Download Using Ludiflash® in Roll Compaction to produce Orally Dispersible

Using Ludiflash® in Roll Compaction to produce
Orally Dispersible Acetaminophen Granules
T. Agnese1, T. Cech1, M. G. Herting2
European Pharma Application Lab, E-mail: [email protected], BASF SE, 67056 Ludwigshafen, Germany
Pharma Ingredients & Services Europe, BASF SE, 67056 Ludwigshafen, Germany
Materials
As active ingredient, acetaminophen powder (Fagron
GmbH & Co. KG, Barsbüttel, Germany) was used.
As excipients, Ludiflash® (composed of mannitol [90 %],
Kollicoat® SR 30 D [5 % solids] and Kollidon® CL-SF
[5 %]) and Kollidon® CL-SF from BASF SE, Ludwigshafen, Germany, were used.
Sucralose (Splenda®, McNeil Nutritionals, Ft. Washington PA, USA) and strawberry flavour (Symrise AG, Holzminden, Germany) were added.
Formulation
The formulations listed in Table 1 were tested.
Table 1: Formulations – amounts in [mg]
#1
#2
#3
#4
Acetaminophen
500.0
500.0
500.0
500.0
Ludiflash®
716.2
653.7
591.2
528.7
–
62.5
125.0
187.5
Sucralose
18.8
18.8
18.8
18.8
Strawberry flavour
15.0
15.0
15.0
15.0
1,250.0
1,250.0
1,250.0
1,250.0
Kollidon® CL-SF
Total weight
Methods
The formulation contains a high dosage of the poorly
compressible acetaminophen (40 %). Additionally, sucralose as a sweetener, strawberry flavour and Ludiflash® as DC excipient were used in the granular formulation. The content of Kollidon® CL-SF as additional
extragranular disintegrant was varied to investigate its
influence on granule’s particle size distribution (PSD)
and granule strength. All excipients were passed
through a roll compactor applying specific compaction
forces of 6, 9, 12, 15 and 18 kN/cm.
As roll compactor, the Mini-Pactor® (Gerteis, Jona,
Switzerland) was used with the settings listed in Table 2.
80
70
60
Cross strip
11 rpm
Particle size distribution
The test was performed with a sieve tower Retsch AS
200 (Retsch GmbH, Haan, Germany) by using sieves in
the range of 90–1,400 µm (according to Ph. Eur.) applying an amplitude of 1.5 mm/’g’ for 15 minutes.
27670 APGI_MD313_DruckA3.indd 1
0.4
0.2
0
50
40
200
400
600
800
1,000
1,200
1,400
Particle size [mg]
6 kN/cm
9 kN/cm
12 kN/cm
15 kN/cm
18 kN/cm
Figure 4: Cumulative particle size distribution of formulation #3 as
function of compression force
1.0
0.8
0.6
0.4
0.2
30
0.0
20
0
200
400
10
600
800
1,000
1,200
1,400
Particle size [mg]
0
6
9 12 15 18 6
#1
9 12 15 18 6
9 12 15 18 6
#2
9 12 15 18
#3
#4
Formulation / compression force [kN/cm2]
Figure 1: Friability of granules after 15 minutes testing time
(mean ± s; n = 2)
Comparing the data at a compression force of 15 kN,
the addition of Kollidon® CL-SF led to stronger granules
indicated by lower friability (Figure 1).
Furthermore, the addition of the extragranular disintegrant influenced the particle size distribution as well.
The more Kollidon® CL-SF was added to the formulation, the coarser were the resulting granules (Figure 2–
Figure 5). Additionally, the difference in PSD of formulation #1 found for the different compression forces
(Figure 2) could be reduced. The dependency of PSD on
compression force could distinctively be reduced as
soon as Kollidon® CL-SF was present in the formulation
and a specific compaction force of at least 9 kN/cm was
applied.
Regardless of the positive effect of Kollidon® CL-SF on
the physical characteristics of the granule, its amount in
the formulation has to be chosen with care. If the content was too high, the mouth feeling would begin to get
unpleasant. This would be due to the fact that a huge
quantity of saliva is being absorbed by this insoluble
excipient.
1.0
0.8
0.6
0.4
0.2
0.0
200
400
600
800
1,000
1,200
1,400
Particle size [mg]
6 kN/cm
9 kN/cm
12 kN/cm
15 kN/cm
18 kN/cm
Figure 2: Cumulative particle size distribution of formulation #1 as
function of compression force
1.0
Cumulative distribution [-]
Star
30 rpm, 40 rpm
180°, 160°
1.5 mm, 1.5 mm
0.6
0.0
Independent of the amount of Kollidon CL-SF in the
powder blend, the compaction of Ludiflash® could be
conducted without any problems. Depending on the
compression force, granule’s strength could decisively
be influenced (Figure 1) whereby the higher the force the
stronger the granules.
0
Smooth, smooth
250 mm, 25 mm
1 rpm
0.8
®
Table 2: Parameter settings for the roll compactor
Rolls
Master, slave
Diameter, width
Speed
Granulator
Rotor type
Rotation speed CW, CCW
Angel CW, CCW
Mesh width, sieve gap
Powder bridge breaker
Type
Speed
Cumulative distribution [-]
Results and Discussion
Cumulative distribution [-]
Materials and Methods
1.0
0.8
0.6
0.4
0.2
0.0
0
200
400
600
800
1,000
1,200
1,400
Particle size [mg]
6 kN/cm
9 kN/cm
12 kN/cm
15 kN/cm
18 kN/cm
Figure 3: Cumulative particle size distribution of formulation #2 as
function of compression force
6 kN/cm
9 kN/cm
12 kN/cm
15 kN/cm
18 kN/cm
Figure 5: Cumulative particle size distribution of formulation #4 as
function of compression force
After roll compaction, one could consider it useful to
separate fine from coarse particles. These fines could
be retuned to the feeder to undergo a second compaction run. However, in this investigation for all granules, a
clear dependency of drug content on particle size could
be found (Figure 6). This could lead to a change in drug
content of the granules over the processing time.
45
Acetaminophen content [%]
Delivering active ingredients via orally dispersible tablets (ODTs) is a current trend in the pharmaceutical industry. Due to the easy and fast application, patient’s
compliance is high for this kind of dosage form.
Ludiflash® is a direct compression (DC) vehicle intended
for an easy formulation of ODTs [1]. Interestingly, granules packaged in sachets showed similar patient’s compliance as with ODTs. This work was to investigate the
usability of Ludiflash® in dry granulation to produce
granules containing acetaminophen.
Friability
An air jet sieve LPS 200 (Rhewum GmbH, Remscheid,
Germany) assembled with a 125 µm sieve was used to
determine both residual fines (remaining un-agglomerated particles) and friability of the granules [2].
Friability [%]
Purpose
Cumulative distribution [-]
1
2
40
35
30
25
0
200
400
600
800
1,000
1,200
1,400
1,600
Mesh size [µm]
Figure 6: Content uniformity of sieve fractions, formulation #1,
compressed with 12 kN/cm (mean ± s; n = 2)
Conclusion
The experiments showed that orally dispersible
granules could easily be produced in roll compaction by using Ludiflash® or its combination with
Kollidon® CL-SF.
A clear dependency of granular strength and PSD
on applied compaction force could be found. On
the other hand, the addition of Kollidon® CL-SF
caused the PSD to become less dependent on the
applied force. Furthermore, the amount of fines
could be reduced. However, too high amounts of
Kollidon® CL-SF can cause an unpleasant mouth
feeling due to huge amounts of saliva absorbed.
References
[1] Kruse, S.; Gebert, S.; Meyer-Böhm, K.; Maschke,
A.; Kolter, K.; Compression Characterization and
lubricant sensitivity of orally disintegrating tablets
based on Ludiflash®; 2008; BASF SE, Ludwigshafen, Germany
[2] Agnese, T.; Mittwollen, J.-P.; Kolter, K.; Herting,
M. G.; An Innovative Method to Determine the
Strength of Granules; AAPS Annual Meeting and
Exposition; Nov. 16–20, 2008; Atlanta, Georgia,
U.S.A.
2nd Conference Innovation in Drug Delivery; October 3–6, 2010;
Aix-en-Provence, France; G-EMP/MD313
23.09.10 08:21