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Choosing the optimal lactose and MCC grade for formulating moisture sensitive drugs
1 DFE Pharma, Klever Strasse 187, 47574 Goch, Germany2 Merlin Powder Characterization Ltd., Leicestershire, LE11 5GW, UK
Shegokar R.1, Heiligenstadt A.1, Villarta, G.1, Stone E.2, Hebbink, G.1
PurposeThe development of robust and cost effective formu-
lations of moisture sensitive drugs is complicated due
to poor flow of drug, variable dissolution rates, and/or
instability. Excipients like microcrystalline cellulose
(MCC) and lactose with low moisture levels can
accelerate their formulation development. The main
objective of this study is to show the tabletability
performance of low moisture MCC and anhydrous
lactose in moisture sensitive tablet formulation.
MethodsLow moisture MCC (Pharmacel® 112), anhydrous lactose
(SuperTab® 21AN, 22AN) and anhydrous granulated
lactose (SuperTab® 24AN) were evaluated for physical-
chemical parameters like particle size, shape and flow
properties. Dwell time sensitivity of the individual
excipients was studied at fast and low tabletting speeds
in a placebo formulation. The dwell time study was
performed on Phoenix hydraulic compaction Simulator.
A model moisture sensitive drug was incorporated in
250 mg tablets composed of anhydrous lactose alone
and in combination with Pharmacel® 112.
Results and discussionThe mean particle size of three anhydrous lactose
grades is in the range of 120-220 µm and that of the
MCC grade between 90-100 µm. Microscopy (SEM)
(Fig. 1) confirmed the fibrous/agglomerated nature of
MCC, the irregular kite like shape of anhydrous lactose
and the spherical shape of anhydrous granulated
lactose. Anhydrous lactose showed superior flow
MCC
functions coefficients compared to Pharmacel® 112
(moderate flow) when tested in pure form (Fig. 2).
All the directly compressible excipients showed very
stable flow and robust tabletting properties (low dwell
time sensitivity) at high speed of 5 ms and low speed
of 50 ms demonstrating the robustness of excipient
performance during scale up (Fig. 3).
The formulation containing anhydrous lactose
(50% w/w) and Pharmacel® 112 (50% w/w) was selected
to incorporate 20% w/w moisture sensitive drug in
250 mg tablets compressed at 10 kN.
Tablets were produced with different grades of
anhydrous lactose and in combination (50-50% w/w)
with Pharmacel® 112 showed similar thickness,
friabi lity and weight variation profiles. The tensile
strength at 10 kN was higher for SuperTab® 24 AN
(anhydrous granulated lactose, 5.4 MPa) followed by
SuperTab® 22AN and SuperTab® 21AN, which showed
similar tensile strength (3 - 4 MPa) (Fig. 4).
Granulated anhydrous lactose (SuperTab® 24AN)
forms compacts with greater strength, and is ideal
excipients for directly compression process. Addition
of Pharmacel® 112 (50% w/w) to anhydrous lactose
further improved the compactibility without changing
the disintegration time to large extent. MCC together
with lactose showed synergistic effect on tabletability
and lowered ejection forces.
ConclusionLow moisture MCC and anhydrous lactose offers a
perfect combi nation of plastic and brittle behavior,
respectively enabling the rapid formulation
development of moisture sensitive drugs. Moderate
flow of MCC can be further improved by addition of
lactose while increased tabletability can be achieved
by addition of MCC. The combined offering of the
both anhydrous grades of lactose and low moisture
MCC grade by DFE Pharma allows therefore the
formulator choice to find the most optimal solution
for their formulation challenge.
Figure 1: Scanning electron micrographs of (A) SuperTab® 21AN (B) SuperTab® 24AN and (C) SuperTab® 30GR (D) Pharmacel® 112.
flow
fun
ctio
n c
oeffi
ent
Mea
n p
arti
cle
size
(µm
)
30 250
Flow D50 (µm)
30200
20
10
550
15 100
0 0SuperTab®
21ANSuperTab®
22ANSuperTab®
24ANPharmacel®
112SuperTab®
30GRPharmacel®
102
25
150
Figure 2: Flow function coefficient (FFC) and mean particle size of anhydrous directly compressed lactoses (SuperTab® AN series) and Pharmacel®112.
Ten
sile
str
engh
t (M
pa)
8 100
80
60
40
20
0
6
3
2
1
4
5
0SuperTab®
21ANSuperTab®
21AN +Pharmacel®
112
7
Figure 4: Tensile strength (Mpa) and disintegration time (sec) of tablets compressed at 10 kN using anhydrous lactose alone and in combination with Pharmacel® 112.
5 ms dwell50 ms dwell
0
1
2
3
4
5
0 50 100 150 200 250
Tab
let t
ensi
le s
tren
gth
(MPa
)
Compaction pressure (Mpa)
SuperTab® 24AN
0
1
2
3
4
5
0 50 100 150 200 250
Tab
let t
ensi
le s
tren
gth
(MPa
)
Compaction pressure (Mpa)
5 ms dwell50 ms dwell
SuperTab® 30GR
0
1
2
3
4
5
0 50 100 150 200 250
Tab
let t
ensi
le s
tren
gth
(MPa
)
Compaction pressure (Mpa)
5 ms dwell50 ms dwell
SuperTab® 21AN
0
1
2
3
4
8
7
6
5
0 50 100 150 200 250
Tab
let t
ensi
le s
tren
gth
(MPa
)
Compaction pressure (Mpa)
5 ms dwell50 ms dwell
Pharmacel® 102
Figure 3: Tensile strength (MPa) of different anhydrous grades of lactose and Pharmacel® at fast and low tabletting speed. The dwell time sensitivity index was calculated from the ratio of slop of both speeds at compaction pressure of 125 MPa.
Dis
inte
grat
ion
tim
e (s
ec)
SuperTab® 22AN
SuperTab® 22AN +
Pharmacel® 112
SuperTab® 24AN
SuperTab® 24AN +
Pharmacel® 112
C
B
D
A
www.dfepharma.com