Real time PCR - European Pharmaceutical Review

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2009 THERMAL ANALYSIS
(a common problem with pressurised
metered dose inhalers (pMDI)).
As has been discussed in the
literature 1 , the processes involved in
particle size reduction during milling
are complex. The mechanical forces
imparted to a crystalline material
during milling result initially in a
reduction in particle size, as the
material fractures along natural fault
lines and crystal defects. Eventually
there comes a point at which the bulk
material can no longer fracture and
maximum particle size reduction has
been achieved. Post this point,
mechanical forces are still being
applied and must be absorbed and
dissipated by the sample; these
processes result initially in production
of surface dislocations and eventually
generation of amorphous regions; so
called process-induced disorder.
As has been well documented
elsewhere 2,3 , the amount of
amorphous material formed in this
way is usually small (of the order of a
few percent w/w); however, the nature
of the force applied (impaction)
means that this amorphous material
must necessarily be located on the
surface of the milled material and,
hence, although the milled material is
predominantly crystalline it behaves
as if it were entirely amorphous.
Newell at al 4 published some inverse
phase gas chromatography (IGC) data
(see Table 1) that convey this point. It
is inevitable that this amorphous
material will crystallise, probably over
a relatively short timeframe as it is
located on a crystalline substrate that
can act as a seed. Crystallisation of
the surface may have disastrous
consequences for the function of the
product 5 , primarily because the force
of adhesion between drug and carrier
will change, altering the balance of
forces that is so important in
modulating product performance from
batch-to-batch and within one batch
over time. As such, it is imperative to
understand the mechanisms and
kinetics of crystallisation, such that its
effects can be ameliorated. Often this
means conditioning (under humidity
or some other suitable plasticising
vapour) the material post micronising
to force crystallisation.
If it is true that particle size
reduction occurs before, and not
concomitantly with, generation of
process induced disorder then it is
apparent that it would be possible to
micronise a sample without
generating any amorphous material.
This would remove the need for
downstream conditioning and ensure
consistent product performance. It is
not possible to optimise milling by
following particle size reduction
alone, since there is no particle sizing
technique that can simultaneously
detect formation of amorphous
content. Returning to the data shown
in Figure 1 (page 28), it is tempting to
set up a process involving four to five
micronising steps, since this seems
to ensure a consistent particle size
distribution; such an approach
does nothing to report the generation
of process induced disorder and
can lead to the batch-to-batch
variability in product performance
noted above.
Here, we show that following the
micronising process with an
additional technique, isothermal
microcalorimetry, affords extra data
that allows optimisation of the
micronising time. In addition, the data
allow the hypothesis that particle size
reduction occurs before the
generation of process induced
disorder to be tested.
Figure 2: Calibration plot of amorphous content versus heat of crystallisation for
salbutamol sulphate, determined with IGPC
The model drug chosen was
salbutamol sulphate (SS), since this is
a drug commonly formulated for
inhalation. Crystalline SS was
prepared by precipitation from
acetone while amorphous SS was
prepared by spray-drying. Crystalline
SS was ball-milled for increasing
periods of time; Laser-diffraction
particle sizing (Mastersizer, Malvern
Instruments Ltd) was used to
measure particle size distributions
and isothermal gas perfusion
calorimetry (IGPC, based in a TAM
Table 1: Dispersive surface energy data (recorded with inverse-phase gas
chromatography) for various lactose samples [4].
Sample Dispersive surface energy (mJ/m 2 )
Amorphous lactose (spray-dried) 37.1 (2.3)
Crystalline lactose monohydrate 31.2 (1.1)
Mixture (ca. 1% w/w amorphous) 41.6 (1.4)
Milled (ca. 1% w/w amorphous) 31.5 (0.4)
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