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

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