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QbD
in P
harm
aceu
tical
Dev
elop
men
t:T
able
t for
mul
atio
n de
sign
spa
ces
for
dire
ct
com
pres
sion
and
rol
ler
com
pact
ion
proc
esse
s
Mor
ten
Alle
sø,
PhD
(M
Sc
Pha
rm)
Pha
rmac
eutic
al s
cien
tist
ISP
E N
ordi
c PA
T C
oP, J
une
1st
2011
KU
-LIF
E, C
open
hage
n
Out
line
1.
In
tro
du
cti
on
to
tab
let
form
ula
tio
ns a
nd
ch
all
en
ges (
CQ
As, excip
ien
ts, C
U
an
d d
isso
luti
on
)2
.O
vervie
w o
f p
ro
cesses a
nd
un
it o
perati
on
s –
ch
osin
g t
he m
ost
co
st
eff
ecti
ve
man
ufa
ctu
rin
g3
.W
hat
is a
sta
nd
ard
fo
rm
ula
tio
n?
4.
Dir
ect
co
mp
ressio
n1.
Composition
2.
Dose homogeneity and theoretical considerations (incl. comparison to practice)
3.
NIR blend data
4.
Design space construction
2
4.
Design space construction
5.
Conclusion and perspectives (more DC form
. implementation i development through decision-
making trees)
5.
Ro
ller c
om
pacti
on
(d
ry g
ran
ula
tio
n)
1.
Introduction to roller compaction
2.
Critical quality attributes of ribbons and the granule (porosity, fines and API in fines)
3.
Ranking of critical process variables
4.
Design space of ribbon and granule properties
5.
Future work
6.
Co
nclu
din
g r
em
arks
Tabl
et fo
rmul
atio
ns a
nd m
anuf
actu
ring.
..
3
Tabl
et fo
rmul
atio
ns a
nd m
anuf
actu
ring.
..
Com
mon
tabl
et c
ompo
sitio
ns
Act
ive
ingr
edie
nt (
AP
I)F
iller
(s)
(+bi
nder
)Lu
bric
ant
Low
dos
e (0
.5%
AP
I)In
term
edia
te d
ose
(10%
AP
I)
Oth
er (
not s
how
n)
4
Hig
h do
se (
20%
AP
I)V
ery
high
dos
e (5
0% A
PI)
Tab
let p
roce
ss te
chno
logi
es
Wet
gra
nula
tion
high
she
ar m
ixer
Wet
Gra
nula
tion
Dire
ct C
ompr
essi
on
Mix
ing
of A
PI w
ithex
cipi
ents
Rol
ler C
ompa
ctio
n
Wet
sie
ving
Dry
ing
in fl
uid
bed
Rol
ler c
ompa
ctio
n
Mix
ing
of A
PI w
ithex
cipi
ents
Tab
let c
ompr
essi
on
Dry
sie
ving
Dry
sie
ving
5
Dry
ing
in fl
uid
bed
Dry
sie
ving
Mix
ing
gran
ulat
e w
ithex
cipi
ents
Tab
let
com
pres
sion
Mix
ing
gran
ule
with
lubr
ican
t
Tab
let c
ompr
essi
on
Tab
let
com
pres
sion
Low
dos
e (0
.5%
AP
I)
Cha
lleng
e: D
ose
hom
ogen
eity
�P
artic
le s
ize
of A
PI i
s cr
itica
l!�
AP
I par
ticle
siz
e co
ntro
l and
the
blen
ding
ste
p ar
e ve
ry c
ritic
al
Inte
rmed
iate
dos
e (1
0% A
PI)
6
Ver
y hi
gh d
ose
(50%
AP
I)C
halle
nge:
Mak
ing
the
tabl
et s
tick
�R
equi
res
good
com
pres
sion
pro
pert
ies
of
AP
I!�
Dry
pro
cess
ing
met
ho
ds
usu
ally
no
t ap
plic
able
Inte
rmed
iate
dos
e (1
0% A
PI)
Hig
h do
se (
20%
AP
I)
Usu
ally
wel
l sui
ted
for
dire
ct
com
pres
sion
and
rol
ler
com
pact
ion
Rat
iona
l sel
ectio
n of
pro
cess
tech
nolo
gy
Exa
mpl
e:IR
-tab
let,
3 st
reng
ths,
10,
20
and
30 m
gD
ose
prop
ortio
nal f
orm
ulat
ion
Par
amet
erW
etD
irect
R
olle
rG
ranu
latio
nC
ompr
essi
onC
ompa
ctio
nU
nit o
pera
tions
, no.
63
5S
cale
up
com
plex
sim
ple
sim
ple
QbD
com
plex
sim
ple
sim
ple
7
QbD
com
plex
sim
ple
sim
ple
AP
I- P
SD
crit
ical
itylo
wer
high
erlo
wer
AP
I sup
ply
until
sca
le-u
p to
pro
duct
ion,
kg
9035
35P
rodu
ctio
n cy
cle
time,
inde
x30
050
100
Typ
ical
pro
duct
ion
thro
ughp
ut, k
g/h
125
400
400
Pre
ferr
ed (
if ap
plic
able
)
12
The
sta
ndar
d fo
rmul
atio
n co
ncep
t...
8
The
sta
ndar
d fo
rmul
atio
n co
ncep
t...
Wha
t is
a st
anda
rd fo
rmul
atio
n?
Sta
nd
ard
fo
rm
ula
tio
n (
SF):
�A
fo
rm
ula
tio
n t
em
pla
te a
pp
lied
to
new
(an
d s
uit
ab
le) H
Lu
AP
Is.
Th
oro
ug
h a
nd
str
uctu
red
do
cu
men
tati
on
is a
vailab
le f
or e
ach
sta
nd
ard
fo
rm
ula
tio
n,
describ
ing
th
e r
ela
tio
nsh
ip b
etw
een
crit
ical
form
ula
tio
n-
an
d p
ro
cess v
aria
ble
s a
nd
on
e o
r s
everal
crit
ical
qu
ality
att
rib
ute
s
Des
ign
spac
e
9
Ad
van
tag
es o
f a S
F:
�In
-dep
th k
no
wle
dg
e o
f th
e f
orm
ula
tio
n i
s a
lread
y a
vailab
le,
i.e.
develo
pab
ilit
yw
ell-k
no
wn
.
�R
ed
ucti
on
of
wo
rklo
ad
of
a d
evelo
pm
en
t p
ro
ject
(efficiency)
Des
ign
spac
e
A s
tand
ard
form
ulat
ion
is a
pla
tform
tech
nolo
gy
(in
-ho
use
term
)
Des
ign
spac
e de
finiti
on
�D
esig
n s
pace:
IC
H Q
8: ”The multidimensional combination and
interaction of input variables(e.g., material
attributes) and process parametersthat have been
demonstrated to provide assurance of quality.
Working within the design space is not considered as
Mul
ti-fa
ctor
ial,
DoE
10
Working within the design space is not considered as
a change”
Uni
t ope
ratio
nsC
ritic
al p
roce
ss p
aram
eter
s (C
PP
)
The
form
ulat
ion,
raw
mat
eria
ls
Crit
ical
qua
lity
attr
ibut
es (
CQ
A)
-rel
ated
to s
peci
ficat
ions
A p
rere
quis
ite fo
r th
e co
nstr
uctio
n of
a d
esig
n sp
ace
is D
oE!
(impl
emen
ting
a co
ntr
ol s
trat
egy
usua
lly r
equi
res
PAT
)
Crit
ical
Qua
lity
Attr
ibut
es o
f the
fina
l tab
lets
Ble
ndin
g tim
e an
d lu
bric
atio
n bl
edin
g tim
e (e
stab
lish
ed b
ased
on
prel
imin
ary
expe
rimen
ts)
-(C
PP
-C
ritic
al P
roce
ss P
aram
eter
)
Tabl
etin
g pr
oper
ties
–Com
pact
ibili
ty a
nd c
ompr
essi
bilit
y–A
dhes
ion
to p
unch
esTa
blet
tech
nica
l pro
pert
ies
–Har
dnes
s >
50
N
11
–Har
dnes
s >
50
N–F
riabi
lity
< 0
.5%
–Dis
inte
grat
ion
time
< 5
min
.
Con
tent
uni
form
ity (
RS
D)
≤ ≤≤≤4%
(C
QA
)
Seg
rega
tion
prop
ertie
s (e
.g. f
luid
izat
ion)
(C
QA
)
Dis
solu
tion?
Sta
bilit
y?A
PI d
epen
dent
(m
olec
ular
pro
pert
ies)
!
Dire
ct c
ompr
essi
on fo
rmul
atio
n...
12
Dire
ct c
ompr
essi
on fo
rmul
atio
n...
Cho
ice
of e
xcip
ient
s-
prev
ious
kno
wle
dge
/ lite
ratu
re
�Fille
r:
Mic
ro
crysta
llin
e c
ellu
lose
× ×××Compatible with m
any APIs
× ×××Plastic deform
ing m
aterial (excellent compactibility)
× ×××Multi-functional: Disintegrant+binder
× ×××Relatively good flowability
�(S
up
er) d
isin
teg
ran
t: C
ro
scarm
ell
ose s
od
ium
× ×××Cross-bound carboxymetylcellulose
13
× ×××Cross-bound carboxymetylcellulose
× ×××Low conc. required
× ×××Effective disintegration agent
× ×××May be incompatible w/ API (ionin interaction)
�Lu
bric
an
t: M
g-s
tearate
× ×××Most effective (anti-adhesive effect)
× ×××Disrupts internal tablet bondings (affects dissolution/disintegration)
× ×××May be incompatible w/ API
For
mul
atio
n co
mpo
sitio
ns a
nd P
SD
of A
PI’s
(es
cita
lopr
am)
�A
PI (
1,
11
an
d 2
0%
w/
w)
�A
vic
el P
H1
02
(d
50
= 1
22
µm
, d
90/
d5
0=
2.0
)
�3
% A
c-d
i-so
l (cro
scarm
ello
se s
od
ium
)
�1
% o
r 2
% M
g-s
tearate
(2
% a
t 2
0%
AP
I)
�A
PI o
f q
ualiti
es D
50=
42
µm
, 6
7 µ
m,
11
4 µ
m a
nd
16
3
µm
(la
ser d
iffr
acti
on
)
14
AP
Id 1
0, µ
md 5
0, µ
md 9
0,µ
md 5
0/d 1
0d 9
0/d50
16.
242
165
6.8
42
8.6
6721
17.
83.
23
1111
424
910
2.2
418
163
338
9.1
2.1
Cen
tral
Com
posi
te F
ace
(CC
F)
desi
gn42
42
µ µµµµ µµµm
AP
I qua
lity
was
add
edm
AP
I qua
lity
was
add
edto
the
desi
gn w
ithou
t to
the
desi
gn w
ithou
t co
mpr
omis
ing
the
desi
gn
com
prom
isin
g th
e de
sign
qu
ality
qual
ity
The
aim
with
the
desi
gned
exp
erim
ent i
s to
app
roxi
mat
e th
e re
spon
se (
CU
-rsd
) by
a q
uadr
atic
pol
ynom
ial (
mod
el)
in o
rder
to:
•Und
erst
and
in m
ore
deta
il ho
w fa
ctor
s: p
artic
le s
ize
and
drug
load
influ
ence
the
resp
onse
; i.e
. get
a m
ap o
f the
sys
tem
(re
spon
se s
urfa
ce m
odel
ling)
.•M
ake
pred
ictio
ns a
nd fi
nd a
reg
ion
of o
pera
bilit
y.T
hus,
the
desi
gn w
ill a
lso
inve
stig
ate
for
any
inte
ract
ion
effe
cts
and
non-
linea
ritie
s in
th
e da
tase
t.
15
the
data
set.
Ana
lyze
2 ta
blet
s fo
r co
nten
t for
eve
ry 2
000t
h pr
oduc
ed (
100
min
tabl
etin
g)C
alcu
late
RS
D o
ver
tabl
etin
g =
Dos
e ho
mog
enei
ty
Ble
ndin
g ev
alua
tion
by N
IR-S
entr
oPat
16
Sen
troP
AT
NIR
spe
ctro
met
er
(Sen
tron
ic G
mbH
, Dre
sden
, Ger
man
y)
The
oret
ical
opt
imal
dos
e ho
mog
enei
ty (
Sre
l = C
U%
)
()
WP
wP
wP
PS
A
bA
aB
Bre
lA
+=
100
%,
P A/B
: rel
ativ
e co
nten
t of A
PI a
nd A
vice
l PH
102,
res
pect
. (P A
+PB=1
)w
a: m
ean
wei
ght (
base
d on
vol
ume
wei
gthe
d vo
lum
e m
ean
∑=
ii
ia
dv
w3
6ρ
π
17
wa
: mea
n w
eigh
t (ba
sed
on v
olum
e w
eigt
hed
volu
me
mea
n
diam
eter
) of
a s
ingl
e pa
rtic
le o
f AP
I and
Avi
cel P
H10
2,
resp
ectiv
ely,
cal
cula
ted
from
the
volu
me
size
dis
trib
utio
n (la
ser
diffr
actio
n)
Assu
mes f
ree f
low
ing
no
n-i
nte
racti
ng
bin
ary m
ixtu
res!
In
th
is c
ase:
ρ ρρρ AP
I≈ ≈≈≈
ρ ρρρ Avic
el
PH
10
2(red
uces r
isk o
f seg
reg
ati
on
)
The
oret
ical
opt
imal
dos
e ho
mog
enei
ty v
ersu
s ex
perim
enta
l
1 m
g ta
ble
t
4.0
6.0
8.0
10.0
12.0
Content RSD (%)
Act
ual
Theo
retic
al
1 m
g ta
blet
1 m
g ta
blet
20 m
g ta
blet
20 m
g ta
blet
20 m
g ta
ble
t
3.0
4.0
5.0
6.0
Content RSD (%)
Act
ual
Theo
retic
al
20 m
g ta
blet
20 m
g ta
blet
18
0.0
2.0
4267
114
163
50 m
g ta
ble
t
0.0
1.0
2.0
3.0
4.0
5.0
6.0
42**
6711
416
3
Content RSD (%)
Act
ual
Theo
retic
al
50 m
g ta
blet
50 m
g ta
blet
Adh
esio
n to
pun
ches
!A
dhes
ion
to p
unch
es!
0.0
1.0
2.0
42**
6711
411
416
3Content RSD (%)
Con
stru
ctin
g th
e de
sign
spa
ce:
Mul
tiple
Lin
ear
Reg
ress
ion
(MLR
)
The
dat
a fr
om th
e st
atis
tical
exp
erim
enta
l des
ign
can
be fi
tted
by m
eans
of m
ultip
le li
near
reg
ress
ion
(MLR
) an
d th
e re
spon
se, y
, can
be
desc
ribed
by
a po
lyno
mia
l fu
nctio
n:C
UR
SD
= b
1k1
+ b
2k2
+ in
tera
ctio
n te
rms
+ c
onst
ant
19
Des
ign
spac
e vi
sual
izat
ion
base
d on
MLR
API, % of tablet
20
AP
I
API, % of tablet
Con
clus
ions
for
DC
sta
ndar
d fo
rmul
atio
n ba
sed
on A
vice
l PH
102
�T
heo
reti
cal
calc
ula
tio
n o
n o
pti
mal
do
se h
om
og
en
eit
y c
orrela
tes
well
wit
h t
he a
ctu
al
valu
es a
s a
very v
alu
ab
le t
oo
l fo
r p
red
icti
on
of
the e
ffect
of
AP
I-P
SD
on
CU
% f
or t
he f
inal
tab
lets
based
on
DC
�A
desig
n s
pace w
as e
sta
blish
ed
base o
n C
FF d
esig
n s
ho
win
g t
he
eff
ect
of
AP
I o
n d
ose h
om
eg
en
eit
y i
n t
he d
ose r
an
ge o
f 1
-2
0%
A
PI.
�B
elo
w A
PI-P
SD
of
d5
0<
ap
pro
x.
40
µm
ad
hesio
n t
o p
un
ch
es o
ccu
r
for 2
0%
AP
I e
ven
at
2%
Mg
-ste
arate
→ →→→E
xte
rn
al
lub
ric
ati
on
21
for 2
0%
AP
I e
ven
at
2%
Mg
-ste
arate
→ →→→E
xte
rn
al
lub
ric
ati
on
�A
vic
el
PH
10
2 i
s a
n e
ffecti
ve f
ille
r/
dis
inte
gran
t p
ro
vid
ing
excellen
t
co
mp
acti
bilit
y a
nd
co
mp
ressib
ilit
y a
nd
tab
let
dis
inte
grati
on
tim
es
< 2
0 s
ec w
ith
3%
su
perd
isin
teg
ran
t A
c-D
i-S
ol.
Ac-D
i-S
ol
mig
ht
be
exclu
ded
(to
be i
nvesti
gate
d)
�S
eg
reg
ati
on
du
e t
o f
luid
izati
on
is r
ed
uced
wh
en
th
e A
PI-P
SD
an
d
do
se i
s r
ed
uced
(d
ue t
o i
ncreased
co
hesio
n b
etw
een
parti
cle
s)
On
goin
g w
ork
on D
C s
tand
ard
form
ulat
ions
�T
he u
se o
f u
sin
g e
xte
rn
al
lub
ric
ati
on
wit
h i
n-p
ro
cess s
prayin
g o
f m
ag
nesiu
m s
tearate
to
elim
inate
po
ten
tial
inco
mp
ati
bil
ity b
etw
een
M
g-s
tearate
an
d A
PI.
�A
ltern
ati
ve f
ille
rs t
han
MC
C i
s i
nvesti
gate
d.
Fo
rm
ula
tio
n s
creen
ing
h
as s
ho
wn
th
e b
est
can
did
ate
s t
o b
e:
Flo
wla
c 1
00
(la
cto
se) a
nd
P
arte
ck M
20
0 (
man
nit
ol)
. A
bin
der i
s n
eed
ed
to
im
pro
ve
co
mp
acti
bilit
y o
f th
e f
inal
ble
nd
.
22
co
mp
acti
bilit
y o
f th
e f
inal
ble
nd
.
Rol
ler
com
pact
ion
form
ulat
ion.
..
23
Rol
ler
com
pact
ion
form
ulat
ion.
..
Rol
ler
com
pact
ion
24
Why
do
dry
gran
ulat
ion
Ad
van
tag
es:
•Im
pro
ve f
low
ab
ilit
y
•Im
pro
ve w
eig
ht
un
ifo
rm
ity
•Im
pro
ve c
on
ten
t u
nif
orm
ity (
po
ssib
ly)
•M
inim
ize s
eg
reg
ati
on
(p
ossib
ly)
CQ
As (
gran
ula
te):
Rib
bo
n p
oro
sit
y (
wo
rk h
ard
en
ing
)W
ork
hard
enin
g (t
able
tabi
lity)
25
•R
ibb
on
po
ro
sit
y (
wo
rk h
ard
en
ing
)
•N
o.
of
fin
es
•B
imo
dal /
un
imo
dal?
•D
istr
ibu
tio
n o
f A
PI i
n s
ieve
fracti
on
s
Wor
k ha
rden
ing
(tab
leta
bilit
y)
Det
erm
ines
impa
ct o
f se
greg
atio
n on
tabl
et c
onte
nt
unifo
rmity
CP
Ps (
RC
):
•C
om
pacti
on
fo
rce
•G
ap
siz
e
•R
oll s
peed
(m
ostl
y u
p-s
calin
g)
•S
ieve s
ize (
tab
let
do
se u
nif
orm
ity)
Ran
king
of c
ritic
al p
roce
ss p
aram
eter
s (C
PP
s)
C
ritic
al Q
ualit
y A
ttrib
ute
(CQ
A)
Pro
cess
/ fo
rmul
atio
n pa
ram
eter
Rib
bon
poro
sity
F
ines
frac
tion
(< 1
25 µ µµµm
) A
PI-
% in
fin
es fr
actio
n
Com
pact
ion
forc
e (k
N)
HIG
H
INT
ER
ME
DIA
TE
U
NK
NO
WN
Gap
siz
e (m
m)
INT
ER
ME
DIA
TE
U
NK
NO
WN
U
NK
NO
WN
26
Gap
siz
e (m
m)
INT
ER
ME
DIA
TE
U
NK
NO
WN
U
NK
NO
WN
Rol
l spe
ed (
rpm
) LO
W
LOW
(up
on
decr
ease
in r
oll
spee
d)
UN
KN
OW
N
Rol
l wid
th (
cm)
NO
NE
N
ON
E
NO
NE
Gra
nula
tor
angl
e (° °°°)
N
ON
E
LOW
U
NK
NO
WN
Gra
nula
tor
spee
d (r
pm)
NO
NE
N
ON
E
NO
NE
Scr
een
type
N
ON
E
HIG
H
UN
KN
OW
N
Scr
een
size
N
ON
E
INT
ER
ME
DIA
TE
IN
TE
RM
ED
IAT
E
CQ
A s
peci
ficat
ions
of i
nter
med
iate
pro
duct
•Rib
bon
poro
sity
∈[3
5 ; 4
0%]
•% r
elat
ive
cont
ent o
f AP
I in
fines
frac
tions
sha
ll be
min
imiz
ed (
≤45
%)
•Fin
es fr
actio
n sh
all b
e m
inim
ized
(≤
30%
)
Por
osity
det
erm
inat
ion:
Ass
esse
d by
oil-
intr
usio
n m
etho
d (in
-hou
se)
27
Ass
esse
d by
oil-
intr
usio
n m
etho
d (in
-hou
se)
Sev
eral
oth
er m
etho
ds w
ere
initi
ally
com
pare
d
Fin
es fr
actio
n of
gra
nula
te:
Det
erm
ined
by
siev
e an
alys
is
Rel
ativ
e A
PI c
onte
nt in
fine
s fr
actio
n:D
eter
min
ed b
y U
V s
pect
roph
otom
etry
Cal
cula
ted
as %
of t
otal
dos
e re
cove
red
in a
giv
en g
ranu
le fr
actio
n
NO
TE
: A
PI p
artic
le s
ize
(d5o
fixed
at 6
5 µm
)!
Cen
tral
com
posi
te fa
ce d
esig
n
3 f
acto
rs
�Drug load (% w/w
)
�Compaction force (kN)
�Gap size (mm)
2 c
en
ter p
oin
ts
28
2 c
en
ter p
oin
ts
Load
(%
) C
omp.
forc
e (k
N)
G
ap (
mm
)
20
3 2
20
9 2
20
3 4
20
9 4
20
6 3
1.1
3 2
1.1
9 2
1.1
3 4
1.1
9 4
1.1
6 3
11
3 3
11
9 3
11
6 2
11
6 4
11 (
CP
) 6
3 11
(C
P)
6 3
Res
ults
from
rol
ler
com
pact
ion
tria
ls
Por
osity
-%
Fin
es-%
R
el. A
PI c
onte
nt (
%)
Load
(%
) C
omp.
fo
rce
(kN
)
Gap
(m
m)
Thr
ough
put
(kg
/hr)
Ela
stic
re
cove
ry
(mm
) d
gw (
µ µµµm)
Thr
ough
put
Oil
< 71
µ µµµm
<
125
µ µµµm
AP
I-R
SD
in
siev
e fr
ac. (
%)
<
71 µ µµµ
m
< 12
5 µ µµµm
1.1
3 2
6.9
0.2
193
45.1
43
.4
12.3
30
.1
76.6
35
.1
55.2
1.
1 9
2 9.
4 0.
2 31
4 25
.8
21.3
5.
7 14
.8
41.6
11
.9
20.4
1.
1 3
4 12
.2
0.3
201
49.4
51
10
.8
27.3
65
.6
27.2
51
.2
1.1
9 4
16.3
0.
3 25
7 32
.7
31.2
9.
3 21
.8
34.0
16
.5
26.9
1.
1 6
3 11
.6
0.2
231
36.1
35
.3
9.7
24.3
53
.2
22.9
37
.2
11
3 3
10.0
0.
3 16
6 45
.4
42.8
15
.3
35.3
72
.2
36.1
65
.8
11
9 3
13.8
0.
3 23
9 24
.7
24.3
9.
2 23
.0
50.4
21
.1
36.8
11
6
2 8.
6 0.
2 21
9 30
.6
27.6
9.
4 24
.5
55.7
22
.7
41.9
11
6
4 15
.9
0.3
221
32.7
34
.8
11.0
25
.8
58.0
26
.0
45.9
11
6
3 12
.3
0.3
202
32.4
33
.3
11.3
28
.2
57.2
26
.4
49.0
11
6
3 11
.9
0.3
215
34.8
33
.9
10.7
26
.1
60.4
27
.7
40.5
2911
6 3
11.9
0.
3 21
5 34
.8
33.9
10
.7
26.1
60
.4
27.7
40
.5
20
3 2
7.1
0.2
182
41.9
40
.8
11.9
31
.5
57.3
26
.1
54.3
20
9
2 9.
5 0.
2 21
8 21
.7
19.8
9.
7 27
.7
46.9
29
.3
42.1
20
3
4 13
.4
0.25
1 15
1 38
.3
45.4
13
.6
39.4
68
.1
18.6
66
.0
20
9 4
17.5
0.
3 23
4 24
.7
27.1
7.
8 23
.5
41.5
16
.1
35.2
20
6
3 12
.2
0.3
224
32.1
33
.6
8.9
25.6
46
.6
18.5
41
.4
Des
ign
spac
e co
nstr
uctio
n (P
LS m
odel
ing)
0.6
0.8
1.0
R2
Q2
Mod
el V
alid
ityR
epro
duci
bilit
y
30
0.0
0.2
0.4
0.6
TP-porosity
Oil-Porosity
Effe
cts
of C
PP
s on
rib
bon/
gran
ule
prop
ertie
s
31
Mod
el e
quat
ion:
Rib
bon
poro
sity
424446
424446
424446
32
2022242628303234363840
510
1520
Oil-Porosity
Load
2022242628303234363840
3.0
4.0
5.0
6.0
7.0
8.0
9.0
Com
p. fo
rce
2022242628303234363840
2.0
2.5
3.0
3.5
4.0
Gap
Mod
el e
quat
ion:
Fin
es fr
actio
n (%
< 1
25 µ
m)
323436
323436
33
18202224262830
24
68
1012
1416
1820
Mod
el e
quat
ion:
AP
I in
gran
ulat
e fr
actio
n (<
125
µm
)
556065
556065
34
253035404550
24
68
1012
1416
1820
API125
Load
253035404550
3.0
4.0
5.0
6.0
7.0
8.0
9.0
Com
p. fo
rce
Opt
imal
pro
cess
set
tings
: Hitt
ing
the
swee
t spo
t
35
Sw
eet s
pot p
lot s
how
ing
the
oper
atin
g re
gion
(de
sign
spa
ce)
for
each
dru
g lo
ad. A
red
sta
r in
dica
tes
the
oper
atin
g co
nditi
ons
used
in u
pcom
ing
verif
icat
ion
batc
hes.
RC
: Con
clus
ions
and
futu
re w
ork
�C
QA
s c
ou
ld b
e w
ell m
od
ele
d a
gain
st
dru
g l
oad
an
d C
PP
s:
co
mp
acti
on
fo
rce a
nd
gap
siz
e.
�N
ext
ste
p:
Verif
icati
on
of
sw
eet
sp
ot
sett
ing
s i
n a
new
exp
erim
en
tal serie
s (
on
-go
ing
; la
rg
er s
cale
) → →→→
prelim
inary
resu
lts s
ho
w g
oo
d r
ep
ro
du
cib
ilit
y f
or p
oro
sit
y a
nd
mo
stl
y
for f
ines f
racti
on
, h
ow
ever,
new
ch
allen
ges a
re n
ow
36
for f
ines f
racti
on
, h
ow
ever,
new
ch
allen
ges a
re n
ow
en
co
un
tered
:
Sampling related issues when m
easuring fines (sample divider)
Tableting step: Adhesion to punches ⇔
further decrease amount of
fines in the granulate (varying the sieve size of the granulator)
�Fin
ally:
Desig
n s
pace d
escib
ing
rela
tio
nsh
ip b
etw
een
AP
I
load
an
d A
PI p
arti
cle
siz
e (
sim
ilar a
s f
or D
C a
nd
usin
g
verif
ied
sw
eet
sp
ot
sett
ing
s f
or t
he R
C s
tep
)
Con
clud
ing
rem
arks
...
37
Con
clud
ing
rem
arks
...
�A
SF n
eed
s t
o b
e c
on
tin
uo
usly
mo
dif
ied
an
d r
efi
ned
!
�R
esu
lts/
data
an
d f
inally in
form
ati
on
is u
sele
ss u
nle
ss u
sed
as p
art
of
a s
tru
ctu
red
fram
ew
ork (
Qb
D).
So
far t
here a
re
13
exp
erim
en
tal p
lan
s a
nd
rep
orts
beh
ind
th
e S
F w
ork!
38
�D
ecis
ion
-makin
g t
oo
l in
Develo
pm
en
t: I
nte
grate
SF r
esu
lts
as f
low
ch
arts
an
d i
n r
isk a
ssessm
en
t te
mp
late
s (
on
-go
ing
).
�G
oo
d a
dvic
e:
Do
n’t
un
deresti
mate
th
e u
sefu
lness o
f ’o
ld’
data
an
d p
revio
us s
tud
ies.
Seek in
form
ati
on
an
d d
ecrease
the e
xp
erim
en
tal
wo
rk lo
ad
marked
ly (
less c
om
ple
x D
oEs).
Tha
nk y
ou...
Que
stio
ns?
39
Tha
nk y
ou...
Que
stio
ns?
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