Dear Reader: Innovations across the entire packageview/en/8806188198357.ExA… · versatile...

Excipients & Actives for Pharma

No. 26, 2011

New and innovative excipients are required to meet today’s in-creasing challenges in the formulation of new drugs and dos-age forms. Products such as our Soluplus® or Kollicoat® Smartseal 30 D have therefore been successfully in-

troduced to meet challenges like the poor solu-bility 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, ex-tending shelf life; we also open up new applica-tion fields for povidone binders and disintegrants – for example, in the field of oxygen-sensitive APIs. In addition, the new PeroXeal packag-ing concept allows easier and safer handling and is better for the environment. Since invent-ing "Kollidon - the Original" 70 years ago, we

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

CONTACT PAGE 20

continue to innovate and set new standards in stability, purity and patient safety.

The new PeroXeal packaging concept is an ex-cellent example of BASF’s continuous pursuit of innovation, both for new and established prod-ucts. To improve the usability of our ingredients for customers, we have optimized the entire "package" – from ordering the product, to pro-cessability (e.g. flow behaviour) and even to dis-posal of the packaging.

Yours sincerely,

Boris JennichesHead of Global Product Management Pharma Ingredients & Services

Kollidon – The Original

www.kollidon.com

Dear Reader: Innovations across the entire package

CONTENTS

Long-term stability data shows advantages1. Re-test period of packaged material can be extended from 36 to 48 months2. Peroxide level is decreased to below 100 ppm

PUBLISHER:

BASF SE Pharma Ingredients & Serviceswww.pharma-ingredients.basf.com

EDITORIAL STAFF:

Ralf FinkAndres-Christian OrthoferKarl KolterJan Bebber

AUTHORS:

Angelika MaschkeBernhard FussneggerClaudia EasterbrookCorinnaTissenCecil TungDominik OdenbachFlorence SiepmannJanna LorenzJürgen SiepmannKarl KolterKathrin Meyer-BöhmKarin EckartMarcel HilkensPeter KleinebuddeRainer FendtRalf HadelerSilvia Mok

CONCEPT/LAYOUT:

Château Louis Strategische Markenführung und Kommunikation GmbH

PRINT:

johnen-druck GmbH & Co. KG

ABOUT US

Trademarks are owned by BASF SE

IN FOCUS: KOLLIDON PACKAGING

Improving on a classic: the new PeroXeal™

packaging concept for Kollidon®

Silvia Mok, Claudia Easterbrook, Bernhard Fussnegger

toxicity reducing agent. And new uses are being discovered all the time, as BASF innovates to ad-dress customer challenges – continuously set-ting new standards in stability, purity and patient safety.

The groundbreaking PeroXeal packaging con-cept 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 re-sult, 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 prod-uct. Witnessing the impact of these flaws on PVP stability and performance, the BASF experts continuously challenged themselves to develop and enhance Kollidon packaging.

FIGURE 1 Comparison of stability data

Kollidon enjoys a long and rich tradition. BASF scientist Walter Reppe invented polyvinyl-pyrrolidone (PVP) over 70 years ago, and we reg-istered 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 vari-ous molecular weights and particle sizes, a vinyl-pyrrolidone/vinyl acetate copolymer and a blend of polyvinyl acetate and polyvinylpyrrolidone.

BASF has a range of Kollidon products for ap-plications across the pharmaceutical sector: this versatile excipient can be deployed as a binder, disintegrant, bioavailability enhancer, film former, solubilizer, lyophilisation agent, suspension sta-bilizer, wetting agent, adhesive, stabilizer, inter-mediate, thickener, dissolution enhancer, and

Povidone K30 instandard market packaging

Kollidon 30 instandard BASF packaging

Kollidon 30in new BASF packaging

Months

ppm

450

400

350

300

250

200

150

100

50

00 1 3 6 9 12 18 24 36 48

Compendial limit

No. 26, 2011Excipients & Actives for Pharma

The hard work paid off: years of research and analysis have culminated in BASF’s new propri-etary aluminum-free PeroXeal packaging concept. The innovative foil comprises three distinct func-tional layers, each specifically designed to shield the product from environmental influences. Com-plemented by inert gas flushing and heat seal-ing, 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 pre-venting 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.

The groundbreaking PeroXeal packaging concept now marks the next stage in the evolution of Kollidon.

No degradation of K value(Usual decrease of K value in contact with air is around 0.2 units per month)

Months

k-va

lue

94

92

90

88

86

84

82

800 1 3 6 9 12 18 24 36 48

Povidone K90 instandard marketpackaging

Kollidon 90F instandard BASF packaging

Kollidon 90Fin new BASFpackaging

FIGURE 2 Comparison of K values

FIGURE 3 Transparent aluminum-free packaging avoids product contamination with aluminum flakes


FIGURE 4 Benefits of the new packaging concept to our customers

The most immediate benefit is consistent perfor-mance in terms of binding, viscosity and adhe-sion – plus enhanced stability opens the door for entirely new applications.

For example, you can now use Kollidon® as an alternative to cellulose when working with oxy-gen-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.

Longer shelf life

Extends excipient shelf life up to 4 years

Greater choice

Provides an alternative to cellulose

Formulationstability

Allows stable formulaions by

reduced API degradation

constant K values

Improved performance and reliability

Formulation withsensitive APIs

Opens new opportunities for formulation with 02-sensitive APIs Formulation

with sensitive APIs

Formulationstability

Greater choice

Longershelf life


INTRODUCTION | Crospovidone is a super-disintegrant 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 distribu-tion. 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 en-suring 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.

CROSPOVIDONE

Binding properties and flow behavior of different crospovidone gradesC.Tissen, M.Hilkens, J.Lorenz, P.Kleinebudde Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Duesseldorf, Germany

METHODS AND MATERIALS | Materials Crospovidone (Kollidon CL, Kollidon CL-F, Kollidon CL-SF, BASF SE, Ludwigshafen, Ger-many), alpha-lactose monohydrate (Tablettose® 80, Meggle, Wasserburg, Germany), dicalcium phosphate (Dicaphos® AN, *Budenheim, Ger-many), magnesium stearate (Welding, Hamburg, Germany).

Methods / Particle size distribution The par-ticle 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 mix-tures 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 tablet-ting 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, Switzer-land). 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 tab-lets 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, Switzer-land) and subsequently calculated as tensile strength according to Fell and Newton [1].

Disintegration testing The disintegration time for 12 tablets of each batch was measured with a disintegration tester (Erweka ZT 32, Heusen-stamm, 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 dur-ing the compression process, resulting in tablets with improved hardness [2]. Consequently, tab-lets with Kollidon CL-SF exhibited the highest values. Even 20% (w/w) almost doubled the de-termined 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.

TABLE 1 Tabletting mixtures

Fraction [%]

Filler 100 95 90 80 60 40 0

Disintegrant 0 5 10 20 40 60 100


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 dical-cium phosphate anhydrate compared to those containing lactose.

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 be-havior is depicted in Figure 4, where different regions represent bulk flowability from very co-hesive to free-flowing. Each tabletting mixture exhibited at least easy-flowing behavior. By ad-ding 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-flow-ing 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.

FIGURE 1 Tensile strength of lactose/crospovidone tablets compressed at 255 MPa. (n = 10, mean ± s)

FIGURE 2 Particle size distributions of Kollidon CL, CL-F and CL-SF, measured with laser light diffraction. (n = 3)

Particle size [µm]

Cum

ulat

ive

fract

ion

[%]

100

80

60

40

20

0

1 10 100 1000

Kollidon CLKollidon CL-FKollidon CL-SF

Disintegrant [%]

6

5

4

3

2

1

00 20 40 60 80 100

Lactose / Kollidon CL-SFLactose / Kollidon CL-FLactose / Kollidon CL

Tens

ile s

treng

th [N

/mm

2 ]


Conclusion Crospovidone grades of small par-ticle size can be used as combined disintegrants and binders. The tensile strength of the directly compressed tablets was almost tripled, depend-ing 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 proper-ties and easy-flowing behavior makes crospovid-one an ideal excipient for direct compression.

REFERENCES

[1] Fell, J.T., Newton, J.M., (1970)."Determination of tablet strength by the diametral-compres-sion test", Journal of Pharmaceutical Sci-ences 59 (5): 688-691.

[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.

FIGURE 3 Tensile strength of lactose/crospovidone and dicalcium phosphate anh./crospovidone tablets compressed at 153 MPa. (n = 10; mean ± s)

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)

Disintegrant [%]

Tens

ile s

treng

th [N

/mm

2 ]

6

5

4

3

2

1

00 20 40 60 80 100

Lactose / Kollidon CLLactose / Kollidon CL-FLactose / Kollidon CL-SFDicalcium phosphate anh. / Kollidon CLDicalcium phosphate anh. / Kollidon CL-FDicalcium phosphate anh. / Kollidon CL-SF

Unco

nfine

d yi

eld

stre

ngth

[Pa]

3000

2000

1000

0

Consolidation stress [Pa]5000 7500 10000

Verycohesive

Cohesiveffc=2

Easy-flowingffc=4

ffc=10 Free-flowing


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

Modeling drug release from Kollidon® SR controlled release matrix tabletsF. 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

CONTROLLED RELEASE

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 de-signed 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 physico-chemical characteristics, the matrix former con-tent as well as the drug load. To accelerate drug release, hydrophilic pore forming excipients such as copovidone can be used. To reduce the velo-city 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 char-acterization, a mechanistic and realistic math-ematical model was to be developed and used to quantitatively predict the effects of tablet dimen-sions on drug release. This approach ena bles faster formulation development by calculating a desired release profile based on a minor set of release experiments.

EXPERIMENTAL METHODS | Tablet prepara-tion Drug-free and diprophylline-loaded Kollidon SR-based tablets (0-60% w/w drug content, 1% colloidal SiO2, 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 hard-ness of the tablets was kept constant (180 N).

Tablet characterization The tablets were ex-posed to 900 mL 0.1 M HCl or phosphate buffer pH 7.4 (USP 30) in a USP 30 rotating paddle ap-paratus (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 dimen-sions (radius and height) were monitored with an optical imaging system. The water uptake and weight loss kinetics of the tablets were deter-mined gravimetrically.

RESULTS AND DISCUSSION | Upon expo-sure 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 es-sentially be attributed to drug release (Figure 1b).

Based on this mathematical approach, a drug release profile can be easily adapted to the specific therapeutic application.

0 2 4 6 8

Time [h]

Wat

er c

onte

nt [%

]

100

75

50

25

0

60% diprophylline

40%

20%

0%

Dry

mas

s [%

]

100

75

50

25

0

0 2 4 6 8

Time [h]

0% diprophylline

20%

40%

60%

a) b)


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

Cross-sections of Kollidon SR tablets exposed for different time periods to 0.1 M HCl contain-ing 0.35% w/w methylene blue are shown in figure 2. Due to concentration gradients, the dye continuously penetrated the tablets. Import-antly, the penetration fronts appeared homo-geneous and neither crack nor cavity formation was observed.

At low and intermediate initial drug content, the tablet height monotonically increased upon ex-posure to the release media, whereas at very high initial drug content, the tablet height de-creased 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

0% diprophylline

40%

20%

6%

Incr

ease

in h

eigh

t [%

]

100

75

50

25

0

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 ma-trix tablets (considering axial as well as radial mass transfer in a cylinder) (equation 1), where Mt and M∞ represent the absolute cumulative amounts of drug released at time t and infinite time, respectively; the qns are the roots of the Bessel function of the first zero order, and R and H denote the initial radius and height of the cy-linder. Figure 4 illustrates the good agreement obtained when fitting this theory to the drug re-lease patterns measured in experiments.


REFERENCES

[1] Siepmann, F; Eckart, K; Maschke, A; Kolter, K; Siepmann, J. Modeling drug release from PVAc/PVP matrix tablets. Journal of Con-trolled Release 141, 216-222, 2010.

[2] J. Crank. The Mathematics of Diffusion. Cla-rendon Press, Oxford, 1975.

Mt

M∞= 1-

32π²

·∑∞

n=1

1q²

n

·exp ( -Rc

q²n

² ·D· t ) ·∑∞

p=0

1(2·p+1)2

·exp ( -(2·p+1)2· π²

H ² ·D·t )

FIGURE 4 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

FIGURE 5 Theoretical prediction (dotted curves) and inde-pendent 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

theoretical prediction

1.3mm, experiment

3.9mm, experiment

Drug

rele

ased

[%]

100

75

50

25

00 6 12 18 24

Time [h]

Based on these calculations, the apparent dif-fusion 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 pre-dictions could successfully be confirmed by independent experiments (symbols in figure 5).

Conclusion Diprophylline release from Kollidon® SR tablets is primarily controlled by diffusion. The mathematical model presented allows for a facili-tated 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.

40% diprophylline

20%

10%

theory

Drug

rele

ased

[%]

100

75

50

25

00 6 12 18 24

Time [h]

Equation 1 Fick’s second law of diffusion


INTRODUCTION | Pharmaceutical formula-tors 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-qual-ity 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 sci-entists. For this purpose, it is of the utmost im-portance 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.

STABILITY OF FORMULATED OXYGEN-SENSITIVE ACTIVE INGREDIENTS

Extended stabilization of active ingredients highly sensitive to oxidation using Kollidon 30 LPAngelika Maschke, Karl Kolter

TABLE 1 Povidone grades used for preparing aqueous acid solutions

Set-up of experiments The effect of Kollidon 30 Low Peroxide in solution on stabilization against oxidation was investigated using ascor-bic acid and hydrocortisone as model substan-ces. 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 ef-fect 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

Using Kollidon 30 LP in the formulation of actives highly sensitive to oxidation can significantly improve drug stability.


FIGURE 1 Stability of ascorbic acid in different povidone solutions incubated at 25°C /60% r.h.

Conclusion

• Using Kollidon® 30 LP in the formulation of actives highly sensitive to oxidation can sig-nificantly improve drug stability.

• A correlation was found between the peroxide content and the stability of the model actives.

• Further investigations to underline the effec-tiveness of Kollidon 30 LP in a dry state will be reported soon.

FIGURE 2 Stability of hydrocortisone in different povidone solutions incubated at 25°C /60% r.h.

Hydr

ocor

tison

e [%

]

100

98

96

94

92

90

0 20 40 60 80 100

Day

Kollidon 30 LP

PVP

PVP peroxide enriched

Solutions without argon

Asco

rbic

aci

d co

nten

t [%

]

100

80

60

40

20

0

0 20 40 60 80 100

Day

Solutions without argon

Kollidon 30 LP

PVP

PVP peroxide enriched

Asco

rbic

aci

d

Day

Solutions with argon

100

80

60

40

20

0

0 20 40 60 80 100


More than 70 pharmaceutical customers and R&D professionals gathered in Singapore for the two-day ExActMelt workshop to explore the in-novative hot-melt extrusion technology. Contrib-uting 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 in-novative technology for processing poorly soluble active pharmaceutical ingredients. The highly interactive two-day workshop at Republic Poly-technic in Singapore provided a much needed opportunity for intensive knowledge exchange between innovative excipient designers and man-ufacturers – 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

HOT MELT EXTRUSION

ExActMelt - improving drug efficiency with hot-melt extrusionCecil Tung

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 solubiliz-ers such as Soluplus® offer superior performance in forming solid solutions during the HME process.

“The combination of theoretical lectures and prac-tical, hands-on demonstrations allowed custom-ers to explore hot-melt extrusion in depth and make them aware of the potential to improve bio-availability and patient compliance. Additionally, the workshop was a great opportunity for custom-ers 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, continu-ing 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.

The combination of theoretical lectures and practical, handson demonstrations allowedcustomers to explore hotmelt extrusion in depth.


CEP procedure and the availability of CEP for BASF productsDominik Odenbach

REGULATORY NEWS

In order to guarantee consistent product quality, pharmaceutical manufacturers must be able to demonstrate standardized, reliable qual-ity of pharmaceutical ingredients in line with ex-isting pharmaceutical monographs. To ensure quality, the Certification Secretariat of the Euro-pean 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 in-formation 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. Accord-ing 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 CEP-based registration is processed quickly.

• IP protection The CEP dossier is only reviewed by one

pub lic regulatory body (EDQM).

Customer benefitsFor the pharmaceutical manufacturer, the CEP makes it easier to assess suppliers and their materials, without the need for conducting time-consuming and costly audits. Marketing autho-rizations are easier to manage because CEP replaces the majority of the application.

Time and costThe 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 dif-ferent health authorities, leading to multiple fees.

For the pharmaceutical manufacturer, the CEP makes it easier to assess suppliers and their materials, without the need for conducting timeconsuming 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, custom-ers will benefit from a straightforward service solution.

All of the following products have valid status and are classified under type chemistry (table 1):


Substancenumber 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

0.9 R1-CEP 1998-086-Rev 04 13/07/2010

891 Copovidone nominal K value 28 BASF SE DE 67056 Ludwigshafen R0-CEP 2007-106-Rev 00 10/10/2008

892 Crospovidone type A and B BASF SE DE 67056 Ludwigshafen Am Rhein

R0-CEP 2007-076-Rev 00 10/10/2008

761 Dexpanthenol BASF SE DE 67056 Ludwigshafen R0-CEP 2006-233-Rev 00 04/11/2008

1200 Dobutamine hydrochloride BASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2006-273-Rev 01 27/04/2010

664 Dopamine hydrochloride BASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2007-049-Rev 00 27/04/2010

487 Ephedrine hydrochloride BASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2006-234-Rev 00 16/01/2008

721 Ibuprofen BASF Corporation US 78343 Bishop R1-CEP 2000-087-Rev 01 18/07/2008

1019 Isotretinoin BASF SE DE 67056 Ludwigshafen R1-CEP 1999-068-Rev 03 07/06/2011

2052 Macrogol 15 hydroxystearate BASF SE DE 67056 Ludwigshafen R0-CEP 2006-095-Rev 02 17/11/2008

1242 Mepivacaine hydrochlorideBASF PHARMA (EVIONNAZ) SA CH 1902 Evionnaz

R1-CEP 2001-305-Rev 02 13/07/2010

1354 Oxybutynin hydrochlorideBASF PHARMA (EVIONNAZ) SA CH 1902 Evionnaz

R1-CEP 2000-108-Rev 03 13/07/2010

TABLE 1 BASF products for which CEP is available


TABLE 1 BASF products for which CEP is available

943 Oxymetazoline hydrochlorideBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2008-064-Rev 01 10/02/2010

1142 Povidone, iodinatedBASF CORPORATION US 07932 Flor-ham Park

R0-CEP 2008-179-Rev 00 02/11/2010

685 Povidone 'nominal K value 12' & 'nominal K value 17'

BASF SE DE 67056 Ludwigshafen Am Rhein

R0-CEP 2007-077-Rev 00 28/08/2009

685 Povidone 'nominal K value 25' and 'nominal K value 30'

BASF SE DE 67056 Ludwigshafen Am Rhein

R0-CEP 2007-079-Rev 00 10/10/2008

685 Povidone 'nominal K value 90'BASF SE DE 67056 Ludwigshafen Am Rhein

R0-CEP 2007-078-Rev 00 19/02/2009

1362 PrilocaineBASF PHARMA (EVIONNAZ) SA CH 1902 Evionnaz

R1-CEP 2002-227-Rev 01 13/07/2010

1363 Prilocaine hydrochlorideBASF PHARMA (EVIONNAZ) SA CH 1902 Evionnaz

R1-CEP 2002-170-Rev 01 13/07/2010

1367 Pseudoephedrine hydrochlorideBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R1-CEP 1998-009-Rev 02 29/07/2008

1260 Selegiline hydrochlorideBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R1-CEP 1999-124-Rev 02 28/02/2007

299 TheophyllineBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R1-CEP 1998-011-Rev 04 30/05/2007

302 Theophylline monohydrateBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R1-CEP 1998-010-Rev 05 28/07/2009

300 Theophylline-ethylenediamine anhydrous

BASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2007-288-Rev 01 09/02/2010

301 Theophylline-ethylenediamine hydrate

BASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2007-289-Rev 02 14/04/2010

1767 Tilidine hydrochloride hemihydrateBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2007-045-Rev 00 07/11/2008

693 Tretinoin BASF SE DE 67056 Ludwigshafen R0-CEP 2009-350-Rev 01 17/03/2011

1162 Xylometazoline hydrochlorideBASF PharmaChemikalien GmbH & Co. KG DE 67056 Ludwigshafen

R0-CEP 2006-286-Rev 00 24/11/2008

1162 Xylometazoline hydrochlorideBASF PHARMA (EVIONNAZ) SA CH 1902 Evionnaz

R1-CEP 2000-061-Rev 02 13/07/2010


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 internation-ally accepted Good Manufacturing Practices for Drug Substances and Excipients. They also meet the requirements for acceptable limits of contam-ination.

Over recent years, an increased number of re-quests for customer audits have been received. As the USP verification program does not pro-vide 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 in-ternational 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 com-mitment to ensuring patient safety by enhancing quality and authenticity throughout the supply chain. This goal is timely in the light of grow-ing 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 par-enteral 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 twoday audit based on the Rx 360 Consortium guidelines for pharmaceutical excipients.

REGULATORY NEWS

USP verification program substituted by RX-360 certification.Ralf Hadeler and Bernhard Fussnegger


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 coat-ing and film-coating equipment. To lead you to enjoy coating success, ExActCoat+ brings to-gether practical experience on materials, pro-cesses and the fascinating theory behind them, all in an interactive way. ExActCoat+ provides a platform for learning more about color deter-mination, 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.

EVENTS

ExActCoat+ Experience coating successKathrin Meyer-Böhm

FIGURE 1 Find the right contact for your specific coating question


It has been announced that the two coating poly-mers Kollicoat IR (ethylene glycol and vinyl al-cohol 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. To-gether with the monographs in the US and the EU pharmacopoeias, the inclusion of Kollicoat IR and Kollicoat SR 30 D underlines BASF’s contin-uous efforts to bring safe and innovative coating excipients to its customers – helping them them tackle today’s and future formulation challenges successfully.

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 formula-tions confirm this.

Since there is an increasing desire on the part of the industry to make better use of this tech-nology in development and manufacturing, the proposed sessions aim to provide ideas and

guidance on the various aspects of implemen-tation. These lectures are different from other HME sessions, which have focused on educat-ing scientists on the basics. Instead, the pro-posed 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 assess-ment approach when implementing this excit-ing, pioneering technology.

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.

Kollicoat® IR and Kollicoat®

SR 30 D to be published in the Handbook of Pharmaceutical Excipients

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.

Kollicoat IR, BASF’s 3rd generation instant re-lease 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 Depart-ment of Health and Ageing.

According to the TGA, Kollicoat IR (Polyethylene glycol-polyvinyl alcohol graft copolymer) is con-sidered to be safe for use as an excipient in oral medicines at concentrations of less than 5% in the finished product.

Kollicoat IR approved by Australian Department of Health and Ageing

Kollicoat IR is currently monographed in the fol-lowing pharmacopoeias:

• Ph.Eur monograph – Macrogol poly(vinyl al-cohol) 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.


Oct 23-27, 2011AAPSWashington D.C., USA

Oct 25-27, 2011CPhI WorldwideFrankfurt, Germany

October, 2011ExActCoatSão Paulo, Brazil

Nov 16, 2011ExActCoatBangkok, Thailand

Nov 21, 2011ExActCoatShanghai, China

Nov 30-Dec 2, 2011CPhI IndiaMumbai, India

March 2011APV ConferenceIstanbul, Turkey

May 9-10ExcipientfestSan Juan, Puerto Rico

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.

AsiaBASF East Asia RegionalThomas PilgramHong KongPhone: +852 [email protected]

EuropeBASF Lampertheim GmbHPeter HoffmannLampertheim, GermanyPhone: +49 621 [email protected]

[email protected]

North AmericaBASF CorporationNigel Langley, Ph.D., MBATarrytown, NY, USAPhone: +1 914 [email protected]

South AmericaBASF S.A.Fabio IkunoSão Paulo – SP BrazilPhone: +55 11 [email protected]

CALENDAR

CONTACT

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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 hot-melt 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.

PREVIEW

Soluplus® - how it solubilizes even the most poorly soluble active ingredients


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