Measured by a Compressed Bulk Density Tester for Small ...vehring/PE Page/CBD_Poster_RDD_2012...
Transcript of Measured by a Compressed Bulk Density Tester for Small ...vehring/PE Page/CBD_Poster_RDD_2012...
Th
e C
om
pre
ssio
n B
eh
avio
r of R
esp
irab
le P
ow
de
rs a
t Diffe
ren
t Re
lativ
e H
um
idity
Me
asu
red
by a
Co
mp
resse
d B
ulk
De
nsity
Te
ste
r for S
ma
ll Sa
mp
le M
asse
s
Abouzar S
ham
saddin
i-Shahrb
abak a
nd R
ein
hard
Vehrin
g
De
pa
rtme
nt o
f Me
ch
an
ica
l En
gin
ee
ring
, Un
ive
rsity
of A
lbe
rta, E
dm
on
ton
, AB
, Ca
na
da
Com
pressed
bu
lk d
ensity
(CB
D) d
escribes th
e bu
lk d
ensity
of a
po
wd
er un
der d
ifferent lev
els of ap
plied
load
and
is an estab
lished
meth
od
for
the
analy
sis of
den
sity
and
co
mp
ressibility
of
pharm
aceutical
po
wd
ers (1
). A
mong th
e facto
rs th
at affect
the
po
wd
er bu
lk d
ensity, th
e moistu
re con
tent o
f a po
wd
er is an o
ften
ov
erloo
ked
factor, in
spite o
f the fact th
at it has b
een sh
ow
n to
play
an im
po
rtant ro
le in co
nso
lidatio
n an
d d
ensificatio
n b
ehav
ior
of p
harm
aceutical in
gred
ients (2
,3). A
new
instru
men
t has b
een
dev
elop
ed to
measu
re com
pressed
bu
lk d
ensity
of sm
all pow
der
samp
les and
to in
vestig
ate the effects o
f relative h
um
idity
on th
e
com
pressio
n b
ehav
ior. In
troductio
n
Resu
lts
Ack
now
ledgem
ent
Referen
ces
+
Meth
od an
d M
aterials
Th
e au
tho
rs w
ish
to
ackno
wled
ge
the
assistance
of
Moh
amm
ed
Bo
raey, M
ehd
i A
zhd
arzadeh
, S
usan
H
oe,
and
Sad
af M
atink
ho
o
du
ring
collectio
n an
d p
rocessin
g o
f the d
ata.
Th
e su
pp
ort
of
the
Can
ada
Fo
un
datio
n
for
Inn
ov
ation
, A
lberta
Ad
van
ced E
du
cation an
d T
echno
log
y, and th
e Natu
ral Scien
ces and
En
gin
eering
Research
Co
un
cil of C
anad
a is ackn
ow
ledg
ed.
Classical
po
wd
er d
ensity
tests th
at w
ere dev
elop
ed fo
r po
wd
ers
with
large p
article size are no
t well su
ited fo
r respirab
le po
wd
ers.
Interp
article forces are larg
e com
pared
to in
ertial forces fo
r small
particles sizes.
Sin
gle v
alue d
ensity
measu
remen
ts are no
t sufficien
t to d
escribe
the
pack
ing
b
ehav
ior
of
po
wd
ers w
ith
small
particle
size. T
he
entire co
mp
ression
curv
e sho
uld
be co
nsid
ered.
Relativ
e hu
mid
ity d
urin
g th
e com
pactio
n test im
pacts th
e results
and
sho
uld
be co
ntro
lled.
Th
e sam
plin
g
histo
ry
sign
ificantly
affects
the
initial
state of
com
pactio
n,
i.e., p
ou
red
den
sity, of
respirab
le p
ow
ders
wh
ich
redu
ces the u
sefuln
ess of classical p
arameters o
f po
wd
er beh
avio
r
such
as Hau
sner ratio
or C
arr ind
ex.
Th
e presen
ted tech
niq
ue is a fast an
d efficien
t meth
od
to m
easure
com
pressed
b
ulk
d
ensity
o
f p
harm
aceutical,
respirab
le p
ow
ders.
Sam
ple m
ass requ
iremen
ts are < 4
0 m
g.
Conclu
sion
In th
is study
six d
ifferent sam
ples w
ere studied
:
Sp
ray
Dried
L-L
eucin
e, with
an aero
dy
nam
ic diam
eter, da =
2µ
m,
represen
ting
a low
particle d
ensity, resp
irable d
osag
e form
.
Cry
stallin
e L
-Leu
cine,
w
ith
a F
eret d
iameter,
dF
1
0µ
m,
represen
ting
hig
hly
flow
able raw
material.
Sp
ray
Dried
Treh
alo
se Dih
yd
rate, d
a = 1
.75
µm
, represen
ting
a
hig
h p
article den
sity, cohesiv
e, respirab
le po
wd
er.
Cry
stallin
e T
rehalo
se D
ihyd
rate,
dF
5
00
µm
, rep
resentin
g
crystallin
e raw m
aterial with
large p
article size.
Sp
ray
Dried
Treh
alo
se-Leu
cine, d
a = 1
.55µ
m, in
a 0.8
/ 0.2
w/w
form
ulatio
n
ratio,
represen
ting
a
po
wd
er of
eng
ineered
micro
particles w
ith co
re-shell stru
cture.
Micro
nized
P
ara
ceta
mol,
dF
4
.5µ
m,
represen
ting
an
activ
e
ph
armaceu
tical ingred
ient in
a traditio
nal resp
irable d
osag
e form
.
The co
mp
ressed b
ulk
den
sity m
easurem
ent w
as based
on
uniax
ial
com
pressio
n o
f a know
n m
ass of p
ow
der co
nfin
ed w
ithin
a small
cylin
drical cav
ity w
ith a v
olu
me o
f abo
ut 5
00
mm
3. A n
on
-rotatin
g
spin
dle (P
I Lin
ear Actu
ator) w
as used
to ex
ert a defin
ed p
ressure o
n
the p
ow
der. T
he fo
rce on
the sam
ple p
an w
as measu
red u
sing
a load
cell. Lab
View
Softw
are was u
sed fo
r con
trol an
d p
rocessin
g.
Sam
ples
were
stored
at
<5
%
RH
an
d
20±
2 °C
in
a
desiccato
r
cabin
et prio
r to in
itiating
the ex
perim
ent. D
urin
g testin
g, sam
ples
were eith
er expo
sed to
labo
ratory
conditio
ns, ty
pically
30±
3 %
RH
,
(blu
e traces in g
raphs) o
r measu
red in
a dry
bo
x u
nd
er nitro
gen
at
<1
%R
H (red
traces in g
raph
s).
The p
ressure at 3
5 k
Pa w
as selected as eq
uiv
alent m
easure fo
r tap
den
sity, T , b
ased o
n a p
revio
usly
pu
blish
ed co
rrelation
(4,5
). Th
e
initial d
ensity
at the start o
f the ex
perim
ent w
as used
as po
ured
den
sity, P .
UA
lberta
Den
sity Tester
RH
Gen
erato
r
Hea
ter
CD
A / N
2
Actu
ato
r
Sam
ple P
an
Alig
nm
ent
Micro
meter
Loa
d C
ell
Instru
men
t
Com
pariso
n
Micro
meritics
Geo
pyc 1
360
Freem
an
FT
4
US
P
Tap
ped
Den
sity
UA
lberta
Den
sity
Tester
Sam
ple
Volu
me
> 0
.35 cm
³ 10 cm
³ >
25 cm
³ <
0.1
5 cm
³
Operatin
g
Tem
peratu
re
15 –
35 °C
A
mbien
t N
/A
-24 –
60 °C
Operatin
g R
H
20 –
80 %
A
mbien
t N
/A
0 –
90 %
Measu
remen
t
Tim
e
420 –
780 s
300 –
600 s
> 3
00 s
40 –
70 s
Po
wd
er is
no
t fully
co
mp
ac
ted
at 3
5 k
Pa
.
La
rge
ch
an
ge
in p
ow
de
r de
ns
ity w
ith
inc
rea
sin
g lo
ad
.
Sa
mp
le P
an
1.
Svaro
vsk
y, L. (1
987), P
ow
der T
estinjg
Guid
e: Meth
ods o
f Measu
ring th
e Physical
Pro
perties o
f Bulk
Pow
ders, P
ublish
ed o
n B
ehalf o
f the M
aterial’s Han
dlin
g B
oard
by
Elsev
ier Applied
Scien
ce, New
York
, US
A
2.
Mir, V
. G., H
einam
aki J., A
ntik
ainen
O., C
olarte A
.I.. Airak
sinen
S., K
arjalainen
M.,
Rev
ored
o
O.
B.,
Nieto
O
. M
., Y
liruusi
J. (2
011
), E
ffect of
Moistu
re on
T
ablet
Compressio
n”, C
arbohydrate P
oly
mers, 8
6(2
), 477-4
83.
3.
Garr J.S
. M., R
ubin
sten M
.H. (1
992), “T
he In
fluen
ce of M
oistu
re Conten
t on th
e
Conso
lidatio
n an
d C
om
pactio
n P
roperties o
f Paracetam
ol”, In
ternatio
nal Jo
urn
al of
Pharm
aceutics, 8
1(2
-3), 1
87-1
92.
4.
Fen
g A
.I., Boraey
M.A
., Gw
in M
.A., F
inlay
P. R., K
ueh
l P. J., Veh
ring
R. (2
011
),
“Mech
anistic
Models
Facilitate
Efficien
t D
evelo
pm
ent
of
Leu
cine
Contain
ing
Micro
particles fo
r Pulm
onary
Drug”, In
trernatio
nal Jo
urn
al of P
harm
aceutics, 4
09(1
-
2), 1
56-1
63.
5.
Thalb
erg
K.,
Lin
dholm
D
. an
d
Axelsso
n
A.
(2004),
“Compressio
n
of
Differen
t
Flo
wab
ility T
ests for P
ow
ders fo
r Inhalatio
n”, P
ow
der T
echnolo
gy, 1
43(3
), 206
-213.
Sa
mp
le
his
tory
c
au
se
s
larg
e
va
riab
ility
at
low
p
res
su
re
an
d
wid
e ra
ng
e o
f H
au
sn
er
ratio
a
nd
Ca
rr ind
ex
for th
e s
am
e p
ow
de
r.
Dry
Am
bien
t
RH
Am
bien
t
RH
Dry
Cry
stallin
e Leu
cine
Sp
ray D
ried L
eucin
e Am
bien
t RH
Dry
Cry
stallin
e Treh
alo
se
Am
bien
t RH
Dry
Sp
ray D
ried T
rehalo
se
Am
bien
t RH
Sp
ray D
ried
Treh
alo
se-Leu
cine
Re
lativ
e h
um
idity
ha
s a
stro
ng
effe
ct o
n
co
mp
res
sib
ility o
f sp
ray d
ried
leu
cin
e.
Am
bien
t RH
Micro
nized
Para
cetam
ol
Hau
sner R
atio
:
T /P
2.3
– 3
.2
Ca
rr In
dex
:
10
0%
x(
T-
P )/T
57
- 69
%
T P
Po
wd
er w
ith la
rge
pa
rticle
siz
e
is c
los
e to
de
ns
e p
ac
kin
g e
ve
n
at lo
w lo
ad
De
ns
e, c
oh
es
ive
po
wd
er w
ith
sm
all p
artic
le s
ize
ha
s a
larg
e
vo
id fra
ctio
n e
ve
n a
t hig
h lo
ad
Re
sp
irato
ry D
rug
De
live
ry 2
01
2, P
ho
en
ix, A
Z, U
SA