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TRANSCRIPT
Excipients & Actives for Pharma | No. 22, May 2009
in 2008, the pharmaceutical industry – inclu -
ding their suppliers like BASF – once again
had to realize “the world is getting smaller”
being more than just a popular phrase.
The whole story was triggered just recently
on July 1st, 2008 when the United States
Pharmacopoeia adopted the globally harmo-
nized concepts on how to regulate residual
solvents in pharmaceuticals (ICH Q3C) into
USP chapter <467>.
Shortly after the Office
of Generic Drugs (OGD)
of the FDA distributed
a remarkable letter:
“USP Chapter <467>
Residual Solvents –
Additional Information”
raising questions, par-
ticularly among globally
located ANDA holders.
BASF and a coalition of
all relevant stakeholders reacted quickly and
could help clarifying the situation: FDA re-
sponded only a couple of weeks later offer-
ing a helpful “flexible, stepwise approach to
application of USP <467> to ANDAs”.
We chose to bring this topic up aiming to illus-
trate the importance of such internatio nally
harmonized regulations.
Early 2008 BASF sites Geismar and Ludwigs -
hafen had undergone and successfully pas -
sed the USP Ingredient Verification Program.
In late 2008, all relevant pharmaceutical
actives and excipients manufactured in Lud-
wigshafen were re-inspected and certified
according to highest GMP standards (ICH
Q7). Besides that, strong efforts paid off after
additional CEP (Certificate of the European
Pharmacopoeia) applications were filed in
2006 and 2007: BASF recently obtained
twelve additional CEPs and is expecting
some more in the future.
This edition of ExAct continues with the
new troubleshooting column, gives updates
on new products, recent registrations and
planned workshops and presents technical
aspects of film coating, granule hardness
and, last not least, as announced in ExAct
21, melt extrusion for pharmaceuticals.
Yours sincerely,
Philipp HebestreitManager, Global Regulatory Affairs
ContentsMelt Extrusion for Pharmaceuticals
Pages 2 – 5
Kollicoat® – Moisture Protection with
Kollicoat® Protect
Pages 6 – 8
Troubleshooting – Film Coating Colour
Variation (Spots)
Pages 9 – 10
News: – BASF opens applications laboratory for
pharmaceutical industry in India
– An innovative method to determine
granule strength
– GMP Re-certification successfully
passed
– Residual Solvents: Recent development
of a hot topic
Pages 11 – 15
New Media: – Updated edition of DVD on BASF
excipients now available
Page 15
Preview:New Polymer for Melt Extrusion
CalendarContact Page 16
ImprintPublisher: BASF SE
Editorial staff: Thorsten Cech, Dejan Djuric,
Claudia Easterbrook, Hubertus Folttmann, Bernhard
Fussnegger, Felicitas Guth, Ralf Hadeler, Hendrik
Hardung, Philipp Hebestreit, Michael Herting,
Karl Kolter, Angelika Maschke, Kathrin Meyer-Böhm,
Vanessa Occhipinti, Andres-Christian Orthofer,
Inge Rademacher, Florian Wildschek
Concept/layout: Château Louis Strategische
Markenführung und Kommunikation GmbH
Print: johnen-druck GmbH & Co. KG
Dear Reader,
Philipp Hebestreit Manager,Global Regulatory Affairs
Trademarks are owned by BASF SE
INTRODUCTIONHot melt extrusion is an estab-
lished manufacturing process
that has been used in the plas-
tics and food industry since the
1930s.
In the 1980s, BASF SE was the
first to apply the melt extrusion
process based on polymers with
a high glass transition tempera-
ture, like polyvinylpyrrolidones,
to pharmaceuticals [1].
Later on, Soliqs, the drug deliv-
ery business of Abbott GmbH &
Co KG, commercialized the tech-
nology and launched several
drugs [2].
Hot melt extrusion is generating
more and more interest as the
percentage of poorly soluble new
chemical entities in drug devel-
opment is constantly increasing.
For such molecules hot melt
extrusion offers an opportunity
to make them orally bioavailable
[3]. Additional benefits are crea-
tion of a reliable drug release
profile and a robust manufactur-
ing process which can be run in
every pharmaceutical factory.
However, as with other break-
K. Kolter, A. Maschke
Melt Extrusion for Pharmaceuticals
Excipients & Actives for Pharma
through innovations, nume rous
obstacles had to be overcome
before commercialization of the
technology and resulting dosage
forms. Compared with other phar-
maceutical technologies like tab-
leting, hot melt extrusion is still
an emerging technology whose
potential has not yet been fully
explored.
The technology itself can be de-
fi ned as a process where a mate-
rial which melts or softens under
elevated temperatures and pres-
sures, is forced through an ori-
fice by screws.
A prerequisite of a polymer to be
used in melt extrusion is thermo-
plastic behavior, however, the
number of such polymers ap-
proved for pharmaceutical use is
limited.
BASF offers polymers with differ-
ent structures and properties for
use in melt extrusion.
In this article we will describe the
suitability of polymers for melt
extrusion, and highlight polymer
properties required for the
process.
Based on the selection of a suit-
able polymer, pharmaceutical
companies can improve dosage
form characteristics as well as
shorten the time to bring a new
drug to the market.
Extrusion processIn principle an extruder consists
of a barrel with screws inside
forcing a material through a die
and shaping it (Figure 1). The
barrel can be heated to plasti-
cize the material and reduce its
viscosity. Since the extruder is
fed at one side and the extruded
material exits it from the other
side, it is a typical continuous
process, which makes it even
more attractive [4].
In most cases corotating inter-
meshing twin-screw extruders
are used. The powder is usually
gravimetrically dosed into the
extruder, heated and more or less
melted in the first part, thereafter
mixed and homogenized by
kneading elements, and at the
end extruded through a die which
can have various shapes. Resi-
dence times in the extruder vary
depending on the screw speed,
screw configuration and feed
rate but range typically from 0.5
to 2 minutes.
Drug delivery systemsHot melt extrusion is mainly used
to formulate poorly soluble ac-
tives as solid dispersions [5]. Of
the various types of solid-solid
systems or solid dispersions,
three are of significant pharma-
ceutical relevance.
Since the poly mer used is usual-
ly amorphous, the drug can be
incorporated either in a crys-
talline state or an amorphous
state or it can be molecularly
dissolved (Figure 2). Based on
the physical status of the drug
and the concentration, the sys-
tem is either thermodynamically
stable or kinetically controlled.
The most reliable and safest sys-
tem is when the drug is molecu-
larly dissolved below the satura-
tion solubility. In this case with-
out severe impact from the envi-
ronment, like uptake of humidity,
no crystallization or change of
the release profiles will occur.
Die
Melting
ScrewTempering
accordings to Thommes (13)
Cylinder
Temperature: above Tg of polymer (80 – 180 °C)Residence time: variable (0.5 – 5 min)
Shaping Mixing
Powder
Extru
date
Engine
Figure 1: Principle of Melt Extrusion Figure 2: Relevant Types of Solid Dispersions
Drug: crystalline amorphous molecularly dissolved
Polymer: amorphous amorphous amorphous
Thermo-dynamic almost stable unstable stable (drug belowstability: (kinetically controlled) saturation solubility)
No. 22, May 2009 | PAGE 3
Based on the pH-dependent
solubility of the polymer, instant-
release, enteric or sustained-
release drug delivery systems
can be developed. The selection
of the polymer strongly deter-
mines the release rate of the
drug (Figure 3). In most cases
instant-release systems have
been developed and commer-
cialized so far.
Polymers for melt extrusionThe polymer must exhibit ther-
moplastic characteristics in order
to permit the melt extrusion pro-
cess and it must be stable at ex-
trusion temperatures. Other rele-
vant characteristics are: suitable
Tg (50 – 180 °C), low hygroscop-
icity and no toxicity since larger
amounts of polymer are applied
(Figure 4). Polymers with a high
solubilization capacity are particu-
larly suitable because large
quantities of drugs can be dis-
solved. Some features like
lipophilicity, solubility parameter
[6, 7], hydrogen bonding accep-
tors or donors [8] and amide
groups are basic prerequisites
for a high solubilization capacity,
as they are for organic solvents
(Figure 5). This explains why
povidone and copovidone are
highly suitable for melt extrusion.
In particular copovidone is much
more lipophilic than many other
water-soluble polymers which
contain hydroxyl groups and,
therefore, best meets the lipo-
ph ilicity of poorly soluble drugs.
Where the drug is incorporated
in a supersaturated form the
whole mixture should have a
very rigid structure in order to
minimize crystallization either
from dissolved drug or from
amorphous drug particles [9].
The formulation, being a solid
solution, dissolves in gastric or
intestinal fluids to form a super-
saturated solution of the drug,
thus enhancing dissolution and
bioavailability [10].
Saturation solubility of drugs in
various polymers was determi -
ned using a film casting proce-
dure out of a drug-polymer solu-
tion in dimethyl formamide.
The casted solution was vacuum
dried at 50 °C. Thereafter the
drug containing polymer film was
stored at ambient conditions for
14 days. Appearance of crystals
in the film proves that saturation
solubility was exceeded whereas
clear transparent films indicate
that saturation solubility was not
reached.
Highest saturation solubilities
were achieved for Kollidon® VA
64 and Kollidon® 30 (Figure 6).
Kollidon® VA 64 Kollicoat® MAE 100P Kollidon® SRKollidon® (Povidone) Eudragit® L 100-55 Polyvinyl acetateKollicoat® IR HPMCAP ECHPMC HPMCAS Eudragit® RSHPCLutrol® F gradesEudragit® EPEG
IR Enteric SR
Figure 3: Polymers for Different Release Profiles
Figure 4: Relevant Polymer Charasteristics
Figure 5: Solubilization Capability
Figure 6: Solubilization Capability
Hygros -copicity
Long termstability
Targetedreleaseprofile
Glasstransitiontempera-
ture
Meltviscosity
Solution &solubilizingcapability
Thermo-stability of
drug &polymer
Physico-chemicalpropertiesof active
Drug +Polymer
Impacts on solubilization capabilityLipophilicitySolubility parameterHydrogen bondingsAmide structures acting as hydrogen acceptors
Excellent solventsDimethyl acetamideDimethyl formamidePyrrolidoneMethyl pyrrolidone
Poor solventsMethanolAcetone
Excellent polymersKollidon VA 64Kollidon 30
Poor polymersKollicoat IRHPC
N C
0
C
C O
OH
,Similia similibus solvuntur‘
Evaporates were prepared with 10, 25, 33 and 50% drug content
Drug content [% dissolved in polymer]
Polymer
Kollidon VA 64
Kollidon 12 PF
Kollidon 30
Kollidon SR
KollicoatMAE 100P
Carbamazepine 17-β- Estradiol Piroxicam Clotrimazole
≥50
33-50
≥50
33-50
33-50
≥50
33-50 33-50 33-50
≥50
≥50
≥50
33-50
33-50
33-50
33-50
33-50
33-50
≥50
≥50
Excipients & Actives for Pharma
Plasticizers added to the poly-
mer can reduce glass transition
temperature and melt viscosity,
and facilitate the extrusion
process [12]. Some actives may
also have a plasticizing effect.
When the process is run at high-
er temperatures there can be an
impact on the polymer itself, like
degradation or discoloration.
This limits the applicable extru-
sion temperature. In figure 9
individual ranges are given, but
whereas Kollidon VA 64, Kollidon
Extrudability is mainly determin-
ed by the glass transition tem-
perature and melt viscosity [11].
Materials of a high molecular
weight generate a high melt vis-
cosity and can hardly be extrud-
ed. A high glass transition tem-
perature requires high process-
ing temperatures which can
degrade sensitive actives. As a
general rule, extrusion processes
should be run at temperatures
20 – 40 °C above glass transition
temperature. Most polymers
demonstrate thixotropic behavior
which means that the viscosity
declines as a function of increa s-
ing shear stress.
Taking both characteristics into
consideration (Figure 7, 8) Kolli-
don VA 64 and Kollidon 12 PF
reveal excellent suitability for
extrusion. Povidones of higher
molecular weight are difficult to
extrude because of higher glass
transition temperatures and melt
viscosities.
12 PF, Kollidon SR and Lutrol
F 127 remain almost unchanged,
Kollicoat IR and Kollicoat Protect
granules were not completely
soluble. In order to achieve a
completely soluble material, a
plasticizer like polyethylene gly-
col should be incorporated and,
thereby, the extrusion tempera-
ture lowered to 100 °C.
Shear stress controlled rotational rheometer (Rheometrics SR5) plate plate geome-
try angular frequency: 1.6 rad/s
Figure 7: Glass Transition Temperatures of Polymers Figure 9: Temperature Range for Extrusion (Pure Polymers)
Figure 8: Melt Viscosity as a Function of Temperature
Kolli
don
VA 6
4
Kolli
don
12 P
F
Kolli
don
30
Kolli
don
90 F Ko
llido
n SR
Kolli
coat
IR
Kolli
coat
MAE
Lutro
l F 1
27
Tg /
Tm [°
C]
Tg [°C] Tm [°C]
10190
149 156 152
208
114
57
39
Temperature [°C]
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
Kollidon 12 PF
Lutrol F 127
Kollidon VA 64
Kollidon SR
Kollicoat IR
Kollicoat Protect
Visc
osity
[Pa
• s]
Temperature [°C]
Kollidon 12 PF
Kollidon VA 64
Kollicoat MAE Kollidon 30
Kollidon SR
1000000
100000
10000
1000
100120 140 160 180 200 220 240
250
200
150
100
50
0
CONCLUSIONS
� Melt extrusion is an excellent process to formulate poorly
soluble drugs and to improve bioavailability.
� Choice of an appropriate polymer is crucial for the formulation
and the process.
� Most important polymer features are:
� Tg and melt viscosity
� Solubilization capacity
� Stability
� Regulatory status
� Formulation properties can be adjusted by use of plasticizers
and solubilizers.
� Formulation should be thermodynamically stable.
No. 22, May 2009 | PAGE 5
REFERENCES
[1] H. H. Görtz, R. Klimesch, K. Lämmerhirt, S. Lang, A. Sanner and R. Spengler,
Verfahren zur Herstellung von festen pharmazeutischen Formen, EP 0240904 B1.
[2] J. Breitenbach and B. Wiesner, The use of polymers in pharmaceutical melt
extrusion, ExAct 20, 8 – 11 (2008).
[3] C. Leuner and J. Dressman, Improving drug solubility for oral delivery using
solid dispersions, Eur. J. Pharm. Biopharm. 50, 47 – 60 (2000).
[4] J. Breitenbach, Melt extrusion: From process to drug delivery technology,
Eur. J. Pharm. Biopharm. 54, 107 – 117 (2002).
[5] M. Crowley et al, Pharmaceutical applications of hot-melt extrusion: part I,
Drug Dev. Ind. Pharm. 33, 909 – 926 (2007).
[6] A. Forster, J. Hempenstall, I. Tucker and T. Rades, Selection of excipients for
melt extrusion with two poorly water-soluble drugs by solubility parameter
calculation and thermal analysis, Int. J. Pharm. 226, 147 – 161 (2001).
[7] J. E. Patterson, M. B. James, A. H. Forster and T. Rades, Melt extrusion and
spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone /
vinylacetate copolymers; Drug Dev. Ind. Pharm 34, 95 – 106 (2008).
[8] A. Foster, J. Hempenstall and T. Rades, Characterization of glass solutions of
poorly water-soluble drugs produced by melt extrusion with hydrophilic
amorphous polymers, J. Pharm. Pharmacology 53, 303 – 315 (2001).
[9] S. Janssens, H. Novoa de Armas, J. P. Remon and G. Van den Mooter,
The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid
dispersions of itraconazole, Eur. J. Pharm. Sci. 30, 288 – 294 (2007).
[10] E. Karavas, G. Ktistis, A. Xenakis and E. Georgarakis, Effect of hydrogen bonding
interactions on the release mechanism of felodipine from nanodispersions with
polyvinylpyrrolidone, Eur. J. Pharm. Biopharm. 63, 103 – 114 (2006).
[11] R. J. Chokshi, H. K. Sandhu, R. M. Iyer, N. H. Shaw, A. W. Malick and H. Zia,
Characterization of physico-mechanical properties of indomethacin and polymers
to assess their suitability for hot melt extrusion processes as a means to
manufacture solid dispersion/solution, J. Pharm Sci. 94 (11, 2463 – 2474 (2005).
[12] A. Ghebremeskel, C. Vemavarapu and M. Lodaya, Use of surfactants as
plasticizers in preparing solid dispersions of poorly soluble API, Int. J. Pharm.
328, 119 – 129 (2007).
[13] M. Thommes, Systematische Untersuchungen zur Eignung von kappa-
Carrageenan als Pelletierhilfsstoff in der Feuchtextrusion/Sphäronisation,
Ph.D Thesis, University of Düsseldorf, 2006.
An extrusion temperature range
of 90 – 140 °C for a drug-contain-
ing mixture seems to be best,
since the drug should survive the
thermal stress lasting for 0.5 – 2
minutes in a non-aqueous envi-
ronment.
In extruded drug delivery sys-
tems the polymer serves as a
matrix and, in consequence,
larger quantities are required
than in its more common use
as binder or coating agent.
It is crucial that the polymers are
non-toxic and approved in vari-
ous countries at high doses.
Kollidon VA 64 completely fulfills
this requirement. Based on toxi-
cological studies, the other poly-
mers may also be applicable in
high doses, but have not yet
been approved in such doses.
Figure 10: Regulatory Status
*according to FDA Inactive Ingredient Guide, **self-affirmed GRAS status, *** according to European regis- tration (MRP) ****grandfathered
Kollidon VA 64 +
Kollidon 30
Polyvinyl acetate
Kollicoat MAE 30DP/Eudragit L 30D
Kollicoat IR
Lutrol F 127
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+**
+****
US Europe Japan GRAS-status US
Maximumpotency * [mg]
854
75
46
67
20,4***
107
–
–
–
–
Developing an Instant Release Moisture Protective Coating Formulation based on Kollicoat® Protect as Film Forming PolymerT. Cech, K. Kolter
INTRODUCTIONA large number of active ingredi-
ents are sensitive to ambient
moisture. It is of general interest
for the pharmaceutical industry
to improve drug stability thereby
extending shelf life.
Applying a moisture protective
coating is an appropriate meas-
ure to prevent solid dosage
forms from taking up humidity.
Instead of using impermeable
and expensive packaging mate-
rials it appears advisable to test
moisture protective instant
release film coatings.
EXPERIMENTAL� MaterialsAs film forming polymer, Kolli-
coat® Protect (Kollicoat® IR:
polyvinyl alcohol 6:4; BASF SE,
Germany) was used.
To investigate the formulation’s
influence on the barrier function
water insoluble pigments and
additional additives as barrier
enhancer were tested (Table 1).
� EquipmentFilm caster: Coatmaster, Erich-
sen Testing Equipment (Ger-
many); knife with different die
gaps (150 – 500 μm); film thick-
ness: MiniTest 600B, Elektro-
Physik (Germany); transmission
tester: Permatran, Mocon (USA)
� MethodsFor the determination of the
WVTR [1] isolated films were
prepared using a Coatmaster.
To prevent sedimentation, the
dispersion was cast in three to
four thin layers (one on top of the
other), depending on the pigment
content and the film density.
RESULTSDependence of the WVTR onthe Type of PigmentsSeveral water insoluble pigments
can be used in film coating for-
mulations. In the first tests the
influence of the type of pigments
(Table 2) on the WVTR was
investigated.
Excipients & Actives for Pharma
OBJECTIVEKollicoat® Protect is a polymer
suitable for moisture protection.
In this article the dependence of
the water vapour transmission
rate (WVTR) on the tested film
formulation is investigated.
The influence of type and amount
of pigments used in the formula-
tions is tested. Furthermore,
additives (Table 1) to improve the
film barrier function are investi-
gated.
The aim is to find the instant
release film coating formulation
with the best protective prop -
erties.
Pigments Additives
1. Talc 4. Polyoxyethylene (100) stearate (Myrj® 59)2. Titanium dioxide 5. Polyoxyethylene (21) stearyl ether (Brij® 721)3. Iron oxide (red) 6. Stearic acid
7. Carnauba wax8. Lecithin9. Xanthan gum
10. Na-lauryl sulfate11. Hydrophobic fumed silica (Aerosil® R972)
Table 1: Water Insoluble Pigments and AdditivesUsed in the Formulations
Figure 1: WVTR as a Function of the Type of PigmentsUsed in the Formulations
Redu
ctio
n in
wat
er v
apor
tran
smis
sion
Formulation
0
-20
-40
-60
-801 2 3 4
Dependence of the WVTR onthe Amount of PigmentsAs water permeates the polymer
the WVTR should depend on the
amount of pigments. To test this,
the same ratio of talc and iron
oxide was mixed with different
quantities of polymer (Table 3).
A clear dependence was found
(Figure 2). The higher the content
of pigments the higher the barrier
function of the film.
It is possible to incorporate
high amounts of pigments in
Kollicoat® Protect.
Therefore, the reduction in trans-
mission compared to the poly-
mer without additives was inves-
tigated (Figure 1). If the stand-
ard deviation is considered, no
significant dependence was
observed. The WVTR seemed
to be unaffected by the type of
insoluble pigments.
No. 22, May 2009 | PAGE 7
Dependence of the WVTR onother AdditivesTheoretically, many additives can
be used as barrier enhancers.
Table 4 shows the additives test-
ed. As a starting point “Formula-
tion #7” was used. Iron oxide
Formulation
Excipient #10 #11 #12 #13 #14 #15 #16 #17
Kollicoat® Protect 50 50 50 50 50 50 50 50Talc 35 35 35 35 35 35 35 35Titanium dioxide 5 5 5 15 – – – –Iron oxide (red) – – – – 13 14.5 13 7Myrj® 59 10 – – – – – – –Brij® 721 – 10 – – – – – –Stearic acid – – 10 – – – – –Carnauba wax – – – 5 – – – –Lecithin – – – – 2 – – –Xanthan gum – – – – – 0.5 – –SDS – – – – – – 2 2Aerosil® R 972 – – – – – – – 6
Formulation
Excipient #5 #6 #7 #8 #9
Kollicoat® Protect 25 40 50 60 75Talc 67 54 45 36 23Iron oxide (red) 8 6 5 4 2
Formulation
Excipient #1 #2 #3 #4
Kollicoat® Protect 50 50 50 50Talc 15 25 35 45Titanium dioxide 30 20 10 0Iron oxide (red) 5 5 5 5
Figure 2: WVTR as a Function of the Amount of PigmentsTable 2: Dependency on the Type of Pigments
Table 3: Dependency of the WVTR on the Amount of Pigments Table 4: Dependency of the WVTR on other Additives
was partly substituted by adding
the additives from Table 4. Again
the total reduction of the WVTR
was calculated, based on the
polymer (Figure 3) and was com-
pared to the standard formula-
tion (#7).
Redu
ctio
n in
wat
er v
apor
per
mea
tion
Formulation
0
-20
-40
-60
-805 6 7 8 9
Excipients & Actives for Pharma
Conclusions� Regardless of the formulation,
coatings based on Kollicoat®
Protect offer a high barrier
function against ambient
moisture [2].
� The WVTR strongly depends
on the amount of insoluble
pigments. The higher the con-
tent, the lower the transmis-
sion rate. However, the type
of pigments is less important.
� Additives used as barrier
enhancers also increase the
brittleness of the film. Never-
theless, sodium lauryl sul-
phate and hydrophobic fumed
silica in combination offered
significant improvement.
By adding most of the barrier
enhancing excipients the proper-
ties of the isolated film got poor-
er (e.g. increasing brittleness).
Therefore, additives should only
be considered if the film’s barrier
function can be improved signifi-
cantly.
Finally, only the combination of
sodium lauryl sulphate and
hydrophobic fumed silica showed
positive results.
The reduction in the WVTR of
“Formulation 17” was about 80%.
Compared to the transmission
rate of a classical coating based
on HPMC the reduction is also
about 80% [2].
REFERENCES
[1] ASTM F-1249
[2] T. Cech, K. Kolter; Comparing
Moisture Protective Instant
Release Coatings for Solid
Oral Dosage Forms;
PBP World Meeting 2008
[3] T. Cech, Benchmarking of Instant
Release Film Coating
Polymers, Bachelor Thesis 2007
PBP World Meeting 2008, 7. – 10. April
2008, Barcelona, Spain, G-MEP/MD214
� As plasticizers are not needed
to improve the coating prop-
erties, film coating formula-
tions based on Kollicoat®
Protect are very easy to for
mulate [3].
� To enhance the protective
properties, the pigment con-
tent has to be increased. This
leads to a low viscosity of the
coating dispersion. Therefore,
adding a gel forming agent
like xanthan gum to increase
viscosity and thereby prevent-
ing sedimentation should be
considered.
Figure 3: WVTR as a Function of Different Additives
Redu
ctio
n in
wat
er v
apor
per
mea
tion
Formulation
0
-20
-40
-60
-8010 11 12 13 14 15 16 17
No. 22, May 2009 | PAGE 9
In the last issue, we addressed
the scuffing effect, which results
in dark spots on the tablets sur-
face. This time we want to ad -
dress another problem, related
to inhomogeneously coloured
tablet surfaces.
Many coated solid oral dosage
forms are manufactured with
product specific colour. If you
have ever faced problems when
incorporating pigments in a film
coating dispersion, this article
will be of particular interest to
you.
ProblemCoating dispersions usually con-
tain other ingredients. Apart from
the film forming polymer, colou-
ring agents also play a decisive
role. As most dyes and lakes
used in the pharmaceutical indu-
stry show a high tendency for
agglomeration, their homoge-
neous incorporation into the
dispersion can often be chal-
lenging.
With functional coatings, a lot of
which are latex dispersions, the
issue of the high density of dyes
and lakes introduces the issue of
sedimentation.
ReasonAs most colour formulations
consist of more than one com-
ponent, agglomerates of one
ingredient would lead to a dee-
per colour impression com-
pared to surface areas with a
more homogeneous colour dis-
tribution. These parts of the film
with a higher pigment concentra-
tion appear as more intensively
coloured spots.
However, these agglomerates
can be caused by different
effects:
Both poor de-agglomeration as
well as sedimentation can lead
to uneven colour distribution of
the colouring agent on the film
coated tablet surfaces.
Pictures 1 and 2 show this effect.
In these two examples for easier
visualisation, the process was
stopped just after applying a
small amount of coating material.
Film Coating: Colour Variation (Spots)T. Cech, F. Wildschek
Picture 1/2 – Coated tablets showing inhomogeneous colour distribution.
Trouble-shootingIdeas and solutionsfor R&D and production
Excipients & Actives for Pharma
SolutionTo overcome this effect, the
cause for the inhomogeneous
distribution of the colouring
agent has to be investigated.
Dyes and lakes in bulk have a
tendency to agglomerate, nece s -
sitating the need for care when
homogeniseing the pigments.
In some cases, though rare, it is
sufficient to break up the agglo-
merates by applying medium to
low mechanical forces (using a
mortar and pestle). But in most
cases, the agglomerates are so
strong, that more elaborate
equipment is needed (e.g. high
shear mixer).
Please keep in mind that the pig-
ments have to be homogenised
separately before mixing in with
the film forming polymer, bearing
in mind the risk of coagulation
[4.] or foam formation.
1. Sedimentation in the finally
prepared dispersion can be
prevented by continuously
stirring at low speed.
2. The tubing is an often under -
estimated part of the coating
equipment. The type, as well
as the quality of the tubing
plays a significant role on
the coating process.
1. Ineffective de-agglomeration,
while preparing the film coat-
ing dispersion.
2. Agglomeration of dispersed
pigments due to sedimenta-
tion in the vessel or beaker,
when the dispersion is not
stirred properly during the
coating process.
3. Agglomeration due to sedi-
mentation in the tubing.
This is caused when the
bore diameter is not adapted
to the spray rate. The larger
the bore diameter, the slower
the velocity of the disper-
sion, which in turn leads
to increased sedimentation
tendency. This effect can
distinctively be seen when
the tubing is either too long
or assembled in a vertical
way.
4. Coagulation of latex disper-
sions and adhesion of the
colouring agent on the tablet
surface. As latex dispersions
are very sensitive to various
influences (e.g. temperature,
mechanical stress, surfac-
tants) this point ought to be
kept in consideration as well.
To prevent sedimentation, it
is important to bear in mind
that the tube thickness and
bore diameter to be used will
depend on the flow rate, vis -
cosity of the dispersion as
well as the type of pump.
A large bore diameter would
result in a slow liquid flow
rate within the hose. This
slow speed would in turn
facilitate sedimentation
effects, especially if the tube
is assembled vertically.
It is important to keep tubing
as short as possible.
3. If the inhomogenous distri-
bution of the colour on the
tablet is due to a wrong
handling of the latex disper-
sion, it is important to criti-
cally review all other constit -
uents of the dispersion as
well as all other process
steps. As mentioned earlier,
latex dispersions being
emulsions are sensitive
systems.
In this regard, using the high
mechanical stress of high
shear mixers would imme-
diately result in the coagula-
tion of the dispersion.
No. 22, May 2009 | PAGE 11
BASF opens applications laboratory forpharmaceutical industry in India
development facilities of BASF
India Ltd. in Mumbai. It is pro -
vided with state-of-the-art
equipment allowing all the pro-
duction processes that are rele-
vant for solid dosage forms,
such as granulation, tabletting
and coating, to be carried out.
In addition, the laboratory also
has a wide range of measuring
equipment, which can be used
to analyze fundamental parame-
ters within the processes. Fin-
ished tablets can also be tested
for friability, dissolution, disinte-
gration or color deviations.
Customers can actually work in
the laboratory on site if they
wish to acquire relevant applica-
tion knowledge. They can also
take trial products made there
back to their own companies,
since the laboratory meets the
“class 100,000 area” clean
roomrequi rements.
sible for BASF’s global Pharma
Ingred ients & Services business
unit. “The new applications lab -
oratory in Mumbai is an important
milestone in achieving this aim.”
In Asia, the pharmaceutical
industry has grown particularly
through the strong market posi-
tion of generics. South and
South-East Asia have a key role
to play here. “The pharmaceuti-
cal manufacturers in the region
are operating on an increasingly
global basis now. This is pre-
senting our customers' local
research and development facili-
ties with huge challenges, such
as those associated with new
systems for releasing active
ingredients”, says Ralf Fink,
head of the regional BASF busi-
ness unit Pharma Ingredients &
Services in Asia.
The new laboratory is integrated
into the existing research and
BASF has opened an applica-
tions laboratory for pharmaceuti-
cal excipients and active ingredi-
ents in Mumbai, India. The aim is
to move even closer to custom -
ers in the key markets of the
Asia-Pacific region. The new lab-
oratory will allow BASF to meet
the requirements of the pharma-
ceutical industry for technical
support more quickly. Customers
will not only be provided with
advice about functional aspects
when choosing products, such
as the excipients Kollidon®, Kolli-
coat®, Cremophor® and Lutrol®.
BASF experts in the laboratory
will also help in optimizing for-
mulations and improving produc-
tion conditions.
“We want to make even more
improvements in the global
range of products and services
we offer our customers”, says
Martin Widmann, who is respon-
News
All the latest from theworld of excipientsand active ingredients
Martin Widmann (left), head of the business unit Pharma Ingredients & Services, and Prasad Chandran (middle), head of BASF
India, at the inauguration of the new lab.
The new laboratory in Mumbai is
the second BASF facility of this
type in Asia, along with a further
applications laboratory in
Shanghai.
Excipients & Actives for Pharma
An innovative method todetermine granule strengthTh. Cech, D. Djuric, M.G. Herting
INTRODUCTIONFor characterization of granules,
the particle size distribution is
the most commonly used para-
meter. However, strength of gra-
nules is another very important
factor to be considered. Granule
strength has to be sufficient to
allow further handling of the
gran ules (e.g. storage in a bulk
or compression). There are
methods described in literature
to determine the strength of gra-
nules. Inghelbrecht and Remon
(1998) described a method,
where the apparatus for determi-
nation of friability of tablets as
described in Ph.Eur. was used
[1]. However, due to the addition
of a defined number of glass
beads the mechanical strength
applied to granules was very
high. The methods for determi-
nation of granule strength des-
cribed in the Ph. Eur. need the
purchase of dedicated equip-
ment or the set up of a new
apparatus that is not commer -
cially available [2]. For measure-
ments using an air-jet sieve no
special equipment has to be
provided. Additionally, none of
the already described methods
in literature allow the handling
in a contained system.
Therefore, the purpose of this
study was to evaluate a new
method for the determination of
granule strength using an air-jet
sieve. During air-jet sieving parti-
cles are fluidized, thrown against
the sieve lid and against each
other. These movements induce
mechanical stress on the granules
leading to abrasion and breakage.
MATERIALS AND METHODSMaterials The following materials were
used as received: Copovidone
(Kollidon VA 64® Fine, BASF,
Germany) and Lactose (Granu-
Lac® 230, Molkerei Meggle,
Germany)
Production of granulesRoll compactor (Mini-Pactor
250/25, Gerteis, Switzerland)
was equipped with smooth rim
rolls of 250 mm diameter and
25 mm width. The gap between
the rolls was kept constant at
3 mm. Speed of rolls was set to
1 rpm. Granules were produced
at different specific compaction
forces (2, 4, 6 and 8 kN/cm) to
obtain granules of different
strength.
Resulting ribbons were directly
granulated with a pocket mould
grooved granulator using a
1.25 mm sieve.
Fines of granule samples were
removed prior to measurement
to assure same starting condi -
tions and to consider solely
agglomerated material. This
removal of fines was performed
at a low flow rate of 20 m³/h for
1 minute. Friability of granules
was estimated and defined as
loss of mass in percent after
sieving at different flow rates
(30, 50 and 70 m³/min) and times
(1, 3, 5, 10 and 15 min).
For each excipient the determi-
nation was conducted 3 times
and the mean value and standard
deviation was reported.
ResultsThe examined flow rates allowed
differentiation between granule
batches produced with different
compaction forces (Figure 3).
At flow rates of 30 m³/h and pro-
cess time of 5 min friability ran-
ged from 45.7% (2 kN/cm) to
6% (8 kN/cm).
Figure 1 – Particle movement during
measurement (used with permission of
Rhewum GmbH)
Figure 2 – Air jet sieve LPS 200,
Rhewum
30 m3/h
1 min 3 min 5 min 10 min 15 min
With higher volume flow rates
and sieving time particle move-
ment and thus mechanical stress
is increasing (Figure 1).
SamplingPrior to further analysis the
powders and granules were divi-
ded using a rotary sample divi-
der (PT 100, Retsch, Germany)
in order to obtain representative
samples with adequate amounts
of all particle fractions.
Friability of granulesGranule friability as an estimate
for granule strength, was deter-
mined with an air-jet sieve (LPS
200, Rhewum, Germany) (Figure
2) equipped with a 125 µm sieve.
Figure 3: Friability of granules (30 m3/h) produced at various specificcompaction forces (n = 3, mean ± s)
friab
ility
[%]
100
specific compaction force [kN/cm]
75
50
25
00 2 4 6 8
No. 22, May 2009 | PAGE 13
RE
GU
LAT
OR
Y A
FFAIR
S
GMP Re-certification successfully passed
1. 12 new CEPs2. 4 new monographs
1. New CEPsActives1. Tilidine hydrochloride
hemihydrate
2. Dobutamine hydrochloride
3. Dopamine hydrochloride
4. Xylometazoline hydro-
chloride
5. Theophylline Ethylene-
diamine (Aminophylline)
6. Theophylline Ethylene-
diamine hydrate
(Aminophylline hydrous)
7. Dexpanthenol
8. Acitretin
Excipients1. Crospovidone Type A and
B (Kollidon® CL, CL-M,
CL-F, CL-SF, Crospovi-
done C)
2. Copovidone Nominal
K-value 28 (Kollidon® VA 64,
VA 64 Fine)
3. Povidone Nominal K-value
25 and Nominal K-value 30
(Kollidon® 25, Kollidon® 30)
4. Povidone Nominal K-value
90 (Kollidon® 90 F)
2. New pharmacopeial monographsUSP/NF Pharmacopeial Forum,
Vol. 35 (1); Jan-Feb 2009:
� Polyvinyl Acetate Dispersion“
(Kollicoat® SR 30 D)
� Polyoxyl 15 Hydroxystearate“
(Solutol® HS 15)
USP/NF Pharmacopeial Forum,
Vol. 35 (2); Mar-Apr 2009:
� Ethylene Glycol and Vinyl
alcohol Graft Copolymer
(Kollicoat® IR)
Food Chemical Codex (FCC)
Supplement 1, 2009:
� Copovidone (Kollidon® VA 64)
For the first time in 2006 the pro-
duction plants in Ludwigshafen
manufacturing Active Pharma-
ceutical Ingredients and Exci-
pients passed successfully the
GMP Inspection of the German
Regulatory Authorities. This
Inspection followed the require-
ments of the ICH Q 7 Guideline.
The GMP Certificate is valid for
three years. Therefore the Re-
Inspection of the authority took
place in November 2008 and
covered additionally the Glycol-
Plant. The availability of both
the GMP Certificate and specific
CEPs enables our customers
to register these Excipients as
atypical Actives.
Using flow rates of 70 m³/h the
friability ranged from 93.5%
(2 kN/cm) to 23.9% (8 kN/cm)
(Figure 4). Altering the time at a
constant flow rate allowed a
clear distinguishing of the diffe-
rent granules. At low flow rates
the required time for differenti -
ation between different granules
Conclusion
Using an air-jet sieve proved to
be a fast and easy method for
measuring granule strength.
The process showed an excel-
lent reproducibility. In contrast
to other methods, it can be used
for high potential drugs as the
whole procedure is performed
in a contained system. Altering
process time or flow rate en-
abled differentiation between
granules of different strength.
70 m3/h
1 min 3 min 5 min 10 min 15 min
REFERENCES
[1] S. Inghelbrecht, J.P. Remon: Interna -
tional Journal of Pharmaceutics 161
(1998), 215 – 224
[2] European Pharmacopeia 6.2, 2.9.41
Friability of granules and spheroids
(2008), 330 – 331
had to be higher than 5 min.
For high flow rates a process
time of 1 min was sufficient.
The standard deviation did not
exceed 1.6% in all performed
trials indicating a very robust
and reproducible method.
Figure 4: Friability of granules (70 m3/h) produced at various specificcompaction forces (n = 3, mean ± s)
friab
ility
[%]
100
specific compaction force [kN/cm]
75
50
25
00 2 4 6 8
Excipients & Actives for PharmaExcipients & Actives for Pharma
The deliberate choice of an ade-
quate solvent may be crucial for
the whole pharmaceutical pro-
cess to achieve the designated
characteristics of a product.
This applies to the manufacture
of drug substances, excipients
and the formulation of drug pro-
ducts, respectively.
BackgroundAccording to Guideline ICH Q3C
‘Note for Guidance on Impuri-
ties: Residual Solvents’, residual
solvents in pharmaceuticals are
defined as organic volatile che-
micals that are used or produced
in the manufacture of drug sub-
stances or excipients, or in the
preparation of drug products [...]
The guideline does not address
solvents deliberately used as
excipients nor does it address
solvates. However, the content
of solvents in such products
should be evaluated and justi-
fied. The Guideline lists toxicol -
ogically acceptable limits for
cases where the solvent cannot
completely be removed from the
final product during the manu-
facturing process.
USP adopted this ICH Guidance
in its General Chapter <467>
“Residual Solvents”. This guid-
ance which was already adop-
ted in Europe for a long time
(Ph.Eur. General Chapter 5.4)
became official as of July 1st,
2008 replacing General Chapter
<467> “Organic Volatile Impuri-
ties”.
The purpose of the revised
chapter is to limit the amount of
solvent that patients receive.
The USP General Notices require
all drug substances, excipients
and products meet the require-
ments in General Chapter <467>
by July 1st 2008. Pharmaceutical
manufacturers that adopted the
requirements of General Chapter
<467> Residual Solvents prior to
July 1st 2008 are expected to
meet the monograph require-
ments for Organic Volatile Impu-
rities.
In <467>, residual solvents have
been separated into three clas-
ses based on their potential toxi-
city level. Class 1 residual sol-
vents are known to cause unac-
ceptable toxicities. Class 2 resi-
dual solvents are associated
with less severe toxicities and
Class 3 residual solvents are
considered the least toxic.
Testing should be performed for
those residual solvents that are
used or produced in the manu-
facture or purification of these
drug substances, excipients or
drug products. For finished pro-
duct, the client may choose to
test either all the individual com-
ponents or the final finished pro-
duct. The USP has stated that a
company does have the option
to develop and validate their
own internal method for deter -
mining residual solvents rather
than using the USP Residual
Solvents <467> method.
StoryIn August 2008, FDA’s Office of
Generic Drugs (OGD) issued a
related draft guidance, Residual
Solvents in Drug Products Mar-
keted in the United States,
stipulating further requirements
exceeding all current guidance,
including USP <467>. At that
time, BASF already met both,
ICH and USP requirements for
its globally marketed products.
Consequently, although being
fully compliant with both ICH
and USP, BASF and many other
suppliers to the pharmaceutical
industry suddenly faced a multi-
tude of urgent requests, mainly
triggered by FDA OGD to ANDA
holders which caused a number
of problems and confusion
regarding the draft guidance and
communications received from
FDA’s OGD, that conflicted with
Chapter <467> of USP.
As a consequence, FDA received
many comments from a vast coa-
lition of stakeholders requesting
additional clarification regarding
the implementation of USP
<467> for generic drugs with
BASF comments submitted
directly and via its trade associa-
tions APIC and SOCMA as soon
as of October 1st.
That`s why on October 10th,
2008, FDA met with these core
industry groups IPEC Americas,
IPEC Europe, GPhA, CHPA,
PhRMA, and SOCMA BPTF to
discuss implementation of USP
<467> and the OGD draft guid -
ance.
Residual Solvents: Recentdevelopment of a hot topicP. Hebestreit
No. 22, May 2009 | PAGE 15
NewMedia
Information on BASF products Late 2005 BASF launched the
first edition of a DVD on BASF’s
broad excipients range. New pro-
ducts launched in recent years
called for an update. This updat-
ed video provides an excellent
overview of our pharmaceutical
excipients, their functionalities
and applications. It also gives an
impression about the quality
standards applied in the produc-
tion of these ingredients. The
DVD can be ordered with the
attached reply card.
©2009
BASFSE
EMP090401e-01
www.pharma-ingredients.basf.com
Pharma Ingredients & Services
Video onBASF Excipients
The updated edition of DVD on BASF excipients now available
Four key areas of concern were
discussed:
� 1: Specific testing versus con-
trol — Industry, said the coali-
tion, believes that the focus
should be on adequate controls
as oppos ed to analytical testing
on each residual solvent (ade-
quate controls being e.g. justifi-
cations of omission of analytical
testing of certain solvents).
� 2: Identification of Class 3
solvents — the coalition felt that
there was no justifiable reason
why Class 3 solvents need to
be identified providing that the
levels are below 0.5%.
� 3: Use of Class 1 solvents —
the coalition asked FDA to esta-
blish what types of information
would be needed to warrant the
contin ued use of Class 1 sol-
vents in certain cases as long
as the levels are below the limits
listed in <467> for these solvents.
� 4: Need for immediate relief
while awaiting revised guid -
ance — the coalition requested
that FDA quickly develop a
mechanism and a path forward
to address the many pending
ANDAs from both a short-term
and a long-term perspective.
The FDA OGD had considered
these comments and sugges -
tions and provided clarifying
questions and answers on Oc-
tober 28th. These clarifications
include a flexible, stepwise
approach to application of USP
<467> to ANDAs to ensure avail-
ability of low cost, high quality,
safe, and effective generic drugs
that meet USP <467> require-
ments.
ConclusionThis Coalition for Rational Imple-
mentation of USP General Chap-
ter <467> was doing a good job
of getting FDA’s attention and
received a quick response (Q&A
letter of October 28th). Essential-
ly this was perceived as a big
relief, particularly with regard to
ANDA holders and their sup-
pliers like BASF.
This exemplarily demonstrates
that it’s up to us as suppliers to
the pharmaceutical industry to
implement internationally ac-
cepted standards available in
global regulations like ICH.
We had to learn that it particular-
ly applies when it comes to dis-
cussions on regulations which
are best known by the ones
which are affected by these regu-
lations on a day-to-day basis: us
as industry working with such
regulations, complying with them
and in case they are unrealistic,
explain why and provide alterna-
tives to the agencies.
“Anticipatory obedience” is pro-
bably the easiest way but in the
long term, it will lead to -step-
by-step- increasing regulatory
requirements.
July 18–22, 2009*The 36th Annual Meeting and
Exposition of the Controlled
Release Society
Copenhagen, Denmark
October 13-15, 2009*CPhI Worldwide
Madrid, Spain
November 8-12, 2009*AAPS Annual Meeting and
Exposition
Los Angeles, CA, USA
March 8-11, 20107th World Meeting on Pharma-
ceutics, Biopharmaceutics
and Pharmaceutical Technology
Valetta, Malta
July 10-14, 2010The 37th Annual Meeting and
Exposition of the Controlled
Release Society
Portland, Oregon, USA
November 14-18, 2010*AAPS Annual Meeting and
Exposition
New Orleans, Lousiana, USA
* BASF participation
Calendar
Important dates
ContactWhat opportunities can weopen up for you? Simply contact your local BASF
representative or one of the regional
offices listed below.
Alternatively, visit our website
www.pharma-ingredients.basf.com
AsiaBASF East Asia Regional
Headquarters Ltd.
Pharma Ingredients & Services
Thomas Pilgram
45th Floor, Jardine House,
No. 1 Connaught Place,
Central, Hong Kong
Phone: +852 27311-589
EuropeBASF SE
Pharma Ingredients & Services
Peter Hoffmann
G-EMP/EM – J 550
67056 Ludwigshafen
Germany
Phone: +49 621 60-76928
North AmericaBASF Corporation
Pharma Ingredients & Services
Javier Beeck
100 Campus Drive
Florham Park, NJ 07932
USA
Phone: +1 973 245-6381
South AmericaBASF S.A.
Pharma Ingredients & Services
Flavia de Assis e Souza
S-EM/VPP
Avenida Faria Lima, 3600 – 9th floor
04538-132 São Paulo – SP
Brazil
Phone: +55 11 3043-2237
Would you like to discuss a particular
challenge or product in more detail?
Or do you have any questions?
Simply call or e-mail us. We would
be glad to help.
EM
P 0
4010
2e-2
2
Preview
In the next issue of ExAct
The demand for solubilizers and
techniques to overcome poor
solubility and bioavailability of
new APIs (active pharmaceutical
ingredients) has greatly increased
in the past years and a stronger
growth in the near future is
expected.
In many cases, the development
of solid oral dosage forms is not
possible and therefore the poorly
water soluble API must be
formulated in a parenteral formu-
lation. Because of their conven-
ience, solid oral dosage forms
are preferred compared to par-
enteral formulations which have
to be injected in many cases by
a physician.
A new technique which is gain-
ing increasing interest in the
pharmaceutical industry is melt
extrusion. This technique and
the suitability of polymers for
melt extrusion are discussed in
this issue of ExAct. However, the
polymers available on the market
have not been developed for
melt extrusion but for other pur-
poses such as dry binders.
BASF has developed a new poly-
mer particularly for melt extru-
sion in order to cope with bio-
availability and solubility hurdles.
Besides other topics, the next
ExAct issue will approach the
topic with this innovative poly-
mer.
New Polymer for Melt Extrusion
Excipients & Actives for PharmaExcipients & Actives for Pharma