Excipients & Actives for Pharma | No. 22, May 2009

in 2008, the pharmaceutical industry – inclu -

ding their suppliers like BASF – once again

had to realize “the world is getting smaller”

being more than just a popular phrase.

The whole story was triggered just recently

on July 1st, 2008 when the United States

Pharmacopoeia adopted the globally harmo-

nized concepts on how to regulate residual

solvents in pharmaceuticals (ICH Q3C) into

USP chapter <467>.

Shortly after the Office

of Generic Drugs (OGD)

of the FDA distributed

a remarkable letter:

“USP Chapter <467>

Residual Solvents –

Additional Information”

raising questions, par-

ticularly among globally

located ANDA holders.

BASF and a coalition of

all relevant stakeholders reacted quickly and

could help clarifying the situation: FDA re-

sponded only a couple of weeks later offer-

ing a helpful “flexible, stepwise approach to

application of USP <467> to ANDAs”.

We chose to bring this topic up aiming to illus-

trate the importance of such internatio nally

harmonized regulations.

Early 2008 BASF sites Geismar and Ludwigs -

hafen had undergone and successfully pas -

sed the USP Ingredient Verification Program.

In late 2008, all relevant pharmaceutical

actives and excipients manufactured in Lud-

wigshafen were re-inspected and certified

according to highest GMP standards (ICH

Q7). Besides that, strong efforts paid off after

additional CEP (Certificate of the European

Pharmacopoeia) applications were filed in

2006 and 2007: BASF recently obtained

twelve additional CEPs and is expecting

some more in the future.

This edition of ExAct continues with the

new troubleshooting column, gives updates

on new products, recent registrations and

planned workshops and presents technical

aspects of film coating, granule hardness

and, last not least, as announced in ExAct

21, melt extrusion for pharmaceuticals.

Yours sincerely,

Philipp HebestreitManager, Global Regulatory Affairs

ContentsMelt Extrusion for Pharmaceuticals

Pages 2 – 5

Kollicoat® – Moisture Protection with

Kollicoat® Protect

Pages 6 – 8

Troubleshooting – Film Coating Colour

Variation (Spots)

Pages 9 – 10

News: – BASF opens applications laboratory for

pharmaceutical industry in India

– An innovative method to determine

granule strength

– GMP Re-certification successfully

passed

– Residual Solvents: Recent development

of a hot topic

Pages 11 – 15

New Media: – Updated edition of DVD on BASF

excipients now available

Page 15

Preview:New Polymer for Melt Extrusion

CalendarContact Page 16

ImprintPublisher: BASF SE

Editorial staff: Thorsten Cech, Dejan Djuric,

Claudia Easterbrook, Hubertus Folttmann, Bernhard

Fussnegger, Felicitas Guth, Ralf Hadeler, Hendrik

Hardung, Philipp Hebestreit, Michael Herting,

Karl Kolter, Angelika Maschke, Kathrin Meyer-Böhm,

Vanessa Occhipinti, Andres-Christian Orthofer,

Inge Rademacher, Florian Wildschek

Concept/layout: Château Louis Strategische

Markenführung und Kommunikation GmbH

Print: johnen-druck GmbH & Co. KG

Dear Reader,

Philipp Hebestreit Manager,Global Regulatory Affairs

Trademarks are owned by BASF SE

INTRODUCTIONHot melt extrusion is an estab-

lished manufacturing process

that has been used in the plas-

tics and food industry since the

1930s.

In the 1980s, BASF SE was the

first to apply the melt extrusion

process based on polymers with

a high glass transition tempera-

ture, like polyvinylpyrrolidones,

to pharmaceuticals [1].

Later on, Soliqs, the drug deliv-

ery business of Abbott GmbH &

Co KG, commercialized the tech-

nology and launched several

drugs [2].

Hot melt extrusion is generating

more and more interest as the

percentage of poorly soluble new

chemical entities in drug devel-

opment is constantly increasing.

For such molecules hot melt

extrusion offers an opportunity

to make them orally bioavailable

[3]. Additional benefits are crea-

tion of a reliable drug release

profile and a robust manufactur-

ing process which can be run in

every pharmaceutical factory.

However, as with other break-

K. Kolter, A. Maschke

Melt Extrusion for Pharmaceuticals

Excipients & Actives for Pharma

through innovations, nume rous

obstacles had to be overcome

before commercialization of the

technology and resulting dosage

forms. Compared with other phar-

maceutical technologies like tab-

leting, hot melt extrusion is still

an emerging technology whose

potential has not yet been fully

explored.

The technology itself can be de-

fi ned as a process where a mate-

rial which melts or softens under

elevated temperatures and pres-

sures, is forced through an ori-

fice by screws.

A prerequisite of a polymer to be

used in melt extrusion is thermo-

plastic behavior, however, the

number of such polymers ap-

proved for pharmaceutical use is

limited.

BASF offers polymers with differ-

ent structures and properties for

use in melt extrusion.

In this article we will describe the

suitability of polymers for melt

extrusion, and highlight polymer

properties required for the

process.

Based on the selection of a suit-

able polymer, pharmaceutical

companies can improve dosage

form characteristics as well as

shorten the time to bring a new

drug to the market.

Extrusion processIn principle an extruder consists

of a barrel with screws inside

forcing a material through a die

and shaping it (Figure 1). The

barrel can be heated to plasti-

cize the material and reduce its

viscosity. Since the extruder is

fed at one side and the extruded

material exits it from the other

side, it is a typical continuous

process, which makes it even

more attractive [4].

In most cases corotating inter-

meshing twin-screw extruders

are used. The powder is usually

gravimetrically dosed into the

extruder, heated and more or less

melted in the first part, thereafter

mixed and homogenized by

kneading elements, and at the

end extruded through a die which

can have various shapes. Resi-

dence times in the extruder vary

depending on the screw speed,

screw configuration and feed

rate but range typically from 0.5

to 2 minutes.

Drug delivery systemsHot melt extrusion is mainly used

to formulate poorly soluble ac-

tives as solid dispersions [5]. Of

the various types of solid-solid

systems or solid dispersions,

three are of significant pharma-

ceutical relevance.

Since the poly mer used is usual-

ly amorphous, the drug can be

incorporated either in a crys-

talline state or an amorphous

state or it can be molecularly

dissolved (Figure 2). Based on

the physical status of the drug

and the concentration, the sys-

tem is either thermodynamically

stable or kinetically controlled.

The most reliable and safest sys-

tem is when the drug is molecu-

larly dissolved below the satura-

tion solubility. In this case with-

out severe impact from the envi-

ronment, like uptake of humidity,

no crystallization or change of

the release profiles will occur.

Die

Melting

ScrewTempering

accordings to Thommes (13)

Cylinder

Temperature: above Tg of polymer (80 – 180 °C)Residence time: variable (0.5 – 5 min)

Shaping Mixing

Powder

Extru

date

Engine

Figure 1: Principle of Melt Extrusion Figure 2: Relevant Types of Solid Dispersions

Drug: crystalline amorphous molecularly dissolved

Polymer: amorphous amorphous amorphous

Thermo-dynamic almost stable unstable stable (drug belowstability: (kinetically controlled) saturation solubility)

No. 22, May 2009 | PAGE 3

Based on the pH-dependent

solubility of the polymer, instant-

release, enteric or sustained-

release drug delivery systems

can be developed. The selection

of the polymer strongly deter-

mines the release rate of the

drug (Figure 3). In most cases

instant-release systems have

been developed and commer-

cialized so far.

Polymers for melt extrusionThe polymer must exhibit ther-

moplastic characteristics in order

to permit the melt extrusion pro-

cess and it must be stable at ex-

trusion temperatures. Other rele-

vant characteristics are: suitable

Tg (50 – 180 °C), low hygroscop-

icity and no toxicity since larger

amounts of polymer are applied

(Figure 4). Polymers with a high

solubilization capacity are particu-

larly suitable because large

quantities of drugs can be dis-

solved. Some features like

lipophilicity, solubility parameter

[6, 7], hydrogen bonding accep-

tors or donors [8] and amide

groups are basic prerequisites

for a high solubilization capacity,

as they are for organic solvents

(Figure 5). This explains why

povidone and copovidone are

highly suitable for melt extrusion.

In particular copovidone is much

more lipophilic than many other

water-soluble polymers which

contain hydroxyl groups and,

therefore, best meets the lipo-

ph ilicity of poorly soluble drugs.

Where the drug is incorporated

in a supersaturated form the

whole mixture should have a

very rigid structure in order to

minimize crystallization either

from dissolved drug or from

amorphous drug particles [9].

The formulation, being a solid

solution, dissolves in gastric or

intestinal fluids to form a super-

saturated solution of the drug,

thus enhancing dissolution and

bioavailability [10].

Saturation solubility of drugs in

various polymers was determi -

ned using a film casting proce-

dure out of a drug-polymer solu-

tion in dimethyl formamide.

The casted solution was vacuum

dried at 50 °C. Thereafter the

drug containing polymer film was

stored at ambient conditions for

14 days. Appearance of crystals

in the film proves that saturation

solubility was exceeded whereas

clear transparent films indicate

that saturation solubility was not

reached.

Highest saturation solubilities

were achieved for Kollidon® VA

64 and Kollidon® 30 (Figure 6).

Kollidon® VA 64 Kollicoat® MAE 100P Kollidon® SRKollidon® (Povidone) Eudragit® L 100-55 Polyvinyl acetateKollicoat® IR HPMCAP ECHPMC HPMCAS Eudragit® RSHPCLutrol® F gradesEudragit® EPEG

IR Enteric SR

Figure 3: Polymers for Different Release Profiles

Figure 4: Relevant Polymer Charasteristics

Figure 5: Solubilization Capability

Figure 6: Solubilization Capability

Hygros -copicity

Long termstability

Targetedreleaseprofile

Glasstransitiontempera-

ture

Meltviscosity

Solution &solubilizingcapability

Thermo-stability of

drug &polymer

Physico-chemicalpropertiesof active

Drug +Polymer

Impacts on solubilization capabilityLipophilicitySolubility parameterHydrogen bondingsAmide structures acting as hydrogen acceptors

Excellent solventsDimethyl acetamideDimethyl formamidePyrrolidoneMethyl pyrrolidone

Poor solventsMethanolAcetone

Excellent polymersKollidon VA 64Kollidon 30

Poor polymersKollicoat IRHPC

N C

0

C

C O

OH

,Similia similibus solvuntur‘

Evaporates were prepared with 10, 25, 33 and 50% drug content

Drug content [% dissolved in polymer]

Polymer

Kollidon VA 64

Kollidon 12 PF

Kollidon 30

Kollidon SR

KollicoatMAE 100P

Carbamazepine 17-β- Estradiol Piroxicam Clotrimazole

≥50

33-50

≥50

33-50

33-50

≥50

33-50 33-50 33-50

≥50

≥50

≥50

33-50

33-50

33-50

33-50

33-50

33-50

≥50

≥50

Excipients & Actives for Pharma

Plasticizers added to the poly-

mer can reduce glass transition

temperature and melt viscosity,

and facilitate the extrusion

process [12]. Some actives may

also have a plasticizing effect.

When the process is run at high-

er temperatures there can be an

impact on the polymer itself, like

degradation or discoloration.

This limits the applicable extru-

sion temperature. In figure 9

individual ranges are given, but

whereas Kollidon VA 64, Kollidon

Extrudability is mainly determin-

ed by the glass transition tem-

perature and melt viscosity [11].

Materials of a high molecular

weight generate a high melt vis-

cosity and can hardly be extrud-

ed. A high glass transition tem-

perature requires high process-

ing temperatures which can

degrade sensitive actives. As a

general rule, extrusion processes

should be run at temperatures

20 – 40 °C above glass transition

temperature. Most polymers

demonstrate thixotropic behavior

which means that the viscosity

declines as a function of increa s-

ing shear stress.

Taking both characteristics into

consideration (Figure 7, 8) Kolli-

don VA 64 and Kollidon 12 PF

reveal excellent suitability for

extrusion. Povidones of higher

molecular weight are difficult to

extrude because of higher glass

transition temperatures and melt

viscosities.

12 PF, Kollidon SR and Lutrol

F 127 remain almost unchanged,

Kollicoat IR and Kollicoat Protect

granules were not completely

soluble. In order to achieve a

completely soluble material, a

plasticizer like polyethylene gly-

col should be incorporated and,

thereby, the extrusion tempera-

ture lowered to 100 °C.

Shear stress controlled rotational rheometer (Rheometrics SR5) plate plate geome-

try angular frequency: 1.6 rad/s

Figure 7: Glass Transition Temperatures of Polymers Figure 9: Temperature Range for Extrusion (Pure Polymers)

Figure 8: Melt Viscosity as a Function of Temperature

Kolli

don

VA 6

4

Kolli

don

12 P

F

Kolli

don

30

Kolli

don

90 F Ko

llido

n SR

Kolli

coat

IR

Kolli

coat

MAE

Lutro

l F 1

27

Tg /

Tm [°

C]

Tg [°C] Tm [°C]

10190

149 156 152

208

114

57

39

Temperature [°C]

50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230

Kollidon 12 PF

Lutrol F 127

Kollidon VA 64

Kollidon SR

Kollicoat IR

Kollicoat Protect

Visc

osity

[Pa

• s]

Temperature [°C]

Kollidon 12 PF

Kollidon VA 64

Kollicoat MAE Kollidon 30

Kollidon SR

1000000

100000

10000

1000

100120 140 160 180 200 220 240

250

200

150

100

50

0

CONCLUSIONS

� Melt extrusion is an excellent process to formulate poorly

soluble drugs and to improve bioavailability.

� Choice of an appropriate polymer is crucial for the formulation

and the process.

� Most important polymer features are:

� Tg and melt viscosity

� Solubilization capacity

� Stability

� Regulatory status

� Formulation properties can be adjusted by use of plasticizers

and solubilizers.

� Formulation should be thermodynamically stable.

No. 22, May 2009 | PAGE 5

REFERENCES

[1] H. H. Görtz, R. Klimesch, K. Lämmerhirt, S. Lang, A. Sanner and R. Spengler,

Verfahren zur Herstellung von festen pharmazeutischen Formen, EP 0240904 B1.

[2] J. Breitenbach and B. Wiesner, The use of polymers in pharmaceutical melt

extrusion, ExAct 20, 8 – 11 (2008).

[3] C. Leuner and J. Dressman, Improving drug solubility for oral delivery using

solid dispersions, Eur. J. Pharm. Biopharm. 50, 47 – 60 (2000).

[4] J. Breitenbach, Melt extrusion: From process to drug delivery technology,

Eur. J. Pharm. Biopharm. 54, 107 – 117 (2002).

[5] M. Crowley et al, Pharmaceutical applications of hot-melt extrusion: part I,

Drug Dev. Ind. Pharm. 33, 909 – 926 (2007).

[6] A. Forster, J. Hempenstall, I. Tucker and T. Rades, Selection of excipients for

melt extrusion with two poorly water-soluble drugs by solubility parameter

calculation and thermal analysis, Int. J. Pharm. 226, 147 – 161 (2001).

[7] J. E. Patterson, M. B. James, A. H. Forster and T. Rades, Melt extrusion and

spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone /

vinylacetate copolymers; Drug Dev. Ind. Pharm 34, 95 – 106 (2008).

[8] A. Foster, J. Hempenstall and T. Rades, Characterization of glass solutions of

poorly water-soluble drugs produced by melt extrusion with hydrophilic

amorphous polymers, J. Pharm. Pharmacology 53, 303 – 315 (2001).

[9] S. Janssens, H. Novoa de Armas, J. P. Remon and G. Van den Mooter,

The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid

dispersions of itraconazole, Eur. J. Pharm. Sci. 30, 288 – 294 (2007).

[10] E. Karavas, G. Ktistis, A. Xenakis and E. Georgarakis, Effect of hydrogen bonding

interactions on the release mechanism of felodipine from nanodispersions with

polyvinylpyrrolidone, Eur. J. Pharm. Biopharm. 63, 103 – 114 (2006).

[11] R. J. Chokshi, H. K. Sandhu, R. M. Iyer, N. H. Shaw, A. W. Malick and H. Zia,

Characterization of physico-mechanical properties of indomethacin and polymers

to assess their suitability for hot melt extrusion processes as a means to

manufacture solid dispersion/solution, J. Pharm Sci. 94 (11, 2463 – 2474 (2005).

[12] A. Ghebremeskel, C. Vemavarapu and M. Lodaya, Use of surfactants as

plasticizers in preparing solid dispersions of poorly soluble API, Int. J. Pharm.

328, 119 – 129 (2007).

[13] M. Thommes, Systematische Untersuchungen zur Eignung von kappa-

Carrageenan als Pelletierhilfsstoff in der Feuchtextrusion/Sphäronisation,

Ph.D Thesis, University of Düsseldorf, 2006.

An extrusion temperature range

of 90 – 140 °C for a drug-contain-

ing mixture seems to be best,

since the drug should survive the

thermal stress lasting for 0.5 – 2

minutes in a non-aqueous envi-

ronment.

In extruded drug delivery sys-

tems the polymer serves as a

matrix and, in consequence,

larger quantities are required

than in its more common use

as binder or coating agent.

It is crucial that the polymers are

non-toxic and approved in vari-

ous countries at high doses.

Kollidon VA 64 completely fulfills

this requirement. Based on toxi-

cological studies, the other poly-

mers may also be applicable in

high doses, but have not yet

been approved in such doses.

Figure 10: Regulatory Status

*according to FDA Inactive Ingredient Guide, **self-affirmed GRAS status, *** according to European regis- tration (MRP) ****grandfathered

Kollidon VA 64 +

Kollidon 30

Polyvinyl acetate

Kollicoat MAE 30DP/Eudragit L 30D

Kollicoat IR

Lutrol F 127

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+**

+****

US Europe Japan GRAS-status US

Maximumpotency * [mg]

854

75

46

67

20,4***

107

–

–

–

–

Developing an Instant Release Moisture Protective Coating Formulation based on Kollicoat® Protect as Film Forming PolymerT. Cech, K. Kolter

INTRODUCTIONA large number of active ingredi-

ents are sensitive to ambient

moisture. It is of general interest

for the pharmaceutical industry

to improve drug stability thereby

extending shelf life.

Applying a moisture protective

coating is an appropriate meas-

ure to prevent solid dosage

forms from taking up humidity.

Instead of using impermeable

and expensive packaging mate-

rials it appears advisable to test

moisture protective instant

release film coatings.

EXPERIMENTAL� MaterialsAs film forming polymer, Kolli-

coat® Protect (Kollicoat® IR:

polyvinyl alcohol 6:4; BASF SE,

Germany) was used.

To investigate the formulation’s

influence on the barrier function

water insoluble pigments and

additional additives as barrier

enhancer were tested (Table 1).

� EquipmentFilm caster: Coatmaster, Erich-

sen Testing Equipment (Ger-

many); knife with different die

gaps (150 – 500 μm); film thick-

ness: MiniTest 600B, Elektro-

Physik (Germany); transmission

tester: Permatran, Mocon (USA)

� MethodsFor the determination of the

WVTR [1] isolated films were

prepared using a Coatmaster.

To prevent sedimentation, the

dispersion was cast in three to

four thin layers (one on top of the

other), depending on the pigment

content and the film density.

RESULTSDependence of the WVTR onthe Type of PigmentsSeveral water insoluble pigments

can be used in film coating for-

mulations. In the first tests the

influence of the type of pigments

(Table 2) on the WVTR was

investigated.

Excipients & Actives for Pharma

OBJECTIVEKollicoat® Protect is a polymer

suitable for moisture protection.

In this article the dependence of

the water vapour transmission

rate (WVTR) on the tested film

formulation is investigated.

The influence of type and amount

of pigments used in the formula-

tions is tested. Furthermore,

additives (Table 1) to improve the

film barrier function are investi-

gated.

The aim is to find the instant

release film coating formulation

with the best protective prop -

erties.

Pigments Additives

1. Talc 4. Polyoxyethylene (100) stearate (Myrj® 59)2. Titanium dioxide 5. Polyoxyethylene (21) stearyl ether (Brij® 721)3. Iron oxide (red) 6. Stearic acid

7. Carnauba wax8. Lecithin9. Xanthan gum

10. Na-lauryl sulfate11. Hydrophobic fumed silica (Aerosil® R972)

Table 1: Water Insoluble Pigments and AdditivesUsed in the Formulations

Figure 1: WVTR as a Function of the Type of PigmentsUsed in the Formulations

Redu

ctio

n in

wat

er v

apor

tran

smis

sion

Formulation

0

-20

-40

-60

-801 2 3 4

Dependence of the WVTR onthe Amount of PigmentsAs water permeates the polymer

the WVTR should depend on the

amount of pigments. To test this,

the same ratio of talc and iron

oxide was mixed with different

quantities of polymer (Table 3).

A clear dependence was found

(Figure 2). The higher the content

of pigments the higher the barrier

function of the film.

It is possible to incorporate

high amounts of pigments in

Kollicoat® Protect.

Therefore, the reduction in trans-

mission compared to the poly-

mer without additives was inves-

tigated (Figure 1). If the stand-

ard deviation is considered, no

significant dependence was

observed. The WVTR seemed

to be unaffected by the type of

insoluble pigments.

No. 22, May 2009 | PAGE 7

Dependence of the WVTR onother AdditivesTheoretically, many additives can

be used as barrier enhancers.

Table 4 shows the additives test-

ed. As a starting point “Formula-

tion #7” was used. Iron oxide

Formulation

Excipient #10 #11 #12 #13 #14 #15 #16 #17

Kollicoat® Protect 50 50 50 50 50 50 50 50Talc 35 35 35 35 35 35 35 35Titanium dioxide 5 5 5 15 – – – –Iron oxide (red) – – – – 13 14.5 13 7Myrj® 59 10 – – – – – – –Brij® 721 – 10 – – – – – –Stearic acid – – 10 – – – – –Carnauba wax – – – 5 – – – –Lecithin – – – – 2 – – –Xanthan gum – – – – – 0.5 – –SDS – – – – – – 2 2Aerosil® R 972 – – – – – – – 6

Formulation

Excipient #5 #6 #7 #8 #9

Kollicoat® Protect 25 40 50 60 75Talc 67 54 45 36 23Iron oxide (red) 8 6 5 4 2

Formulation

Excipient #1 #2 #3 #4

Kollicoat® Protect 50 50 50 50Talc 15 25 35 45Titanium dioxide 30 20 10 0Iron oxide (red) 5 5 5 5

Figure 2: WVTR as a Function of the Amount of PigmentsTable 2: Dependency on the Type of Pigments

Table 3: Dependency of the WVTR on the Amount of Pigments Table 4: Dependency of the WVTR on other Additives

was partly substituted by adding

the additives from Table 4. Again

the total reduction of the WVTR

was calculated, based on the

polymer (Figure 3) and was com-

pared to the standard formula-

tion (#7).

Redu

ctio

n in

wat

er v

apor

per

mea

tion

Formulation

0

-20

-40

-60

-805 6 7 8 9

Excipients & Actives for Pharma

Conclusions� Regardless of the formulation,

coatings based on Kollicoat®

Protect offer a high barrier

function against ambient

moisture [2].

� The WVTR strongly depends

on the amount of insoluble

pigments. The higher the con-

tent, the lower the transmis-

sion rate. However, the type

of pigments is less important.

� Additives used as barrier

enhancers also increase the

brittleness of the film. Never-

theless, sodium lauryl sul-

phate and hydrophobic fumed

silica in combination offered

significant improvement.

By adding most of the barrier

enhancing excipients the proper-

ties of the isolated film got poor-

er (e.g. increasing brittleness).

Therefore, additives should only

be considered if the film’s barrier

function can be improved signifi-

cantly.

Finally, only the combination of

sodium lauryl sulphate and

hydrophobic fumed silica showed

positive results.

The reduction in the WVTR of

“Formulation 17” was about 80%.

Compared to the transmission

rate of a classical coating based

on HPMC the reduction is also

about 80% [2].

REFERENCES

[1] ASTM F-1249

[2] T. Cech, K. Kolter; Comparing

Moisture Protective Instant

Release Coatings for Solid

Oral Dosage Forms;

PBP World Meeting 2008

[3] T. Cech, Benchmarking of Instant

Release Film Coating

Polymers, Bachelor Thesis 2007

PBP World Meeting 2008, 7. – 10. April

2008, Barcelona, Spain, G-MEP/MD214

� As plasticizers are not needed

to improve the coating prop-

erties, film coating formula-

tions based on Kollicoat®

Protect are very easy to for

mulate [3].

� To enhance the protective

properties, the pigment con-

tent has to be increased. This

leads to a low viscosity of the

coating dispersion. Therefore,

adding a gel forming agent

like xanthan gum to increase

viscosity and thereby prevent-

ing sedimentation should be

considered.

Figure 3: WVTR as a Function of Different Additives

Redu

ctio

n in

wat

er v

apor

per

mea

tion

Formulation

0

-20

-40

-60

-8010 11 12 13 14 15 16 17

No. 22, May 2009 | PAGE 9

In the last issue, we addressed

the scuffing effect, which results

in dark spots on the tablets sur-

face. This time we want to ad -

dress another problem, related

to inhomogeneously coloured

tablet surfaces.

Many coated solid oral dosage

forms are manufactured with

product specific colour. If you

have ever faced problems when

incorporating pigments in a film

coating dispersion, this article

will be of particular interest to

you.

ProblemCoating dispersions usually con-

tain other ingredients. Apart from

the film forming polymer, colou-

ring agents also play a decisive

role. As most dyes and lakes

used in the pharmaceutical indu-

stry show a high tendency for

agglomeration, their homoge-

neous incorporation into the

dispersion can often be chal-

lenging.

With functional coatings, a lot of

which are latex dispersions, the

issue of the high density of dyes

and lakes introduces the issue of

sedimentation.

ReasonAs most colour formulations

consist of more than one com-

ponent, agglomerates of one

ingredient would lead to a dee-

per colour impression com-

pared to surface areas with a

more homogeneous colour dis-

tribution. These parts of the film

with a higher pigment concentra-

tion appear as more intensively

coloured spots.

However, these agglomerates

can be caused by different

effects:

Both poor de-agglomeration as

well as sedimentation can lead

to uneven colour distribution of

the colouring agent on the film

coated tablet surfaces.

Pictures 1 and 2 show this effect.

In these two examples for easier

visualisation, the process was

stopped just after applying a

small amount of coating material.

Film Coating: Colour Variation (Spots)T. Cech, F. Wildschek

Picture 1/2 – Coated tablets showing inhomogeneous colour distribution.

Trouble-shootingIdeas and solutionsfor R&D and production

Excipients & Actives for Pharma

SolutionTo overcome this effect, the

cause for the inhomogeneous

distribution of the colouring

agent has to be investigated.

Dyes and lakes in bulk have a

tendency to agglomerate, nece s -

sitating the need for care when

homogeniseing the pigments.

In some cases, though rare, it is

sufficient to break up the agglo-

merates by applying medium to

low mechanical forces (using a

mortar and pestle). But in most

cases, the agglomerates are so

strong, that more elaborate

equipment is needed (e.g. high

shear mixer).

Please keep in mind that the pig-

ments have to be homogenised

separately before mixing in with

the film forming polymer, bearing

in mind the risk of coagulation

[4.] or foam formation.

1. Sedimentation in the finally

prepared dispersion can be

prevented by continuously

stirring at low speed.

2. The tubing is an often under -

estimated part of the coating

equipment. The type, as well

as the quality of the tubing

plays a significant role on

the coating process.

1. Ineffective de-agglomeration,

while preparing the film coat-

ing dispersion.

2. Agglomeration of dispersed

pigments due to sedimenta-

tion in the vessel or beaker,

when the dispersion is not

stirred properly during the

coating process.

3. Agglomeration due to sedi-

mentation in the tubing.

This is caused when the

bore diameter is not adapted

to the spray rate. The larger

the bore diameter, the slower

the velocity of the disper-

sion, which in turn leads

to increased sedimentation

tendency. This effect can

distinctively be seen when

the tubing is either too long

or assembled in a vertical

way.

4. Coagulation of latex disper-

sions and adhesion of the

colouring agent on the tablet

surface. As latex dispersions

are very sensitive to various

influences (e.g. temperature,

mechanical stress, surfac-

tants) this point ought to be

kept in consideration as well.

To prevent sedimentation, it

is important to bear in mind

that the tube thickness and

bore diameter to be used will

depend on the flow rate, vis -

cosity of the dispersion as

well as the type of pump.

A large bore diameter would

result in a slow liquid flow

rate within the hose. This

slow speed would in turn

facilitate sedimentation

effects, especially if the tube

is assembled vertically.

It is important to keep tubing

as short as possible.

3. If the inhomogenous distri-

bution of the colour on the

tablet is due to a wrong

handling of the latex disper-

sion, it is important to criti-

cally review all other constit -

uents of the dispersion as

well as all other process

steps. As mentioned earlier,

latex dispersions being

emulsions are sensitive

systems.

In this regard, using the high

mechanical stress of high

shear mixers would imme-

diately result in the coagula-

tion of the dispersion.

No. 22, May 2009 | PAGE 11

BASF opens applications laboratory forpharmaceutical industry in India

development facilities of BASF

India Ltd. in Mumbai. It is pro -

vided with state-of-the-art

equipment allowing all the pro-

duction processes that are rele-

vant for solid dosage forms,

such as granulation, tabletting

and coating, to be carried out.

In addition, the laboratory also

has a wide range of measuring

equipment, which can be used

to analyze fundamental parame-

ters within the processes. Fin-

ished tablets can also be tested

for friability, dissolution, disinte-

gration or color deviations.

Customers can actually work in

the laboratory on site if they

wish to acquire relevant applica-

tion knowledge. They can also

take trial products made there

back to their own companies,

since the laboratory meets the

“class 100,000 area” clean

roomrequi rements.

sible for BASF’s global Pharma

Ingred ients & Services business

unit. “The new applications lab -

oratory in Mumbai is an important

milestone in achieving this aim.”

In Asia, the pharmaceutical

industry has grown particularly

through the strong market posi-

tion of generics. South and

South-East Asia have a key role

to play here. “The pharmaceuti-

cal manufacturers in the region

are operating on an increasingly

global basis now. This is pre-

senting our customers' local

research and development facili-

ties with huge challenges, such

as those associated with new

systems for releasing active

ingredients”, says Ralf Fink,

head of the regional BASF busi-

ness unit Pharma Ingredients &

Services in Asia.

The new laboratory is integrated

into the existing research and

BASF has opened an applica-

tions laboratory for pharmaceuti-

cal excipients and active ingredi-

ents in Mumbai, India. The aim is

to move even closer to custom -

ers in the key markets of the

Asia-Pacific region. The new lab-

oratory will allow BASF to meet

the requirements of the pharma-

ceutical industry for technical

support more quickly. Customers

will not only be provided with

advice about functional aspects

when choosing products, such

as the excipients Kollidon®, Kolli-

coat®, Cremophor® and Lutrol®.

BASF experts in the laboratory

will also help in optimizing for-

mulations and improving produc-

tion conditions.

“We want to make even more

improvements in the global

range of products and services

we offer our customers”, says

Martin Widmann, who is respon-

News

All the latest from theworld of excipientsand active ingredients

Martin Widmann (left), head of the business unit Pharma Ingredients & Services, and Prasad Chandran (middle), head of BASF

India, at the inauguration of the new lab.

The new laboratory in Mumbai is

the second BASF facility of this

type in Asia, along with a further

applications laboratory in

Shanghai.

Excipients & Actives for Pharma

An innovative method todetermine granule strengthTh. Cech, D. Djuric, M.G. Herting

INTRODUCTIONFor characterization of granules,

the particle size distribution is

the most commonly used para-

meter. However, strength of gra-

nules is another very important

factor to be considered. Granule

strength has to be sufficient to

allow further handling of the

gran ules (e.g. storage in a bulk

or compression). There are

methods described in literature

to determine the strength of gra-

nules. Inghelbrecht and Remon

(1998) described a method,

where the apparatus for determi-

nation of friability of tablets as

described in Ph.Eur. was used

[1]. However, due to the addition

of a defined number of glass

beads the mechanical strength

applied to granules was very

high. The methods for determi-

nation of granule strength des-

cribed in the Ph. Eur. need the

purchase of dedicated equip-

ment or the set up of a new

apparatus that is not commer -

cially available [2]. For measure-

ments using an air-jet sieve no

special equipment has to be

provided. Additionally, none of

the already described methods

in literature allow the handling

in a contained system.

Therefore, the purpose of this

study was to evaluate a new

method for the determination of

granule strength using an air-jet

sieve. During air-jet sieving parti-

cles are fluidized, thrown against

the sieve lid and against each

other. These movements induce

mechanical stress on the granules

leading to abrasion and breakage.

MATERIALS AND METHODSMaterials The following materials were

used as received: Copovidone

(Kollidon VA 64® Fine, BASF,

Germany) and Lactose (Granu-

Lac® 230, Molkerei Meggle,

Germany)

Production of granulesRoll compactor (Mini-Pactor

250/25, Gerteis, Switzerland)

was equipped with smooth rim

rolls of 250 mm diameter and

25 mm width. The gap between

the rolls was kept constant at

3 mm. Speed of rolls was set to

1 rpm. Granules were produced

at different specific compaction

forces (2, 4, 6 and 8 kN/cm) to

obtain granules of different

strength.

Resulting ribbons were directly

granulated with a pocket mould

grooved granulator using a

1.25 mm sieve.

Fines of granule samples were

removed prior to measurement

to assure same starting condi -

tions and to consider solely

agglomerated material. This

removal of fines was performed

at a low flow rate of 20 m³/h for

1 minute. Friability of granules

was estimated and defined as

loss of mass in percent after

sieving at different flow rates

(30, 50 and 70 m³/min) and times

(1, 3, 5, 10 and 15 min).

For each excipient the determi-

nation was conducted 3 times

and the mean value and standard

deviation was reported.

ResultsThe examined flow rates allowed

differentiation between granule

batches produced with different

compaction forces (Figure 3).

At flow rates of 30 m³/h and pro-

cess time of 5 min friability ran-

ged from 45.7% (2 kN/cm) to

6% (8 kN/cm).

Figure 1 – Particle movement during

measurement (used with permission of

Rhewum GmbH)

Figure 2 – Air jet sieve LPS 200,

Rhewum

30 m3/h

1 min 3 min 5 min 10 min 15 min

With higher volume flow rates

and sieving time particle move-

ment and thus mechanical stress

is increasing (Figure 1).

SamplingPrior to further analysis the

powders and granules were divi-

ded using a rotary sample divi-

der (PT 100, Retsch, Germany)

in order to obtain representative

samples with adequate amounts

of all particle fractions.

Friability of granulesGranule friability as an estimate

for granule strength, was deter-

mined with an air-jet sieve (LPS

200, Rhewum, Germany) (Figure

2) equipped with a 125 µm sieve.

Figure 3: Friability of granules (30 m3/h) produced at various specificcompaction forces (n = 3, mean ± s)

friab

ility

[%]

100

specific compaction force [kN/cm]

75

50

25

00 2 4 6 8

No. 22, May 2009 | PAGE 13

RE

GU

LAT

OR

Y A

FFAIR

S

GMP Re-certification successfully passed

1. 12 new CEPs2. 4 new monographs

1. New CEPsActives1. Tilidine hydrochloride

hemihydrate

2. Dobutamine hydrochloride

3. Dopamine hydrochloride

4. Xylometazoline hydro-

chloride

5. Theophylline Ethylene-

diamine (Aminophylline)

6. Theophylline Ethylene-

diamine hydrate

(Aminophylline hydrous)

7. Dexpanthenol

8. Acitretin

Excipients1. Crospovidone Type A and

B (Kollidon® CL, CL-M,

CL-F, CL-SF, Crospovi-

done C)

2. Copovidone Nominal

K-value 28 (Kollidon® VA 64,

VA 64 Fine)

3. Povidone Nominal K-value

25 and Nominal K-value 30

(Kollidon® 25, Kollidon® 30)

4. Povidone Nominal K-value

90 (Kollidon® 90 F)

2. New pharmacopeial monographsUSP/NF Pharmacopeial Forum,

Vol. 35 (1); Jan-Feb 2009:

� Polyvinyl Acetate Dispersion“

(Kollicoat® SR 30 D)

� Polyoxyl 15 Hydroxystearate“

(Solutol® HS 15)

USP/NF Pharmacopeial Forum,

Vol. 35 (2); Mar-Apr 2009:

� Ethylene Glycol and Vinyl

alcohol Graft Copolymer

(Kollicoat® IR)

Food Chemical Codex (FCC)

Supplement 1, 2009:

� Copovidone (Kollidon® VA 64)

For the first time in 2006 the pro-

duction plants in Ludwigshafen

manufacturing Active Pharma-

ceutical Ingredients and Exci-

pients passed successfully the

GMP Inspection of the German

Regulatory Authorities. This

Inspection followed the require-

ments of the ICH Q 7 Guideline.

The GMP Certificate is valid for

three years. Therefore the Re-

Inspection of the authority took

place in November 2008 and

covered additionally the Glycol-

Plant. The availability of both

the GMP Certificate and specific

CEPs enables our customers

to register these Excipients as

atypical Actives.

Using flow rates of 70 m³/h the

friability ranged from 93.5%

(2 kN/cm) to 23.9% (8 kN/cm)

(Figure 4). Altering the time at a

constant flow rate allowed a

clear distinguishing of the diffe-

rent granules. At low flow rates

the required time for differenti -

ation between different granules

Conclusion

Using an air-jet sieve proved to

be a fast and easy method for

measuring granule strength.

The process showed an excel-

lent reproducibility. In contrast

to other methods, it can be used

for high potential drugs as the

whole procedure is performed

in a contained system. Altering

process time or flow rate en-

abled differentiation between

granules of different strength.

70 m3/h

1 min 3 min 5 min 10 min 15 min

REFERENCES

[1] S. Inghelbrecht, J.P. Remon: Interna -

tional Journal of Pharmaceutics 161

(1998), 215 – 224

[2] European Pharmacopeia 6.2, 2.9.41

Friability of granules and spheroids

(2008), 330 – 331

had to be higher than 5 min.

For high flow rates a process

time of 1 min was sufficient.

The standard deviation did not

exceed 1.6% in all performed

trials indicating a very robust

and reproducible method.

Figure 4: Friability of granules (70 m3/h) produced at various specificcompaction forces (n = 3, mean ± s)

friab

ility

[%]

100

specific compaction force [kN/cm]

75

50

25

00 2 4 6 8

Excipients & Actives for PharmaExcipients & Actives for Pharma

The deliberate choice of an ade-

quate solvent may be crucial for

the whole pharmaceutical pro-

cess to achieve the designated

characteristics of a product.

This applies to the manufacture

of drug substances, excipients

and the formulation of drug pro-

ducts, respectively.

BackgroundAccording to Guideline ICH Q3C

‘Note for Guidance on Impuri-

ties: Residual Solvents’, residual

solvents in pharmaceuticals are

defined as organic volatile che-

micals that are used or produced

in the manufacture of drug sub-

stances or excipients, or in the

preparation of drug products [...]

The guideline does not address

solvents deliberately used as

excipients nor does it address

solvates. However, the content

of solvents in such products

should be evaluated and justi-

fied. The Guideline lists toxicol -

ogically acceptable limits for

cases where the solvent cannot

completely be removed from the

final product during the manu-

facturing process.

USP adopted this ICH Guidance

in its General Chapter <467>

“Residual Solvents”. This guid-

ance which was already adop-

ted in Europe for a long time

(Ph.Eur. General Chapter 5.4)

became official as of July 1st,

2008 replacing General Chapter

<467> “Organic Volatile Impuri-

ties”.

The purpose of the revised

chapter is to limit the amount of

solvent that patients receive.

The USP General Notices require

all drug substances, excipients

and products meet the require-

ments in General Chapter <467>

by July 1st 2008. Pharmaceutical

manufacturers that adopted the

requirements of General Chapter

<467> Residual Solvents prior to

July 1st 2008 are expected to

meet the monograph require-

ments for Organic Volatile Impu-

rities.

In <467>, residual solvents have

been separated into three clas-

ses based on their potential toxi-

city level. Class 1 residual sol-

vents are known to cause unac-

ceptable toxicities. Class 2 resi-

dual solvents are associated

with less severe toxicities and

Class 3 residual solvents are

considered the least toxic.

Testing should be performed for

those residual solvents that are

used or produced in the manu-

facture or purification of these

drug substances, excipients or

drug products. For finished pro-

duct, the client may choose to

test either all the individual com-

ponents or the final finished pro-

duct. The USP has stated that a

company does have the option

to develop and validate their

own internal method for deter -

mining residual solvents rather

than using the USP Residual

Solvents <467> method.

StoryIn August 2008, FDA’s Office of

Generic Drugs (OGD) issued a

related draft guidance, Residual

Solvents in Drug Products Mar-

keted in the United States,

stipulating further requirements

exceeding all current guidance,

including USP <467>. At that

time, BASF already met both,

ICH and USP requirements for

its globally marketed products.

Consequently, although being

fully compliant with both ICH

and USP, BASF and many other

suppliers to the pharmaceutical

industry suddenly faced a multi-

tude of urgent requests, mainly

triggered by FDA OGD to ANDA

holders which caused a number

of problems and confusion

regarding the draft guidance and

communications received from

FDA’s OGD, that conflicted with

Chapter <467> of USP.

As a consequence, FDA received

many comments from a vast coa-

lition of stakeholders requesting

additional clarification regarding

the implementation of USP

<467> for generic drugs with

BASF comments submitted

directly and via its trade associa-

tions APIC and SOCMA as soon

as of October 1st.

That`s why on October 10th,

2008, FDA met with these core

industry groups IPEC Americas,

IPEC Europe, GPhA, CHPA,

PhRMA, and SOCMA BPTF to

discuss implementation of USP

<467> and the OGD draft guid -

ance.

Residual Solvents: Recentdevelopment of a hot topicP. Hebestreit

No. 22, May 2009 | PAGE 15

NewMedia

Information on BASF products Late 2005 BASF launched the

first edition of a DVD on BASF’s

broad excipients range. New pro-

ducts launched in recent years

called for an update. This updat-

ed video provides an excellent

overview of our pharmaceutical

excipients, their functionalities

and applications. It also gives an

impression about the quality

standards applied in the produc-

tion of these ingredients. The

DVD can be ordered with the

attached reply card.

©2009

BASFSE

EMP090401e-01

www.pharma-ingredients.basf.com

Pharma Ingredients & Services

Video onBASF Excipients

The updated edition of DVD on BASF excipients now available

Four key areas of concern were

discussed:

� 1: Specific testing versus con-

trol — Industry, said the coali-

tion, believes that the focus

should be on adequate controls

as oppos ed to analytical testing

on each residual solvent (ade-

quate controls being e.g. justifi-

cations of omission of analytical

testing of certain solvents).

� 2: Identification of Class 3

solvents — the coalition felt that

there was no justifiable reason

why Class 3 solvents need to

be identified providing that the

levels are below 0.5%.

� 3: Use of Class 1 solvents —

the coalition asked FDA to esta-

blish what types of information

would be needed to warrant the

contin ued use of Class 1 sol-

vents in certain cases as long

as the levels are below the limits

listed in <467> for these solvents.

� 4: Need for immediate relief

while awaiting revised guid -

ance — the coalition requested

that FDA quickly develop a

mechanism and a path forward

to address the many pending

ANDAs from both a short-term

and a long-term perspective.

The FDA OGD had considered

these comments and sugges -

tions and provided clarifying

questions and answers on Oc-

tober 28th. These clarifications

include a flexible, stepwise

approach to application of USP

<467> to ANDAs to ensure avail-

ability of low cost, high quality,

safe, and effective generic drugs

that meet USP <467> require-

ments.

ConclusionThis Coalition for Rational Imple-

mentation of USP General Chap-

ter <467> was doing a good job

of getting FDA’s attention and

received a quick response (Q&A

letter of October 28th). Essential-

ly this was perceived as a big

relief, particularly with regard to

ANDA holders and their sup-

pliers like BASF.

This exemplarily demonstrates

that it’s up to us as suppliers to

the pharmaceutical industry to

implement internationally ac-

cepted standards available in

global regulations like ICH.

We had to learn that it particular-

ly applies when it comes to dis-

cussions on regulations which

are best known by the ones

which are affected by these regu-

lations on a day-to-day basis: us

as industry working with such

regulations, complying with them

and in case they are unrealistic,

explain why and provide alterna-

tives to the agencies.

“Anticipatory obedience” is pro-

bably the easiest way but in the

long term, it will lead to -step-

by-step- increasing regulatory

requirements.

July 18–22, 2009*The 36th Annual Meeting and

Exposition of the Controlled

Release Society

Copenhagen, Denmark

October 13-15, 2009*CPhI Worldwide

Madrid, Spain

November 8-12, 2009*AAPS Annual Meeting and

Exposition

Los Angeles, CA, USA

March 8-11, 20107th World Meeting on Pharma-

ceutics, Biopharmaceutics

and Pharmaceutical Technology

Valetta, Malta

July 10-14, 2010The 37th Annual Meeting and

Exposition of the Controlled

Release Society

Portland, Oregon, USA

November 14-18, 2010*AAPS Annual Meeting and

Exposition

New Orleans, Lousiana, USA

* BASF participation

Calendar

Important dates

ContactWhat opportunities can weopen up for you? Simply contact your local BASF

representative or one of the regional

offices listed below.

Alternatively, visit our website

www.pharma-ingredients.basf.com

AsiaBASF East Asia Regional

Headquarters Ltd.

Pharma Ingredients & Services

Thomas Pilgram

45th Floor, Jardine House,

No. 1 Connaught Place,

Central, Hong Kong

Phone: +852 27311-589

thomas.pilgram@basf.com

EuropeBASF SE

Pharma Ingredients & Services

Peter Hoffmann

G-EMP/EM – J 550

67056 Ludwigshafen

Germany

Phone: +49 621 60-76928

peter.wolfgang.hoffmann@basf.com

North AmericaBASF Corporation

Pharma Ingredients & Services

Javier Beeck

100 Campus Drive

Florham Park, NJ 07932

USA

Phone: +1 973 245-6381

javier.beeck@basf.com

South AmericaBASF S.A.

Pharma Ingredients & Services

Flavia de Assis e Souza

S-EM/VPP

Avenida Faria Lima, 3600 – 9th floor

04538-132 São Paulo – SP

Brazil

Phone: +55 11 3043-2237

flavia.souza@basf.com

Would you like to discuss a particular

challenge or product in more detail?

Or do you have any questions?

Simply call or e-mail us. We would

be glad to help.

EM

P 0

4010

2e-2

2

Preview

In the next issue of ExAct

The demand for solubilizers and

techniques to overcome poor

solubility and bioavailability of

new APIs (active pharmaceutical

ingredients) has greatly increased

in the past years and a stronger

growth in the near future is

expected.

In many cases, the development

of solid oral dosage forms is not

possible and therefore the poorly

water soluble API must be

formulated in a parenteral formu-

lation. Because of their conven-

ience, solid oral dosage forms

are preferred compared to par-

enteral formulations which have

to be injected in many cases by

a physician.

A new technique which is gain-

ing increasing interest in the

pharmaceutical industry is melt

extrusion. This technique and

the suitability of polymers for

melt extrusion are discussed in

this issue of ExAct. However, the

polymers available on the market

have not been developed for

melt extrusion but for other pur-

poses such as dry binders.

BASF has developed a new poly-

mer particularly for melt extru-

sion in order to cope with bio-

availability and solubility hurdles.

Besides other topics, the next

ExAct issue will approach the

topic with this innovative poly-

mer.

New Polymer for Melt Extrusion

Excipients & Actives for PharmaExcipients & Actives for Pharma