UCL SCHOOL OF PHARMACY
PHAYG062
Preformula2on
Amorphous
materials
Learning
objec2ves
• To
define
the
amorphous
state
• To
know
the
structure
of
amorphous
materials
• To
understand
how
amorphous
matrices
will
change
with
9me
– Relaxa9on
• To
discuss
the
changes
that
occur
at
the
glass
transi9on
temperature
• To
appreciate
which
processing
methods
can
produce
amorphous
materials
• To
know
some
advantages
and
disadvantages
of
amorphous
forms
The
amorphous
state
• Widely
studied,
poorly
understood
• Many
of
the
terms
used
originate
from
the
polymer
field
• Effect
of
amorphous
material
oDen
not
considered
– Misunderstanding
of
defini9on
– No
understanding
that
an
amorphous
(or
par9ally
amorphous)
material
may
have
been
formed
• Generally,
amorphous
materials
only
characterised
when
product
is
formulated
to
be
amorphous
Defini2on
• Amorphous
(Gk,
lack
of
form)
• Easiest
conceptualisa9on
is
to
consider
a
material
with
the
molecular
structure
of
a
liquid,
but
the
viscosity
of
a
solid
Degree of disorder
Liquid Solid
Viscosity
Amorphous
materials
• Commonly
encountered
in
everyday
life
Energy or volume
Glass Supercooled liquid Liquid
(i) Aging
(ii) (ii) Recovery
(i)
Temperature
TK Ta Tg mp
Forma2on
• Easily
formed
during
processing
and
manufacture
• Some
techniques
produce
almost
en9rely
amorphous
material
– Spray-‐drying
– Freeze-‐drying
– Quench-‐cooling
• Others
produce
par9ally
amorphous
material
– Ball
or
air-‐jet
milling
– Compac9on
Spray-‐drying
Hot air
Sample
inlet
Air outlet
Dry product
Freeze-‐drying
• Based
on
triple-‐point
of
water
• Sample
is
frozen,
placed
under
vacuum
and
reheated
• Can
also
use
t-‐butanol
as
a
solvent
Pressure (Pa) 105 2 1
Liquid
Vapour
Solid
610
Triple point
3 4
0.0075 Temperature (oC)
Both
amorphous
but…
• Note
that
while
both
materials
are
amorphous,
proper9es
likely
to
be
significantly
different
(porosity,
stability,
dissolu9on
rate
etc).
Uninten2onal
forma2on
• Any
technique
that
applies
a
force
to
a
sample
can
make
it
par9ally
amorphous
– Localised
input
of
energy
can
disrupt
molecules
out
of
a
crystalline
alignment
– Importantly,
because
force
is
usually
applied
at
the
surface,
while
percent
amorphous
material
might
be
low,
the
effects
it
exerts
might
be
significant
Macroscopic properties different
For
example:
IGC
data
for
various
lactose
samples*
Sample Surface Energy / mJ m-2
Amorphous lactose (spray dried) 37.1 ± 2.3
Crystalline lactose monohydrate 31.2 ± 1.1
Milled (ca. 1% w/w amorphous) 41.6 ± 1.4
Physical blend of crystalline and amorphous 31.5 ± 0.4
(99:1)
*Newell et al , Pharm Res 18 (2001) 662
Characteris2cs
of
amorphous
materials
• Glass
transi9on
temperature
• Below
Tg
material
is
termed
bri%le*
• Above
Tg
material
is
termed
rubbery*
• One
formalism
is
to
consider
molecules
as
being
in
structural
equilibrium
with
temperature
above
Tg
but
not
below
Energy or volume
Glass Supercooled liquid Liquid
(i) Aging
(ii) (ii) Recovery
(i)
Temperature
TK Ta Tg mp
Relaxa2on
• With
9me,
amorphous
materials
will
relax
– Essen9ally
all
the
molecules
begin
to
move
into
a
greater
structural
alignment
– Excess
energy
is
lost,
so
system
tends
towards
supercooled
liquid
state
– Eventually
crystallisa9on
will
occur
– Will
occur
faster
with
• Temperature
• and/or
addi9on
of
a
plas9ciser
Advantages
of
amorphous
materials
• No
crystal
laXce
energy,
so
main
barrier
to
dissolu9on
overcome
• Therefore,
rapid
dissolu9on
leading
to
high
concentra9ons
Crystalline and amorphous MOM*
*Sato
et
al,
Chem.
Pharm.
Bull.,
29:2675-‐2682,
1981.
Disadvantages
of
amorphous
materials
• However,
stability
can
oDen
be
decreased
– Uptake
of
water
and/or
greater
molecular
mobility
so
faster
rate
of
reac9on
• Data
shows
temperature
stability
of
cefotoxi9n
sodium*
• Crystalline
(top)
• Amorphous
(bofom)
• 40oC
(r)
60oC
(£)
80oC
()
*Oberholtzer
et
al,
J.
Pharm.
Sci.,
68:863-‐866,
1979
Why
consider
amorphous
forms?
• Drivers
for
move
to
amorphous
formula9on
– Increasing
molecular
weight
of
ac9ve
– Use
of
deriva9sed
polymeric
ac9ves*
– Use
of
polymeric
excipients
– Increasing
number
of
BCS
class
II
ac9ves
as
lead
compound
– Formula9on
of
fast-‐dissolving
oral
formula9ons
– Instability
in
solu9on,
but
IV
route
needed
*For instance, PolyTherics Ltd
Amorphous
drug
products
• In
other
words,
choose
amorphous
formula9on
because
– Ac9ve
or
excipient
can’t
be
crystallised
– Increased
dissolu9on
rate
confers
a
solubility
advantage
– Ac9ve
is
too
unstable
in
solu9on,
but
must
be
administered
intravenously
Amorphous
drug
products
• Three
main
formula9on
types
– Solid
amorphous
dispersions
– Lyophilized
powders
– Oral
fast-‐dissolving
tablets/films
Solid
amorphous
dispersions
• Drug
is
dissolved
in
a
(usually
polymeric)
matrix
– Molecular
dispersion
-‐
solid
solu9on
– Par9culate
dispersion
-‐
solid
suspension
2 component, 2 phase 2 component, 1 phase
Case
example:
SporanoxTM
(itraconazole)
• Itraconazole
has
very
poor
solubility
• During
manufacture
drug
and
HMPC
in
ethanol
and
dichloromethane
are
sprayed
onto
sugar
core
• Solid
solu9on
formed
on
surface
• Granules
are
put
in
hard
capsules
HPMC/itraconazole solid
solution
Sugar core
Oral
fast-‐dissolving
tablets
• Generally
formulated
for
marke9ng
advantage
rather
than
bioavailability
• ‘Melt’
in
mouth
with
no
need
for
added
water
• Freeze-‐dried
tablet
Case
example:
Nurofen
meltlets
• Mechanical
strength
of
freeze-‐dried
ibuprofen
an
issue
• Co-‐formulate
with
a
sugar
(mannitol)
for
strength
-‐
a
‘matrix
former’
– Also
helps
taste-‐masking
• Also
add
a
collapse
protectant
(oDen
glycine)
• Freeze-‐dry
solu9on
directly
in
blister
pack
• Suspension
formed
in
mouth
-‐
easily
swallowed
Lyophilized
powders
• Freeze-‐dried
powder
in
sealed
vial
• Used
when
IV
solu9on
is
required
but
ac9ve
is
unstable
in
solu9on
– Drugs
that
hydrolyse
(penicillins)
– Biologics
(vaccines)
• Can’t
recons9tute
with
water
(not
isotonic
with
blood)
• Use
saline
BP
or
recons9tu9on
solu9on
Summary
• Amorphous
state
is
a
non-‐equilibrium
state
• Viscosity
of
a
solid,
structure
of
a
liquid
• Formed
by
various
processes
– Deliberate
formula9on
(high
content)
– Accidental
inclusion
(low
content)
• Can
have
desirable
quali9es
– Dissolu9on
rate
and
bioavailability
• But
also
undesirable
– Loss
of
physical
form
– Chemical
instability
