Dear Reader: Innovations across the entire package - Pharma ...

Excipients & Actives for Pharma
No. 26, 2011
CONTENTS
Dear Reader:
Innovations across the entire package
Improving on a classic:
the new PeroXeal packaging
concept for Kollidon PAGES 2 – 4
Binding properties and flow
behavior of different
crospovidone grades PAGES 5 – 7
Modeling drug release from
Kollidon ® SR controlled release
matrix tablets PAGES 8 – 10
Extended stabilization of active
ingredients highly sensitive to
oxidation using Kollidon 30 LP PAGES 11 – 12
ExActMelt – improving drug
efficiency with hot-melt extrusion PAGE 13
CEP procedure and the availability
of CEP for BASF products PAGES 14 – 16
REGULATORY NEWS PAGES 17
EVENTS PAGE 18
BREAKING NEWS PAGE 19
CALENDAR PAGE 20
PREVIEW PAGE 20
New and innovative
excipients are required
to meet today’s increasing
challenges
in the formulation of
new drugs and dosage
forms. Products
such as our Soluplus ®
or Kollicoat ® Smartseal
30 D have therefore
been successfully introduced
to meet challenges like the poor solubility
of APIs or effective taste masking. But do
we always need to use new excipients? How
can we further broaden the application range of
well-established excipients?
By looking at the entire “package” of our
Kollidon products, we were able to significantly
improve the quality and broaden the application
range of our binders and disintegrants. With
our latest improvement - the new PeroXeal
packaging concept - we not only maintain high
purity levels over a longer period of time, extending
shelf life; we also open up new application
fields for povidone binders and disintegrants
– for example, in the field of oxygen-sensitive
APIs. In addition, the new PeroXeal packaging
concept allows easier and safer handling
and is better for the environment. Since inventing
"Kollidon - the Original" 70 years ago, we
continue to innovate and set new standards in
stability, purity and patient safety.
The new PeroXeal packaging concept is an excellent
example of BASF’s continuous pursuit of
innovation, both for new and established products.
To improve the usability of our ingredients
for customers, we have optimized the entire
"package" – from ordering the product, to processability
(e.g. flow behaviour) and even to disposal
of the packaging.
Yours sincerely,
Boris Jenniches
Head of Global Product Management Pharma Ingredients & Services
Kollidon – The Original
www.kollidon.com
CONTACT PAGE 20

Excipients & Actives for Pharma
No. 26, 2011
IN FOCUS: KOLLIDON PACKAGING
Improving on a classic: the new PeroXeal
packaging concept for Kollidon ®
Silvia Mok, Claudia Easterbrook, Bernhard Fussnegger
PUBLISHER:
BASF SE
Pharma Ingredients & Services
www.pharma-ingredients.basf.com
EDITORIAL STAFF:
Ralf Fink
Andres-Christian Orthofer
Karl Kolter
Jan Bebber
AUTHORS:
Angelika Maschke
Bernhard Fussnegger
Claudia Easterbrook
CorinnaTissen
Cecil Tung
Dominik Odenbach
Florence Siepmann
Janna Lorenz
Jürgen Siepmann
Karl Kolter
Kathrin Meyer-Böhm
Karin Eckart
Marcel Hilkens
Peter Kleinebudde
Rainer Fendt
Ralf Hadeler
Silvia Mok
CONCEPT/LAYOUT:
Château Louis Strategische Markenführung
und Kommunikation GmbH
PRINT:
ABOUT US
johnen-druck GmbH & Co. KG
Kollidon enjoys a long and rich tradition.
BASF scientist Walter Reppe invented polyvinylpyrrolidone
(PVP) over 70 years ago, and we registered
its first pharmaceutical applications in the
1950s – making us the most experienced team in
the industry. Manufactured to the most exacting
of quality standards in a world-class plant, the
Kollidon product family comprises soluble and
insoluble grades of polyvinylpyrrolidone of various
molecular weights and particle sizes, a vinylpyrrolidone/vinyl
acetate copolymer and a blend
of polyvinyl acetate and polyvinylpyrrolidone.
BASF has a range of Kollidon products for applications
across the pharmaceutical sector: this
versatile excipient can be deployed as a binder,
disintegrant, bioavailability enhancer, film former,
solubilizer, lyophilisation agent, suspension stabilizer,
wetting agent, adhesive, stabilizer, intermediate,
thickener, dissolution enhancer, and
ppm
toxicity reducing agent. And new uses are being
discovered all the time, as BASF innovates to address
customer challenges – continuously setting
new standards in stability, purity and patient
safety.
The groundbreaking PeroXeal packaging concept
now marks the next stage in the evolution
of Kollidon. Previously, the standard market
packaging comprised tie-wrapped polyethylene
inner liners with an air-filled headspace. As a result,
the excipient was easily contaminated by
oxygen, allowing peroxide to form. The use of
aluminum in the liner also led to problems, as
flakes sometimes made their way into the product.
Witnessing the impact of these flaws on PVP
stability and performance, the BASF experts
continuously challenged themselves to develop
and enhance Kollidon packaging.
Long-term stability data shows advantages
1. Re-test period of packaged material can be extended from 36 to 48 months
2. Peroxide level is decreased to below 100 ppm
Povidone K30 in
standard market
450
packaging
Compendial limit
400
350
300
Kollidon 30 in
250
standard BASF
200
packaging
150
Kollidon 30
100
in new BASF
50
packaging
0
0 1 3 6 9 12 18 24 36 48
Months
Trademarks are owned by BASF SE
FIGURE 1
Comparison of stability data
Page 2

Excipients & Actives for Pharma
No. 26, 2011
The hard work paid off: years of research and
analysis have culminated in BASF’s new proprietary
aluminum-free PeroXeal packaging concept.
The innovative foil comprises three distinct functional
layers, each specifically designed to shield
the product from environmental influences. Complemented
by inert gas flushing and heat sealing,
the packaging significantly reduces peroxide
levels and eliminates the risk of contamination
with aluminum flakes – at no additional cost to
the customer.
The PeroXeal edge has allowed BASF to raise
the bar even further in the PVP market. By preventing
degradation of the excipients’ superior
quality and incredible freshness, the packaging
concept has increased Kollidon’s shelf life to
four years. So worrying about peroxide levels, K
values and API degradation is a thing of the past.
FIGURE 2
No degradation of K value
(Usual decrease of K value in contact with air is around
0.2 units per month)
k-value
94
92
Kollidon 90F in
90
88
standard BASF
packaging
86
84
82
Povidone K90 in
standard market
packaging
80
0 1 3 6 9 12 18 24 36 48
Comparison of K values
Months
Kollidon 90F
in new BASF
packaging
The groundbreaking
PeroXeal packaging
concept now marks the
next stage in the evolution
of Kollidon.
FIGURE 3
Transparent aluminum-free packaging avoids product contamination with aluminum flakes
Page 3

Excipients & Actives for Pharma
No. 26, 2011
The most immediate benefit is consistent performance
in terms of binding, viscosity and adhesion
– plus enhanced stability opens the door for
entirely new applications.
Formulation with
sensitive APIs
Formulation
stability
For example, you can now use Kollidon ® as an
alternative to cellulose when working with oxygen-sensitive
ingredients. What’s more, the
transparent inner lining is compatible with NIR
testing – so packaging can remain sealed until
the product is actually being used, retaining
Kollidon’s original freshness. Thanks to
PeroXeal, the best PVP portfolio on the market
just got even better.
Opens new opportunities for
formulation with 0 2 -sensitive APIs
Greater choice
Provides an alternative to cellulose
Greater
choice
Formulation
with sensitive
APIs
Longer
shelf life
Formulation
stability
Allows stable formulaions by
reduced API degradation
constant K values
Improved performance and
reliability
Longer shelf life
Extends excipient shelf life up
to 4 years
FIGURE 4
Benefits of the new packaging concept to our customers
Page 4

Excipients & Actives for Pharma
No. 26, 2011
CROSPOVIDONE
Binding properties and flow behavior of
different crospovidone grades
C.Tissen, M.Hilkens, J.Lorenz, P.Kleinebudde Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Duesseldorf, Germany
INTRODUCTION | Crospovidone is a superdisintegrant
commonly used in quantities of 2-5 %
(w/w) to accelerate the disintegration of tablets.
Several grades of Kollidon CL are commercially
available and differ only in particle size distribution.
The drawbacks of traditional disintegrants
are often poor flowability or a negative influence
on the compactibility of tableting mixtures.
However, robust mechanical properties and low
friability should be achieved in order to facilitate
further production steps, e.g. coating processes.
Therefore, a combination of a dry binder and a
disintegrant is often required to improve the
mech anical properties of a tablet while still ensuring
complete disintegration.
The purpose of this study was to investigate the
binding properties of crospovidone grades of
different particle size distributions and elucidate
their influence on tensile strength.
METHODS AND MATERIALS | Materials
Crospovidone (Kollidon CL, Kollidon CL-F,
Kollidon CL-SF, BASF SE, Ludwigshafen, Germany),
alpha-lactose monohydrate (Tablettose ®
80, Meggle, Wasserburg, Germany), dicalcium
phosphate (Dicaphos ® AN, *Budenheim, Germany),
magnesium stearate (Welding, Hamburg,
Germany).
Methods / Particle size distribution The particle
size distribution of the various Kollidon CL
grades was analyzed using laser light diffraction
(Helos, Sympatec GmbH, Clausthal-Zellerfeld,
Germany). Measurements were performed in
triplicate with a dry dispersing unit (Vibri, Rhodos
T4.1, Sympatec GmbH, Claustha-Zellerfeld,
Germany) at 1.0 bar.
Flowability The flowability of the tabletting mixtures
was analyzed in duplicate with a ring shear
tester (RST-01.c, RST-CONTROL 95 Schulze
Schuettguttechnik, Wolfenbuettel, Germany).
Consolidation stress and unconfined yield
strength were used to characterize flowability.
Normal stress during pre-shearing was 5000 Pa.
Compression of tablets Table 1 shows tabletting
mixtures containing different ratios of filler
(Tablettose 80, Dicaphos AN) and disintegrant
(Kollidon CL; Kollidon CL-F, Kollidon CL-SF).
Each formulation was blended for 20 minutes in
a laboratory-scale Turbula mixer (Turbula T2F,
Bachofen AG Maschinenfabrik, Basel, Switzerland).
Afterwards, 0.5% w/w magnesium stearate
was added as a lubricant and the mixtures were
blended for two further minutes.
Each mixture was compressed to flat-faced tablets
of 12 mm diameter at 153 and 255 MPa, using
a rotary die press (Pressima, IMA Kilian, Cologne,
Germany). Crushing forces were determined with
a hardness tester (HT-1, Sotax, Basel, Switzerland)
and subsequently calculated as tensile
strength according to Fell and Newton [1].
TABLE 1
Fraction [%]
Filler 100 95 90 80 60 40 0
Disintegrant 0 5 10 20 40 60 100
Tabletting mixtures
Disintegration testing The disintegration time
for 12 tablets of each batch was measured with
a disintegration tester (Erweka ZT 32, Heusenstamm,
Germany) according to Ph.Eur. Because
of the extreme turbidity of the disintegration
medium after a few seconds, all batches were
analyzed without using a beaker.
RESULTS AND DISCUSSION | Discussion
The tensile strength of the lactose/crospovidone
tablets varied from 0.9 to 5.1 N/mm² (Figure 1).
Irrespective of the amount of Kollidon CL, the
tablets exhibited no increase in tensile strength.
In contrast, crospovidone grades with smaller
particle sizes led to improved tensile strength.
The higher the amount of Kollidon CL-F and
Kollidon CL-SF, the higher the tensile strength
of the resulting tablets. As the particle size of
crospovidone decreased, the detected tensile
strength increased (Figure 2). The tensile strength
of tablets is known to be affected by the variation
in particle size of the excipients used. Smaller
particles facilitate interparticulate bonding during
the compression process, resulting in tablets
with improved hardness [2]. Consequently, tablets
with Kollidon CL-SF exhibited the highest
values. Even 20% (w/w) almost doubled the determined
tensile strength.
All crospovidone grades could successfully
be compressed to tablets without filler; tablets
consisting of pure Kollidon CL-SF exhibited the
highest tensile strength.
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Excipients & Actives for Pharma
No. 26, 2011
To investigate the influence of the type of filler,
tablets with varying ratios of crospovidone grades
and dicalcium phosphate anhydrate as filler
were compressed (Figure 3). Again, the resulting
tensile strength of the tablets depended on the
grade and amount of the crospovidone used.
The tablets containing Kollidon ® CL did not show
an increase in tensile strength, whereas those
containing Kollidon CL-F and Kollidon CL-SF
showed increasing values. The increase was
more pronounced for tablets made with dicalcium
phosphate anhydrate compared to those
containing lactose.
Tensile strength [N/mm 2 ]
6
5
4
3
2
1
Lactose / Kollidon CL-SF
Lactose / Kollidon CL-F
Lactose / Kollidon CL
In addition to good binder properties, tabletting
excipients for direct compression should exhibit
good flowability. All formulations were analyzed
with a ring shear tester; the detected flow behavior
is depicted in Figure 4, where different
regions represent bulk flowability from very cohesive
to free-flowing. Each tabletting mixture
exhibited at least easy-flowing behavior. By adding
different grades and ratios of crospovidone
to lactose, flowability changed from free-flowing
to easy-flowing. Kollidon CL-SF, which has the
smallest particle size, led to formulations with the
worst flowability. However, all analyzed tabletting
mixtures still exhibited easy-flowing or free-flowing
behavior. Adding Kollidon CL-SF produces a
minor effect only on flow properties; this can be
neglected during compression. For every batch,
all analyzed tablets disintegrated disintegrated in
less than 70 seconds.
0
FIGURE 1 Tensile strength of lactose/crospovidone tablets compressed at 255 MPa. (n = 10, mean ± s)
Cumulative fraction [%]
0 20 40 60 80 100
100
80
60
40
Kollidon CL
Kollidon CL-F
Kollidon CL-SF
Disintegrant [%]
20
0
1 10 100 1000
Particle size [µm]
FIGURE 2 Particle size distributions of Kollidon CL, CL-F and CL-SF, measured with laser light diffraction. (n = 3)
Page 6

Excipients & Actives for Pharma
No. 26, 2011
Tensile strength [N/mm 2 ]
6
5
4
3
2
1
Lactose / Kollidon CL
Lactose / Kollidon CL-F
Lactose / Kollidon CL-SF
Dicalcium phosphate anh. / Kollidon CL
Dicalcium phosphate anh. / Kollidon CL-F
Dicalcium phosphate anh. / Kollidon CL-SF
Conclusion Crospovidone grades of small particle
size can be used as combined disintegrants
and binders. The tensile strength of the directly
compressed tablets was almost tripled, depending
on particle size and amount of crospovidone
used. In addition to the dry binder properties, all
mixtures containing different grades and ratios
of crospovidone exhibited at least easy-flowing
behavior. The combination of dry binder properties
and easy-flowing behavior makes crospovidone
an ideal excipient for direct compression.
REFERENCES
0
0 20 40 60 80 100
Disintegrant [%]
[1] Fell, J.T., Newton, J.M., (1970)."Determination
of tablet strength by the diametral-compression
test", Journal of Pharmaceutical Sciences
59 (5): 688-691.
FIGURE 3
Tensile strength of lactose/crospovidone and dicalcium phosphate anh./crospovidone tablets compressed at
153 MPa. (n = 10; mean ± s)
[2] McKenna, A. (1982). “Effect of particle size
on the compaction mechanism and tensile
strength of tablets.” Journal of Pharmacy and
Pharmacology 34(6): 347-351.
3000
Very
cohesive
ff c =2
Cohesive
Unconfined yield strength [Pa]
2000
1000
ff c =4
Easy-flowing
ff c =10
Free-flowing
0
5000 7500 10000
Consolidation stress [Pa]
FIGURE 4
Flowability of tabletting mixtures with different ratio of disintegrant. (blue symbols = Kollidon® CL-SF,
red symbols = Kollidon® CL-F, green symbols = Kollidon® CL, black symbols = pure lactose)
Page 7

Excipients & Actives for Pharma
No. 26, 2011
CONTROLLED RELEASE
Modeling drug release from Kollidon ® SR controlled
release matrix tablets
F. Siepmann,1 K. Eckart,1 A. Maschke,2 K. Kolter,2 J. Siepmann1*
1INSERM U 1008, College of Pharmacy, Univ. Lille Nord de France, 3 rue du Professeur Laguesse, 59006 Lille, France 2BASF, The Chemical Company, 67056 Ludwigshafen, Germany
INTRODUCTION | In the development of
controlled release formulations for oral drug
delivery, matrix tablets play a major role. Among
matrix materials, Kollidon SR, a blend of polyvinyl
acetate and polyvinylpyrrolidone, has been designed
for sustained release applications. To
achieve the most suitable drug release profile, the
formulation scientist can vary the composition of
the matrix formulation. Factors influencing drug
release are the solubility of the drug, its physicochemical
characteristics, the matrix former content
as well as the drug load. To accelerate drug
release, hydrophilic pore forming excipients such
as copovidone can be used. To reduce the velocity
of drug release, the absolute concentration
of matrix material can be increased.
Purpose The aim of this study was to better
understand the mass transport mechanisms
controlling drug release from Kollidon SR matrix
tablets. Based on thorough experimental characterization,
a mechanistic and realistic mathematical
model was to be developed and used to
quantitatively predict the effects of tablet dimensions
on drug release. This approach ena bles
faster formulation development by calculating a
desired release profile based on a minor set of
release experiments.
Based on this mathematical
approach, a drug
release profile can be
easily adapted to the
specific therapeutic
application.
100
a) b)
Tablet characterization The tablets were exposed
to 900 mL 0.1 M HCl or phosphate buffer
pH 7.4 (USP 30) in a USP 30 rotating paddle apparatus
(37°C, 80 rpm). At predetermined points
in time, 3 mL samples were withdrawn and
ana lyzed spectrophotometrically for their drug
content (λ=274 nm). Changes in tablet dimensions
(radius and height) were monitored with an
optical imaging system. The water uptake and
weight loss kinetics of the tablets were determined
gravimetrically.
RESULTS AND DISCUSSION | Upon exposure
to the release medium, the water content
of the tablets increased rapidly and steeply but
then leveled off (Figure 1a). In contrast, the dry
mass of the system continuously decreased
throughout the observation period, and could essentially
be attributed to drug release (Figure 1b).
100
EXPERIMENTAL METHODS | Tablet preparation
Drug-free and diprophylline-loaded Kollidon
SR-based tablets (0-60% w/w drug content, 1%
colloidal SiO 2 , 0.5% magnesium stearate) were
prepared by direct compression. The drug and
polymer powder were blended and compressed
with a single-punch tableting machine (flat-faced
punches: 5, 11.3 or 16 mm in diameter). The hardness
of the tablets was kept constant (180 N).
Water content [%]
75
50
25
0
60% diprophylline
40%
20%
0%
0 2 4 6 8
Time [h]
Dry mass [%]
75
50
25
0
0% diprophylline
20%
40%
60%
0 2 4 6 8
Time [h]
FIGURE 1
Effects of the initial diprophylline content on: (a) water uptake and (b) dry mass loss of Kollidon SR tablets upon
exposure to phosphate buffer pH 7.4 (diameter = 11.3 mm). Reprinted from reference [1], with permission
Page 8

Excipients & Actives for Pharma
No. 26, 2011
Cross-sections of Kollidon SR tablets exposed
for different time periods to 0.1 M HCl containing
0.35% w/w methylene blue are shown in
figure 2. Due to concentration gradients, the
dye continuously penetrated the tablets. Importantly,
the penetration fronts appeared homogeneous
and neither crack nor cavity formation
was observed.
At low and intermediate initial drug content, the
tablet height monotonically increased upon exposure
to the release media, whereas at very
high initial drug content, the tablet height decreased
again after a certain lag time (figure 3).
FIGURE 2
Macroscopic pictures of cross-sections of Kollidon SR-based tablets upon exposure to 0.1 M HCl containing 0.35% w/w
methylene blue for different time periods (as indicated) (initial diprophylline content: 20%). Reprinted from reference [1],
with permission
Increase in height [%]
100
75
50
25
0
0% diprophylline
40%
20%
6%
0 2 4 6 8
Time [h]
For tablets with an initial drug content below
60% w/w, the following analytical solution
of Fick’s second law of diffusion was used to
quantify drug release from the investigated matrix
tablets (considering axial as well as radial
mass transfer in a cylinder) (equation 1), where
M t and M ∞ represent the absolute cumulative
amounts of drug released at time t and infinite
time, respectively; the q n s are the roots of the
Bessel function of the first zero order, and R and
H denote the initial radius and height of the cylinder.
Figure 4 illustrates the good agreement
obtained when fitting this theory to the drug release
patterns measured in experiments.
FIGURE 3
Effects of the initial diprophylline content on changes in the height of Kollidon SR tablets upon exposure to phosphate
buffer pH 7.4 (diameter = 11.3 mm). Reprinted from reference [1], with permission
Page 9

Excipients & Actives for Pharma
No. 26, 2011
Based on these calculations, the apparent diffusion
coefficient of the drug in the polymeric
matrix could be determined: D = 1.7, 2.4 and
4.0 x 10 -7 cm²/s for 10, 20 and 40% initial drug
content. Knowing these values, the resulting
drug release kinetics can be predicted for arbi trary
tablet dimensions. One example is shown in
figure 5 (dotted curves). These theoretical predictions
could successfully be confirmed by
independent experiments (symbols in figure 5).
Equation 1
M t
M∞
= 1-
32
π²
·∑∞
n=1
Fick’s second law of diffusion
1
·exp
q² ( -
n
R c
q² n
² ·D·t ) ·∑∞
p=0
1
(2·p+1) 2 ·exp ( - (2·p+1)2· π²
H ²
·D·t
)
Conclusion Diprophylline release from Kollidon ®
SR tablets is primarily controlled by diffusion. The
mathematical model presented allows for a facilitated
optimization of this type of drug delivery
system. Based on this mathematical approach, a
drug release profile can be easily adapted to the
specific therapeutic application by reducing the
necessary experiments and hereby facilitating
faster formulation development.
REFERENCES
[1] Siepmann, F; Eckart, K; Maschke, A; Kolter,
K; Siepmann, J. Modeling drug release from
PVAc/PVP matrix tablets. Journal of Controlled
Release 141, 216-222, 2010.
[2] J. Crank. The Mathematics of Diffusion. Clarendon
Press, Oxford, 1975.
Drug released [%]
100
75
50
25
0
FIGURE 4
40% diprophylline
20%
10%
theory
0 6 12 18 24
Time [h]
Experiment (symbols) and theory (curves):
Diprophylline release from Kollidon SR tablets
with different initial drug loadings in phosphate
buffer pH 7.4. (diameter = 11.3 mm). Reprinted
from reference [1], with permission
Drug released [%]
100
75
50
25
0
FIGURE 5
theoretical prediction
1.3mm, experiment
3.9mm, experiment
0 6 12 18 24
Time [h]
Theoretical prediction (dotted curves) and independent
experimental verification (symbols):
Effects of the tablet height on diprophylline
release from Kollidon SR tablets in phosphate
buffer pH 7.4 (drug loading: 20%, diameter = 11.3 mm).
Reprinted from reference [1], with permission
Page 10

Excipients & Actives for Pharma
No. 26, 2011
STABILITY OF FORMULATED OXYGEN-SENSITIVE ACTIVE INGREDIENTS
Extended stabilization of active ingredients highly sensitive
to oxidation using Kollidon 30 LP
Angelika Maschke, Karl Kolter
INTRODUCTION | Pharmaceutical formulators
regularly require a low peroxide content in
the excipients used to avoid degradation of the
active ingredients (APIs) used. BASF fulfils this
need to the maximum extent with its high-quality
Kollidon grades and the packaging concept
introduced in this ExAct issue (see pages 2-4).
Moreover, the formulation of drugs that are
highly sensitive to oxidation has become an
additional major challenge for formulation scientists.
For this purpose, it is of the utmost importance
to use excipients with an especially
low peroxide content.
Considering the close contact between active
ingredients and excipients during wet granu lation
or direct compression, the peroxide level of the
excipient has a strong impact on the stability
of the API. As a first formulation approach, the
stability of the API in a binder solution allows
the appropriate binder to be identified. The goal
of this study was to investigate the effect of the
peroxide content of povidone on API stability in
solution.
Using Kollidon 30 LP in
the formulation of actives
highly sensitive to
oxidation can significantly
improve drug stability.
Set-up of experiments The effect of Kollidon
30 Low Peroxide in solution on stabilization
against oxidation was investigated using ascorbic
acid and hydrocortisone as model substances.
Povidones of different peroxide content (see
table 1) were used to prepare a 20% aqueous
solution. Ascorbic acid was incorporated at a
0.1% level and hydrocortisone at 0.025%.
For the stability study, the samples were filled
in glass vials incubated with or without argon,
closed with a rubber cap and sealed with a
cramp. The solutions were stored for 3 months at
25°C and 60% relative humidity. The API content
was determined by HPLC.
Results Both drug substances showed higher
stability in solutions prepared with Kollidon 30 LP.
After 1 month in Kollidon 30 LP solution, the
ascorbic acid content was 50% vs. 30% in a
PVP solution with a starting peroxide level of
< 260ppm (Figure 1). A similar stabilization effect
was found for hydrocortisone solutions
(Figure 2).
Povidone
Peroxide content
Kollidon 30 LP Very low < 20 ppm
PVP 30 Low < 260 ppm
PVP 30 Enriched 370 ppm
TABLE 1
Povidone grades used for preparing aqueous acid solutions
Page 11

Excipients & Actives for Pharma
No. 26, 2011
Solutions without argon
Solutions with argon
100
100
80
Kollidon 30 LP
80
Ascorbic acid content [%]
60
40
PVP
PVP peroxide enriched
Ascorbic acid
60
40
20
20
0
0 20 40 60 80 100
0
0 20 40 60 80 100
Day
Day
FIGURE 1
Stability of ascorbic acid in different povidone solutions incubated at 25°C /60% r.h.
Hydrocortisone [%]
100
98
96
94
Solutions without argon
Conclusion
• Using Kollidon ® 30 LP in the formulation of
actives highly sensitive to oxidation can significantly
improve drug stability.
• A correlation was found between the peroxide
content and the stability of the model actives.
• Further investigations to underline the effectiveness
of Kollidon 30 LP in a dry state will
be reported soon.
92
Kollidon 30 LP
PVP
PVP peroxide enriched
90
0 20 40 60 80 100
Day
FIGURE 2
Stability of hydrocortisone in different povidone solutions incubated at 25°C /60% r.h.
Page 12

Excipients & Actives for Pharma
No. 26, 2011
HOT MELT EXTRUSION
ExActMelt - improving drug efficiency with hot-melt extrusion
Cecil Tung
More than 70 pharmaceutical customers and
R&D professionals gathered in Singapore for the
two-day ExActMelt workshop to explore the innovative
hot-melt extrusion technology. Contributing
to the development of the talent pool for the
pharmaceutical industry, workshop participants
also witnessed BASF extend its “Joint RP-BASF
Pharmaceutical Technology Lab Program” with
Republic Polytechnic.
BASF and high-tech pharmaceutical equipment
supplier ThermoFisher teamed up again for a
closer look at Hot-Melt Extrusion (HME), an innovative
technology for processing poorly soluble
active pharmaceutical ingredients. The highly
interactive two-day workshop at Republic Polytechnic
in Singapore provided a much needed
opportunity for intensive knowledge exchange
between innovative excipient designers and manufacturers
– a must for any new technology.
Pharmaceutical customers from more than 10
Asian countries participated in the workshop to
learn more about this state-of-the-art technology
that dramatically improves the bioavailability of
active pharmaceutical ingredients. Providing a
detailed insight into how the technology works
and how it can help pharmaceutical processing,
the workshop demonstrated that, combined with
Thermo Fisher’s HME machine, BASF’s solubilizers
such as Soluplus ® offer superior performance
in forming solid solutions during the HME process.
The combination of
theoretical lectures
and practical, hands-on
demonstrations allowed
customers to explore
hot-melt extrusion in
depth.
“The combination of theoretical lectures and practical,
hands-on demonstrations allowed customers
to explore hot-melt extrusion in depth and
make them aware of the potential to improve bioavailability
and patient compliance. Additionally,
the workshop was a great opportunity for customers
and R&D professionals to meet and discuss
burning issues in the pharmaceutical industry,”
said Thomas Pilgram, Regional Head of BASF
Pharma Ingredients & Services in Asia Pacific.
During the workshop, BASF also officially renewed
the “Joint RP-BASF Pharmaceutical Technology
Lab Program” with Republic Polytechnic, continuing
to foster students’ interest in pharmaceutical
technology and research. Through the program,
pharmaceutical technologists and scientists will
be trained and made aware of BASF’s innovative
excipient development pipeline, underlining the
company's commitment to building up the talent
pool for the industry.
BASF will continue to explore opportunities for
cooperating with universities and institutions
similar to Republic Polytechnic. In addition, the
company will continue to establish its links with
research centers and science institutes as well
as leading pharmaceutical companies.
The panel discussion was a great opportunity for pharmaceutical professionals to discuss
burning issues within the industry.
“Joint RP-BASF Pharmaceutical Technology Lab Program” Memorandum Of Understanding
signing ceremony demonstrates BASF’s commitment to sustainable development with the goal
of increasing collective expertise, experience and resources for the pharmaceutical industry.
Page 13

Excipients & Actives for Pharma
No. 26, 2011
REGULATORY NEWS
CEP procedure and the availability of CEP for BASF products
Dominik Odenbach
In order to guarantee consistent product
quality, pharmaceutical manufacturers must be
able to demonstrate standardized, reliable quality
of pharmaceutical ingredients in line with existing
pharmaceutical monographs. To ensure
quality, the Certification Secretariat of the European
Directorate for the Quality of Medicines
(EDQM) grants Certificates of Suitability of
Monographs of the European Pharmacopoeia
(CEP) to manufacturers who can show that their
production is compliant with the existing
pharmaceutical monograph of the European
Pharmacopoeia. To apply for this certificate,
pharma ceutical ingredients manufacturers must
present a comprehensive dossier, including information
on chemistry, manufacturer, process,
characterization, controls, reference standards,
container closure systems, stability.
The CEP procedure was created in 1994. CEPs
are accepted in all 36 member states of the
European Pharmacopoeia Convention. According
to the EDQM, non-European countries also
accept CEP (e.g. Argentina, Brazil, Malaysia,
Mexico, New Zealand, Russian Federation,
Singa pore, South Africa, Taiwan, and others).
The CEP procedure has many advantages:
• Efficiency through centralization
Only the EDQM reviews the applications and
grants CEPs. A DMF must be reviewed by
indi vidual health authorities, but the CEP
procedure is a single centralized evaluation.
There is no duplication of work. Potential
diver gences in assessment are avoided.
• Less documentation
Once granted, the CEP is only a few pages
long whereas a DMF is a dossier with a large
volume of documentation, which must be
reviewed with each new registration.
• Speed
The information provided in the dossier is
approved by the EDQM only once, with the
granting of a CEP. After this, each CEPbased
registration is processed quickly.
• IP protection
The CEP dossier is only reviewed by one
pub lic regulatory body (EDQM).
Customer benefits
For the pharmaceutical manufacturer, the CEP
makes it easier to assess suppliers and their
materials, without the need for conducting timeconsuming
and costly audits. Marketing authorizations
are easier to manage because CEP
replaces the majority of the application.
For the pharmaceutical
manufacturer, the CEP
makes it easier to assess
suppliers and their materials,
without the need for
conducting time-consuming
and costly audits.
BASF is seeking to achieve CEP for its active
ingredients and selected excipients. This will
allow the company to supply customers with
products compliant with the quality standards
of the European Pharmacopoeia. Plus, customers
will benefit from a straightforward service
solution.
All of the following products have valid status
and are classified under type chemistry (table 1):
Time and cost
The CEP procedure saves time (fixed time
frames; a single regulatory body) and cuts costs
for the industry and the licensing authorities. A
CEP costs a one-off fee of approx. 3,000 euros,
whereas a DMF will have to be provided to different
health authorities, leading to multiple fees.
Page 14

Excipients & Actives for Pharma
No. 26, 2011
Substance
number Substance Certificate holder Certificate number Issue date
1385 Acitretin BASF SE DE 67056 Ludwigshafen
R0-CEP 2007-201-
Rev 01
22/01/2009
1688 Articaine hydrochloride
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
R1-CEP 2002-198-
Rev 01
13/07/2010
541 Bupivacaine hydrochloride
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
R1-CEP 2004-043-
Rev 01
13/07/2010
267 Caffeine
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
R1-CEP 1998-022-
Rev 02
16/12/2009
543 Carbamazepine
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
891 Copovidone nominal K value 28 BASF SE DE 67056 Ludwigshafen
892 Crospovidone type A and B
BASF SE DE 67056 Ludwigshafen
Am Rhein
761 Dexpanthenol BASF SE DE 67056 Ludwigshafen
1200 Dobutamine hydrochloride
664 Dopamine hydrochloride
487 Ephedrine hydrochloride
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
721 Ibuprofen BASF Corporation US 78343 Bishop
1019 Isotretinoin BASF SE DE 67056 Ludwigshafen
2052 Macrogol 15 hydroxystearate BASF SE DE 67056 Ludwigshafen
1242 Mepivacaine hydrochloride
1354 Oxybutynin hydrochloride
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
0.9 R1-CEP 1998-
086-Rev 04
R0-CEP 2007-106-
Rev 00
R0-CEP 2007-076-
Rev 00
R0-CEP 2006-233-
Rev 00
R0-CEP 2006-273-
Rev 01
R0-CEP 2007-049-
Rev 00
R0-CEP 2006-234-
Rev 00
R1-CEP 2000-087-
Rev 01
R1-CEP 1999-068-
Rev 03
R0-CEP 2006-095-
Rev 02
R1-CEP 2001-305-
Rev 02
R1-CEP 2000-108-
Rev 03
13/07/2010
10/10/2008
10/10/2008
04/11/2008
27/04/2010
27/04/2010
16/01/2008
18/07/2008
07/06/2011
17/11/2008
13/07/2010
13/07/2010
TABLE 1
BASF products for which CEP is available
Page 15

Excipients & Actives for Pharma
No. 26, 2011
943 Oxymetazoline hydrochloride
1142 Povidone, iodinated
685
685
Povidone 'nominal K value 12' &
'nominal K value 17'
Povidone 'nominal K value 25' and
'nominal K value 30'
685 Povidone 'nominal K value 90'
1362 Prilocaine
1363 Prilocaine hydrochloride
1367 Pseudoephedrine hydrochloride
1260 Selegiline hydrochloride
299 Theophylline
302 Theophylline monohydrate
300
301
Theophylline-ethylenediamine
anhydrous
Theophylline-ethylenediamine
hydrate
1767 Tilidine hydrochloride hemihydrate
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF CORPORATION US 07932 Florham
Park
BASF SE DE 67056 Ludwigshafen
Am Rhein
BASF SE DE 67056 Ludwigshafen
Am Rhein
BASF SE DE 67056 Ludwigshafen
Am Rhein
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
693 Tretinoin BASF SE DE 67056 Ludwigshafen
1162 Xylometazoline hydrochloride
1162 Xylometazoline hydrochloride
BASF PharmaChemikalien GmbH &
Co. KG DE 67056 Ludwigshafen
BASF PHARMA (EVIONNAZ) SA CH
1902 Evionnaz
R0-CEP 2008-064-
Rev 01
R0-CEP 2008-179-
Rev 00
R0-CEP 2007-077-
Rev 00
R0-CEP 2007-079-
Rev 00
R0-CEP 2007-078-
Rev 00
R1-CEP 2002-227-
Rev 01
R1-CEP 2002-170-
Rev 01
R1-CEP 1998-009-
Rev 02
R1-CEP 1999-124-
Rev 02
R1-CEP 1998-011-
Rev 04
R1-CEP 1998-010-
Rev 05
R0-CEP 2007-288-
Rev 01
R0-CEP 2007-289-
Rev 02
R0-CEP 2007-045-
Rev 00
R0-CEP 2009-350-
Rev 01
R0-CEP 2006-286-
Rev 00
R1-CEP 2000-061-
Rev 02
10/02/2010
02/11/2010
28/08/2009
10/10/2008
19/02/2009
13/07/2010
13/07/2010
29/07/2008
28/02/2007
30/05/2007
28/07/2009
09/02/2010
14/04/2010
07/11/2008
17/03/2011
24/11/2008
13/07/2010
TABLE 1
BASF products for which CEP is available
Page 16

Excipients & Actives for Pharma
No. 26, 2011
REGULATORY NEWS
USP verification program substituted by RX-360 certification.
Ralf Hadeler and Bernhard Fussnegger
In 2008, USP awarded BASF SE and BASF
Corporation the USP Verified Mark after BASF
fulfilled all USP verification requirements: GMP
audit, a thorough documentation review and tests
for purity and potency. The products supplied
under this program are the soluble Kollidon ®
grades, the copovidones and crospovidones of
BASF SE and the Kollidon 30 and PVP-iodine
grades manufactured in the BASF production site
in Geismar, Louisiana. Pharmaceutical product
manufacturers who buy USP-verified ingredients
have the guarantee that these are consistent in
quality from batch to batch, meet label and/or
certificate-of-analysis claims for identification,
strength, purity, and quality, and that they are
manufactured in accordance with the internationally
accepted Good Manufacturing Practices for
Drug Substances and Excipients. They also meet
the requirements for acceptable limits of contamination.
Over recent years, an increased number of requests
for customer audits have been received.
As the USP verification program does not provide
any additional documents for third party
audits, BASF SE has decided to discontinue the
USP program. The Rx360 certification program
was selected as a promising alternative.
Rx 360 was incorporated in June 2009 as an international
non-profit consortium consisting of
over 50 organizations of excipient manufacturers
and users and further members with an observer
status. It aims to support an industry-wide commitment
to ensuring patient safety by enhancing
quality and authenticity throughout the supply
chain. This goal is timely in the light of growing
and threats to an increasingly complex and
global supply chain. Management of this aspect
of the pharmaceutical industry has become one
of the top public health concerns with respect to
consumer safety. The globalization of distribution
for both drug components and finished products
has led to many complications that it is hoped
Rx360 can help resolve.
Three independent production sites at BASF SE
in Ludwigshafen successfully passed a two-day
audit based on the Rx 360 Consortium guidelines
for pharmaceutical excipients.
It is worth noting that Kollidon 12 PF and Kollidon
17 PF are among the products registered for parenteral
application and that these products were
considered to be APIs. A risk-based approach
was taken here and these products were audited
according to the requirements of ICH Q7.
Overall, no critical observations were made.
The audit report states that BASF operates in
accordance with the requirements of ISO 9001,
IPEC-PQG Guideline and ICH Q7.
The signed audit report is available upon request.
Three independent
production sites at BASF
SE in Ludwigshafen
successfully passed a
two-day audit based on
the Rx 360 Consortium
guidelines for pharmaceutical
excipients.
Page 17

Excipients & Actives for Pharma
No. 26, 2011
EVENTS
ExActCoat + Experience coating success
Kathrin Meyer-Böhm
Experience coating success BASF invites you
to a new era of coating events: ExActCoat + is a
comprehensive and interactive series of events
designed to broaden knowledge on film coating
and film-coating equipment. To lead you to
enjoy coating success, ExActCoat + brings together
practical experience on materials, processes
and the fascinating theory behind them,
all in an interactive way. ExActCoat + provides
a platform for learning more about color determination,
colored coating systems, instant- and
sustained-release coating, protective coating
and coating equipment. Coating experts from
across the industry and from academia will be
your partners, helping you find answers to your
most difficult coating questions.
After the successful launch of ExActCoat + in
2010 in Asia, the unique event series will be
continued around the globe. Keep a look-out
for an ExActCoat + event near you. Events are
planned for the US, South America and Asia
in the fall of 2011. If you have any questions,
please contact your sales representatives. They
will be glad to help.
FIGURE 1
Find the right contact for your specific coating question
Page 18

Excipients & Actives for Pharma
No. 26, 2011
BREAKING NEWS
Andreas Gryczke, BASF’s expert for hot-melt extrusion, will appear
at this year's AAPS with posters covering various aspects of this
innovative production technology.
The use of melt extrusion processes in the
pharmaceutical industry is a highly promising
approach to the various challenges presented
by current and future formulations.
Melt extrusion is still a recent development in
the pharmaceutical industry. So far, academia
and industry focused on getting to grips with
the basics of hot-melt extrusion. However, it
has been established that this new technology
has great potential for the formulation of drugs
containing poorly soluble or poorly permeable
active ingredients. The first commercial formulations
confirm this.
Since there is an increasing desire on the part
of the industry to make better use of this technology
in development and manufacturing, the
proposed sessions aim to provide ideas and
Posters at AAPS 2011 presented by
Andreas Gryczke, featuring the hot-melt
extrusion technique
• Small-scale miscibility screening for
solid dispersions in tablets prepared by
injection molding: a study on itraconazole
in combination with Soluplus ® .
• In-line monitoring of a hot-melt extrusion
process using near-infrared spectros
copy.
• Investigation of tablets made by injection
molding: R&D-stage manufacturing and
characterization of theophylline-PEO
tablets.
guidance on the various aspects of implementation.
These lectures are different from other
HME sessions, which have focused on educating
scientists on the basics. Instead, the proposed
sessions will deal with the process itself,
its implementation and its characterization. The
goal is to provide the industry and researchers
with insights into the process, its advantages
and disadvantages and to offer guidance on
how to mitigate problems using a risk assessment
approach when implementing this exciting,
pioneering technology.
Kollicoat ® IR and Kollicoat ®
SR 30 D to be published in the
Handbook of Pharmaceutical
Excipients
Kollicoat IR approved by Australian Department
of Health and Ageing
It has been announced that the two coating polymers
Kollicoat IR (ethylene glycol and vinyl alcohol
grafted copolymer) and Kollicoat SR 30 D
(polyvinyl acetate dispersion) are to be included
in the Handbook of Pharmaceutical Excipients.
Both polymers will appear in the online version
of the handbook as of August 2011, and in the
upcoming 7th edition of the print version. Together
with the monographs in the US and the
EU pharmacopoeias, the inclusion of Kollicoat IR
and Kollicoat SR 30 D underlines BASF’s continuous
efforts to bring safe and innovative coating
excipients to its customers – helping them them
tackle today’s and future formulation challenges
successfully.
Kollicoat IR, BASF’s 3rd generation instant release
coating, has already been approved by the
health authorities in Europe, Canada and Japan.
We are pleased to inform you that Kollicoat IR
is now also approved by the Therapeutic Goods
Administration (TGA) of the Australian Department
of Health and Ageing.
According to the TGA, Kollicoat IR (Polyethylene
glycol-polyvinyl alcohol graft copolymer) is considered
to be safe for use as an excipient in oral
medicines at concentrations of less than 5% in
the finished product.
Kollicoat IR is currently monographed in the following
pharmacopoeias:
• Ph.Eur monograph – Macrogol poly(vinyl alcohol)
grafted copolymer
• USP-NF monograph – Ethylene Glycol and
Vinyl Alcohol Graft Copolymer
Self-affirmed GRAS status is expected end of
2011; listing in the FDA’s Inactive Ingredients
database (IIG) in early 2012.
Page 19

Excipients & Actives for Pharma
No. 26, 2011
CALENDAR
Oct 23-27, 2011
AAPS
Washington D.C., USA
Oct 25-27, 2011
CPhI Worldwide
Frankfurt, Germany
October, 2011
ExActCoat
São Paulo, Brazil
Nov 16, 2011
ExActCoat
Bangkok, Thailand
Nov 21, 2011
ExActCoat
Shanghai, China
Nov 30-Dec 2, 2011
CPhI India
Mumbai, India
PREVIEW
Soluplus ® - how it solubilizes even the
most poorly soluble active ingredients
With its outstanding solubilization properties, our award-winning Soluplus is designed to specifically
dissolve poorly soluble active pharmaceutical ingredients. Due to its high flowability and excellent
extrudability, Soluplus exhibits superior performance in forming solid solutions, especially in hotmelt
extrusion processes. With Soluplus, formulators are now able to achieve effective dosage forms
using only a fraction of a poorly soluble drug. This is because the small amount is solubilized and
becomes bioavailable to a very high extent. In our next edition of ExAct, we will present theoretical
proof of Soluplus’ outstanding solubilization capability, and how it helps formulators tackle the most
challenging of active ingredients – for today’s formulations, and in the future.
CONTACT
What opportunities can we open up for you?
Would you like to discuss a particular challenge or product in detail? Or do you have any
questions? Simply call or e-mail us. We will be glad to help.
March 2011
APV Conference
Istanbul, Turkey
May 9-10
Excipientfest
San Juan, Puerto Rico
Asia
BASF East Asia Regional
Thomas Pilgram
Hong Kong
Phone: +852 27311-589
thomas.pilgram@basf.com
Europe
BASF Lampertheim GmbH
Peter Hoffmann
Lampertheim, Germany
Phone: +49 621 60-76928
peter.wolfgang.hoffmann@basf.com
North America
BASF Corporation
Nigel Langley, Ph.D., MBA
Tarrytown, NY, USA
Phone: +1 914 785-3828
nigel.langley@basf.com
South America
BASF S.A.
Fabio Ikuno
São Paulo – SP Brazil
Phone: +55 11 3043-2083
fabio-luis.ikuno@basf.com
www.pharma-ingredients.basf.com
pharma-ingredients@basf.com
03_040102e-26