. as shown schematically in Figure 5.
and the surface and free energy begins to
decrease. This is due to the fact that the IGC-SEA
pulse experiment is discontinuous meaning that
the equilibrium partial pressure and therefore the
amount adsorbed depends on the sample mass to
vapour probe concentration ratio.
The results also reveal a considerable
complication of these kinds of experiments. At
infinite dilution conditions the retention volumes,
where the surface and free energies are
calculated from, are independent of surface
coverage and therefore vapour concentration. At
finite concentration, however, this is not the case
and the retention volume changes significantly
with surface coverage and vapour concentration.
Therefore, surface and free energies at finite
Figure 5. Correlation of peak form and sorption concentration only present meaningful numbers
isotherm for finite and infinite dilution. if they are calculated from probe retention
As an example the octane peak of the volumes at the same surface coverage. For this
experiments with different masses of reason the calculation used at infinite dilution
microcrystalline cellulose has been analysed and cannot be applied without a previous correction
the isotherm has been calculated according to the for surface coverage. Such a procedure is
peak maximum method as described in [4]. The explained in [6].
corresponding isotherms are shown in Figure 6. The significant deviation for the 8 mg sample
cannot simply be explained by a shift to finite
concentration conditions since isotherms should
always coincide, independent of the sample mass.
For this reason the observed deviation has to be
due to insufficient retention that causes an
increase in variability. The difference between
methane and octane for an 8 mg sample is less
than 0.1 min which could be considered as an
accuracy limit in the experience of the authors.
Figure 6. Octane isotherms for different masses of
Prosolv (calculated by PeakMaximum method).
It can be seen that the isotherms all coincide
nicely with the exception of the 8 mg
measurement. This proves again the good
Conclusions
reproducibility of the experiments. All isotherms
above 128 mg are quasi linear (correlation The findings of this study explain the sometimes
coefficient >0.999). This is in good agreement different results reported in literature for
with the surface and free energy values reported identical materials as most authors only pay
above where the results are overall independent attention to minimising the injection vapour
of sample mass above 128 mg. Below this mass concentration but neglect to look at the effect of
there are no infinite dilution conditions present sample mass on the concentration regime. It is
iGC SEA
Technical
Note 804

therefore recommended to carry out experiments


on new materials which haven’t been
investigated previously with different column
masses to ensure true infinite dilution conditions
(no change in surface or free energy with mass).
Finite concentration experiments can also reveal
interesting results but the surface coverage needs
to be taken into account. Injections with less than
0.1 min difference between the probe molecule
and methane should not be considered for
further analysis.
Acknowledgement:
SMS thanks Simone B. Reutenauer and Frank
Thielmann for their contributions to the Technical
note.

References
[1]Frank Thielmann, David Butler, Determination of the dispersive surface
energy of Paracetamol by iGC at infinite dilution, SMS Application Note
202 (2000).
[2]Simone B. Reutenauer Reproducibility of the Dispersive Component of
Surface Energy measured by Inverse Gas Chromatography. Part I: Low
Energetic Materials, SMS Technical Note 801 (2003).
[3]Simone B. Reutenauer Reproducibility of the Dispersive Component of
Surface Energy measured by Inverse Gas Chromatography. Part II: Highly
Energetic Materials, SMS Technical Note 802 (2003).
[4]Frank Thielmann, Ingo Florian, The Measurement of Isotherms by Pulse
IGC, SMS Application Note 208 (2002).
[5]Frank Thielmann, Daniel Burnett, Isotherm Types and Adsorption
Mechanisms of Solvents on Pharmaceutical Excipients, SMS Application
Note 26 (2004).
[6]
Surface Energetic Heterogeneity Profiles by iGC Surface Energy Analyzer,
SMS Application Note 224.

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