2.9.26. Specific surface area by gas adsorption
volume change or sample dilution is needed. Alternatively,
determine the content of active substance(s) remaining
in the gum residue. Carry out the test successively on
6 medicated chewing gums.
The quantity of active substance(s) dissolved in a specified
time is expressed as a percentage of the content stated on
the label.
Figure 2.9.25.-2 – Funnel
(dimensions in millimetres)
Figure 2.9.25.-3 – Guide (section G-G)
(dimensions in millimetres)
01/2008:20926
2.9.26. SPECIFIC SURFACE AREA BY
GAS ADSORPTION
INTRODUCTION
The specific surface area of a powder is determined by
physical adsorption of a gas on the surface of the solid and
by calculating the amount of adsorbate gas corresponding to
a monomolecular layer on the surface. Physical adsorption
results from relatively weak forces (van der Waals forces)
306 See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 6.
between the adsorbate gas molecules and the adsorbent
surface of the test powder. The determination is usually
carried out at the temperature of liquid nitrogen. The
amount of gas adsorbed can be measured by a volumetric or
continuous flow procedure.
BRUNAUER, EMMETT AND TELLER (BET) THEORY AND
SPECIFIC SURFACE AREA DETERMINATION
MULTI-POINT MEASUREMENT
The data are treated according to the Brunauer, Emmett and
Teller (BET) adsorption isotherm equation :
(1)
P = partial vapour pressure of adsorbate gas in
equilibrium with the surface at 77.4 K (b.p. of
liquid nitrogen), in pascals,
Po = saturated pressure of adsorbate gas, in pascals,
Va = volume of gas adsorbed at standard temperature
and pressure (STP) [273.15 K and atmospheric
pressure (1.013 × 105 Pa)], in millilitres,
Vm = volume of gas adsorbed at STP to produce an
apparent monolayer on the sample surface, in
millilitres,
C = dimensionless constant that is related to the
enthalpy of adsorption of the adsorbate gas on
the powder sample.
A value of Va is measured at each of not less than 3 values of
P/Po.
Then the BET value
is plotted against P/Po according to equation (1). This
plot should yield a straight line usually in the approximate
relative pressure range 0.05 to 0.3. The data are considered
acceptable if the correlation coefficient, r, of the linear
regression is not less than 0.9975 ; that is, r2 is not less than
0.995. From the resulting linear plot, the slope, which is
equal to (C − 1)/VmC, and the intercept, which is equal to
1/VmC, are evaluated by linear regression analysis. From
these values, Vm is calculated as 1/(slope + intercept), while
C is calculated as (slope/intercept) + 1. From the value of
Vm so determined, the specific surface area, S, in m2·g–1, is
calculated by the equation :
(2)
N = Avogadro constant (6.022 × 1023 mol− 1),
a = effective cross-sectional area of one adsorbate
molecule, in square metres (0.162 nm2 for
nitrogen and 0.195 nm2 for krypton),
m = mass of test powder, in grams,
22400 = volume occupied by 1 mole of the adsorbate
gas at STP allowing for minor departures from
the ideal, in millilitres.
A minimum of 3 data points is required. Additional
measurements may be carried out, especially when
non-linearity is obtained at a P/Po value close to 0.3.
EUROPEAN PHARMACOPOEIA 6.0
Because non-linearity is often obtained at a P/Po value
below 0.05, values in this region are not recommended.
The test for linearity, the treatment of the data, and the
calculation of the specific surface area of the sample are
described above.
SINGLE-POINT MEASUREMENT
Normally, at least 3 measurements of Va each at different
values of P/Po are required for the determination of specific
surface area by the dynamic flow gas adsorption technique
(Method I) or by volumetric gas adsorption (Method II).
However, under certain circumstances described below, it
may be acceptable to determine the specific surface area
of a powder from a single value of Va measured at a single
value of P/Po such as 0.300 (corresponding to 0.300 mole
of nitrogen or 0.001038 mole fraction of krypton), using the
following equation for calculating Vm :
(3)
The specific surface area is then calculated from the value of
Vm by equation (2) given above.
The single-point method may be employed directly for a series
of powder samples of a given material for which the material
constant C is much greater than unity. These circumstances
may be verified by comparing values of specific surface area
determined by the single-point method with that determined
by the multiple-point method for the series of powder
samples. Close similarity between the single-point values and
multiple-point values suggests that 1/C approaches zero.
The single-point method may be employed indirectly for a
series of very similar powder samples of a given material for
which the material constant C is not infinite but may be
assumed to be invariant. Under these circumstances, the
error associated with the single-point method can be reduced
or eliminated by using the multiple-point method to evaluate
C for one of the samples of the series from the BET plot,
from which C is calculated as (1 + slope/intercept). Then Vm
is calculated from the single value of Va measured at a single
value of P/Po by the equation :
(4)
The specific surface area is calculated from Vm by equation (2)
given above.
EXPERIMENTAL TECHNIQUES
This section describes the methods to be used for the sample
preparation, the dynamic flow gas adsorption technique
(Method I) and the volumetric gas adsorption technique
(Method II).
SAMPLE PREPARATION
Outgassing
Before the specific surface area of the sample can be
determined, it is necessary to remove gases and vapours that
may have become physically adsorbed onto the surface after
manufacture and during treatment, handling and storage. If
outgassing is not achieved, the specific surface area may be
reduced or may be variable because an intermediate area
of the surface is covered with molecules of the previously
adsorbed gases or vapours. The outgassing conditions are
critical for obtaining the required precision and accuracy
of specific surface area measurements on pharmaceuticals
because of the sensitivity of the surface of the materials.
General Notices (1) apply to all monographs and other texts
2.9.26. Specific surface area by gas adsorption
Conditions. The outgassing conditions must be
demonstrated to yield reproducible BET plots, a constant
weight of test powder, and no detectable physical or chemical
changes in the test powder.
The outgassing conditions defined by the temperature,
pressure and time should be chosen so that the original
surface of the solid is reproduced as closely as possible.
Outgassing of many substances is often achieved by applying
a vacuum, by purging the sample in a flowing stream of a
non-reactive, dry gas, or by applying a desorption-adsorption
cycling method. In either case, elevated temperatures
are sometimes applied to increase the rate at which
the contaminants leave the surface. Caution should be
exercised when outgassing powder samples using elevated
temperatures to avoid affecting the nature of the surface and
the integrity of the sample.
If heating is employed, the recommended temperature
and time of outgassing are as low as possible to achieve
reproducible measurement of specific surface area in an
acceptable time. For outgassing sensitive samples, other
outgassing methods such as the desorption-adsorption
cycling method may be employed.
Adsorbate
The standard technique is the adsorption of nitrogen of
analytical quality at liquid nitrogen temperature.
For powders of low specific surface area (< 0.2 m2·g− 1) the
proportion adsorbed is low. In such cases the use of krypton
at liquid nitrogen temperature is preferred because the low
vapour pressure exerted by this gas greatly reduces error.
The use of larger sample quantities where feasible (equivalent
to 1 m2 or greater total surface area using nitrogen) may
compensate for the errors in determining low surface areas.
All gases used must be free from moisture.
Quantity of sample
Accurately weigh a quantity of the test powder such that the
total surface of the sample is at least 1 m2 when the adsorbate
is nitrogen and 0.5 m2 when the adsorbate is krypton.
Lower quantities of sample may be used after appropriate
validation.
MEASUREMENTS
Because the amount of gas adsorbed under a given pressure
tends to increase on decreasing the temperature, adsorption
measurements are usually made at a low temperature.
Measurement is performed at 77.4 K, the boiling point of
liquid nitrogen.
Method I : the dynamic flow method
Principle
In the dynamic flow method (see Figure 2.9.26.-1), the
recommended adsorbate gas is dry nitrogen or krypton,
while helium is employed as a diluent gas, which is not
adsorbed under the recommended conditions.
A minimum of 3 mixtures of the appropriate adsorbate gas
with helium are required within the P/Po range 0.05 to 0.30.
The gas detector-integrator should provide a signal that is
approximately proportional to the volume of the gas passing
through it under defined conditions of temperature and
pressure. For this purpose, a thermal conductivity detector
with an electronic integrator is one among various suitable
types. A minimum of 3 data points within the recommended
range of 0.05 to 0.30 for P/Po is to be determined.
Procedure
A known mixture of the gases, usually nitrogen and helium,
is passed through a thermal conductivity cell, through the
sample, again through the thermal conductivity cell and
then to a recording potentiometer.
307
2.9.26. Specific surface area by gas adsorption EUROPEAN PHARMACOPOEIA 6.0

Immerse the sample cell in liquid nitrogen, then the sample Procedure
adsorbs nitrogen from the mobile phase. This unbalances
Admit a small amount of dry nitrogen into the sample tube
the thermal conductivity cell, and a pulse is generated on
to prevent contamination of the clean surface, remove the
a recorder chart.
sample tube, insert the stopper, and weigh it. Calculate
Remove from the coolant ; this gives a desorption peak equal the weight of the sample. Attach the sample tube to the
in area and in the opposite direction to the adsorption peak. volumetric apparatus. Cautiously evacuate the sample down
Since this is better defined than the adsorption peak, it is to the specified pressure (e.g. between 2 Pa and 10 Pa).
the one used for the determination. Alternatively, some instruments operate by evacuating to a
defined rate of pressure change (e.g. less than 13 Pa/30 s)
To effect the calibration, inject a known quantity of adsorbate and holding for a defined period of time before commencing
into the system, sufficient to give a peak of similar magnitude the next step.
to the desorption peak and obtain the proportion of gas If the principle of operation of the instrument requires the
volume per unit peak area. determination of the dead volume in the sample tube, for
example, by the admission of a non-adsorbed gas, such as
Use a nitrogen/helium mixture for a single-point helium, this procedure is carried out at this point, followed
determination and several such mixtures or premixing by evacuation of the sample. The determination of dead
2 streams of gas for a multiple-point determination. volume may be avoided using difference measurements, that
Calculation is essentially the same as for the volumetric is, by means of reference and sample tubes connected by a
method. differential transducer. The adsorption of nitrogen gas is
then measured as described below.
Method II : the volumetric method
Raise a Dewar vessel containing liquid nitrogen at 77.4 K
Principle up to a defined point on the sample cell. Admit a sufficient
volume of adsorbate gas to give the lowest desired relative
In the volumetric method (see Figure 2.9.26.-2), the pressure. Measure the volume adsorbed, Va. For multipoint
recommended adsorbate gas is nitrogen which is admitted measurements, repeat the measurement of Va at successively
into the evacuated space above the previously outgassed higher P/Po values. When nitrogen is used as the adsorbate
powder sample to give a defined equilibrium pressure, P, of gas, P/Po values of 0.10, 0.20, and 0.30 are often suitable.
the gas. The use of a diluent gas, such as helium, is therefore
unnecessary, although helium may be employed for other REFERENCE MATERIALS
purposes, such as to measure the dead volume.
Periodically verify the functioning of the apparatus using
Since only pure adsorbate gas, instead of a gas mixture, is appropriate reference materials of known surface area, such
employed, interfering effects of thermal diffusion are avoided as α-alumina, which should have a specific surface area
in this method. similar to that of the sample to be examined.

Figure 2.9.26.-1. — Schematic diagram of the dynamic flow method apparatus

308 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 6.0 2.9.29. Intrinsic dissolution

Figure 2.9.26.-2. — Schematic diagram of the volumetric method apparatus

01/2008:20927 influenced by extrinsic factors (test conditions), such as
hydrodynamics, temperature, viscosity, pH, buffer strength
2.9.27. UNIFORMITY OF MASS and ionic strength of the dissolution medium.
The assessment of intrinsic dissolution rate of a solid
OF DELIVERED DOSES FROM substance involves the preparation of a compact. Assurance
MULTIDOSE CONTAINERS of appropriate compaction properties of the powder to be
tested is needed prior to performing the test.
The following test is intended for oral dosage forms such
The intrinsic dissolution rate is determined by exposing a
as granules, powders for oral use and liquids for oral use,
constant area of the compacted substance to an appropriate
which are supplied in multidose containers provided at
dissolution medium, while maintaining constant stirring
manufacture with a measuring device.
rate, temperature, ionic strength and pH.
Weigh individually 20 doses taken at random from one or The intrinsic dissolution rate is expressed in terms of
more containers with the measuring device provided and dissolved mass of substance per time per exposed area,
determine the individual and average masses. Not more than typically in milligrams per minute per square centimetre
2 of the individual masses deviate from the average mass (mg·min− 1·cm− 2).
by more than 10 per cent and none deviates by more than
20 per cent. APPARATUS
A typical apparatus consists of a punch and die fabricated
out of hardened steel. The base of the die has 3 threaded
01/2008:20929 holes for the attachment of a surface plate made of polished
steel, providing a mirror-smooth base for the compact.
2.9.29. INTRINSIC DISSOLUTION The die has a 0.1-1.0 cm diameter cavity into which a
measured amount of the powder to be tested is placed. The
The test is intended to determine the intrinsic dissolution punch is then inserted in the die cavity and the material is
rate of pure solid substances following compaction. It is compressed, generally using a benchtop hydraulic press. A
carried out under specified experimental conditions such hole through the head of the punch allows insertion of a
that a practical measure of the intrinsic dissolution rate is metal rod to facilitate removal from the die after the test. A
obtained. compact is formed in the cavity with a single face of defined
The intrinsic dissolution rate is a theoretical value referring area exposed on the bottom of the die (Figure 2.9.29.-1). The
to pure solid substances having null porosity, but, practically, bottom of the die cavity is threaded so that at least 50-75 per
intrinsic dissolution rate is determined on substances having cent of the compact can dissolve without falling out of the
a minimal porosity. die. The top of the die has a threaded shoulder that allows
it to be attached to a holder. The holder is mounted on
PRINCIPLE a laboratory stirring device, and the entire die, with the
The intrinsic dissolution rate is defined as the dissolution compact still in place, is immersed in the dissolution medium
rate of pure substances following compaction under the and rotated by the stirring device.
condition of constant surface area. Its assessment is useful
PROCEDURE
in the characterisation of active substances and excipients.
Weigh the material onto a piece of weighing paper. Attach
The dissolution rate of pure substances can be affected by all
the surface plate to the underside of the die, and secure it
the solid state properties such as crystal habit, crystallinity,
with the 3 provided screws. Transfer the sample of powder
amorphism, polymorphism, pseudo-polymorphism, particle
tested into the die cavity. Place the punch into the chamber,
size and specific surface area. In addition, it can also be

General Notices (1) apply to all monographs and other texts 309