Kollicoat® MAEEnteric coating.

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The Preface2

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Trademarks are owned

by BASF Aktiengesellschaft

Kollicoat® MAE 30 DP is anaqueous dispersion, Kollicoat®

MAE 100 P the correspondingredispersable powder grade.Both products can be applied inaqueous spraying formulas andare not burdened with thedisadvantages arising fromorganic solvents. Sub- and topcoatings are normally unnec-essary. Kollicoat® MAE 100 P canalso be sprayed from organicsolvents if required.Tablets coated even with smallamounts of Kollicoat® MAE with-stand gastric juices as well asrigours of handling, packing andstorage, exhibiting stable en-teric release profiles. Production times with aqueous Kollicoat® MAE 30 DP are com-paratively short, leading to reduced manufacturing costs.When exposure to extremeclimatic conditions (frost or tem-peratures > 30°C) cannot beexcluded during transport or stor-age, the redispersable powderKollicoat® MAE 100 P is theenteric coating material tochoose.

Kollicoat® MAE provides aneffective barrier to gastric juicewhich

■ protects the stomach from drugs such as indomethacin, diclofenac or aspirin,

■ protects acid-sensitive drugs, e. g. pancreatin from the contents of the stomach,

■ increases the bioavailability of active ingredients so that high local drug concentrationsare achieved in the small intestine increasing the bioavailability or

■ releases the active ingredient, e. g. laxatives, at its site of action, the intestine.

Kollicoat® MAE 30 DPand Kollicoat® MAE 100 P

(methacrylic acid/ethylacrylate copolymer) are

“state of the art” film-forming agents for a

reliable, convenient andcost-saving enteric

coating of solid oraldosage forms.

The Product 3

Product forms:Kollicoat® MAE 30 DP ismarketed as an aqueousdispersion with a solids contentof 30 %. The milky white, low-viscosity product has a faint,characteristic odour.

The dispersion contains 0.7 %sodium lauryl sulfate (USP) and2.3 % Polysorbate 80 (Ph. Eur.) asemulsifying agents. The per-centages in each case refer to thesolids content.

Kollicoat® MAE 100 P is a white,redispersable powder, originatingfrom the Kollicoat® MAE 30 DPdispersion. Prior to spray dryingthe dispersion is partially neutrali-zed with NaOH. This eases redis-persion for the final formulation ofthe spray suspension. The prod-uct consists of 95.8 % copolymer,max. 2.3 % Polysorbate 80 (Ph.Eur.) and max. 0.7 % sodiumlauryl sulfate (USP). About 1.2 %sodium hydroxide was applied forneutralisation.

Both Kollicoat® MAE grades areweakly acidic and dissolve at apH above 5.5.

Trivial names:Methacrylic Acid CopolymerDispersion (USP-NF), MethacrylicAcid Copolymer LD (JPE), andMethacrylic Acid-Ethyl AcrylateCopolymer (Ph. Eur.).

Pharmacopoeia:Kollicoat® MAE 30 DP complieswith the requirements of theEuropean Pharmacopoeiamonograph “Polyacrylatedispersion 30 %”, the USP-NFmonograph “Methacrylic AcidCopolymer Dispersion” and theJPE monograph “MethacrylicAcid Copolymer LD”.

Structural formula:Kollicoat® MAE gradesare copolymers de-rived from methacrylicacid/ethyl acrylate.

CH3

CH2 C

COOH

CH2 CH

COOC2H5n m

The ratio of the components in the copolymer is roughly 1:1.The average molecular weight is in the order of 250,000.

The Application4

Perforated pan coater

Kollicoat® MAE applied in lowcoating levels, 0.5–2.0 mg/cm2

solids, can be used for thefollowing purposes:

■ Masking unpleasant tastes andodours

■ Protecting incompatible activesubstances

■ Protection against atmo-spheric humidity (short-term)

Kollicoat® MAE applied in highcoating levels, e. g. 10 to 20 mg/cm2 is able to protect drugs during long-term storage against humidity. Even hygro-scopic drugs or drugs sensitive to hydrolysis can be coated with this aqueous dispersion by usinga reduced spraying rate at thebeginning of the coating process.

Kollicoat® MAE can beapplied as enteric

coating to all conven-tional solid oral dosage

forms, e. g. tablets,capsules, pellets andgranules. The normal

amount of polymerapplied is 4–6 mg per

cm2 of tablet surface, or10 to 30 % by weight on

particles such aspellets, granules or

crystals with sizes inthe range of about 0.5

to 3.0 mm.

Tablet-coating made simple.

In combination with sustained release polymers Kollicoat®

MAE slows down a too quickrelease of active material in theinitial phase of dissolution.

Kollicoat® MAE 30 DP andKollicoat® MAE 100 P can beprocessed as aqueous polymerdispersions in all film-coating orfluidised-bed equipment that iscommonly used in the pharma-ceutical industry. Kollicoat® MAE100 P can also be sprayed fromorganic solution. Perforatedcoating pans are particularly suit-able for tablets whereas fluid-bedcoaters are preferred for small par-ticles that have a stronger ten-dency to agglomerate.

The Formulation 5

Fluid bed coater

The recommendedaddition rate ofplasticizer is 10–25 %,referred to the drypolymer. 1.2-propyleneglycol improves theprocessability andenteric resistance of thefilm coatings andshould be the preferredplasticizer. Triethylcitrate also exhibitsgood properties withregard to the resistanceagainst gastric juice.

Instructions for processing:

It is essential to add plasticizer to improve the flexibility of the films. Suitable plasticizers or gloss intensifiers are■ 1.2-Propylene glycol■ Triethyl citrate■ Polyethylene glycols and■ Triacetin

Spray suspensions with a15–30 % solids content give good results and the shortest spraying times.

The following recommendations are made to avoid problems in incorporating excipients in the aqueous suspensions:■ Dilute the dispersion to a

solids content of 20 %■ Stir the desired excipient in

the form of a dilute solution orsuspension into the dispersion.

The direct addition of pure plasti-cizer or pigments to the undilutedfilm-former can cause coagulation.

The following excipients canbe used in formulas with Kollicoat® MAE grades:

Release and smoothing agents■ Talc■ Syloid■ Aerosil■ Kaolin

Colorants for the film coatings■ Titanium dioxide■ Colored pigments

(e. g. iron oxides)

The polymer in these Kollicoat® MAE products has a high pigmentbinding capacity, with the result that up to twice the amount ofpigments or other excipients maybe added.

Stabilizing agents(usually not necessary)■ Nonionic emulsifiers, e. g. ■ Cremophor® RH 40 ■ Lutrol® F68

Antifoaming agents(usually not necessary)■ Simethicone

The Example6

Colored entericfilm coating

based on Kollicoat®

MAE 30 DP

Coating pan Accela CotaSize of batch 5 kgInlet air temperature 60 °C/140 °FProduct temperature 30–35 °C/86–95 °FRate of spraying 40 g/minTime of spraying 30 minPressure 2–3 bar

Machine parameters:The spraying trials were performed in a Manesty 24"Accela Cota coating pan.

Solids content of the spray suspension: 22.3 %Content of polymer (solids): 15.0 %Polymer applied: 4.8 mg/cm2

Total solids applied: 7.0 mg/cm2

Composition of the spray suspension:The formula for 5 kg of cores(diameter 9 mm; weight 330 mg):

Coating suspensionKollicoat® MAE 30 DPPropylene glycolWaterPigment suspensionIron oxide red 30Titanium dioxideTalcWater

Parts by weight [g]

60027

393

66

48120

1,200

% composition

50.02.3

32.7

0.50.54.0

10.0100.0

7

Preparation of the spraysuspension withKollicoat® MAE 30 DP:

■ Coating suspension.Propylene glycol is first stirredinto the given amount of water.Then Kollicoat® MAE 30 DP is stirred in.

■ Pigment suspension.Iron oxide red 30, titanium dioxide, and talc are intensively stirred in water andhomogenized (corundum disk mill or Ultra Turrax).

■ Spray suspension.The pigment suspension is stirred into the coating sus-pension. It is recommended tostir the spray suspension during spraying in order toavoid sedimentation.

Preparation of the spraysuspension withKollicoat® MAE 100 P:

■ Coating suspension.Kollicoat® MAE 100 P is care-fully stirred into the given amount of water. The stirrer speed is adapted to the vis-cosity from time to time avoid-ing foam production. To com-plete the redispersion the system is stirred for 3 to 4 hours. Finally the plasticizeris added.

■ Pigment suspension.Iron oxide red 30, titanium dioxide, and talc areintensively stirred in water and homogenized (corundum disk mill or Ultra Turrax).

■ Spray suspension.The pigment suspension is stirred into the coating sus-pension. It is recommended to stir the spray suspension during spraying in order toavoid sedimentation.

Coating suspension +Pigment suspension =

Spray suspension

(Please find further formulationsin our “Technical Information –

Kollicoat® MAE grades”)H2O H2O

Coatingsuspension

Pigmentsuspension

6. Pigment suspensionstirred intocoating suspension

1. Propylene glycol2. Kollicoat®

MAE 30 DP

3. Iron oxide red 304. Titanium dioxide5. Talc

The Example

Colored entericfilm coatingbased on Kollicoat®

MAE 30 DP/100 P

8 The Example

100

80

60

40

20

0

rele

ase

[%]

Release test(pH 6.8 buffer)Diclofenac Na

time [min]5560 90 120 5 10 15 20 25 30 35 40 45 5030

Acetylsalicylic acid

Resistancetest (0,1 N HCI)

Composition of the spray suspension:The formula has been calculated for 500 g of crystals(diameter 0.3–1.0 mm):

Coating equipment WSG Aeromatic Strea 1Size of batch 500 gAir supply temperature 60 °C/140 °FExhaust air temperature 35 °C/95 °FSpraying pressure 2–3 barTime of spraying 100 min

Polymer suspensionKollicoat® MAE 100 PPropylene glycolWaterPigment suspensionTitanium dioxideIron oxide red 30TalcWater

Parts by weight [g]

75.011.3

336.2

2.52.5

20.052.5

500.0

% composition

15.02.25

67.25

0.50.54.0

10.5100.0

Solids content of the spray suspension: 22.25%Solid polymer in the spray suspension: 15.0 %Solid polymer applied: 4.0 mg/cm2

Total solids applied: 5.9 mg/cm2

Machine parameters:The spraying trials were performed in a WSGAeromatic Strea 1 fluidised bed granulator.

Release rates of diclofenac Na pellets andacetylsalicylic acid crystals.

Colored entericfilm coating

based on Kollicoat®

MAE 100 P

The CoatingProcess

9

In a comparative study*different materials forenteric coating wereinvestigated:

Hydroxypropyl methyl-cellulose acetatesuccinate (HPMCAS),2 different hydroxy-propyl methylcellulosephthalate (HPMCP)products, celluloseacetate phthalate (CAP)and methacrylicacid/ethyl acrylatecopolymer 1:1(Kollicoat® MAE).

Caffeine cores werecoated in an AccelaCota 24”.The composition of thespray suspensions andsolutions, the methodof preparation and theprocess parameterswere taken from therespective manufac-turer’s technical datasheets.

One of the HPMCPproducts was sprayedin an organic solvent,all others in aqueousmedium.

* K. Kolter, S. Scheiffele, G. SchepkyKOLLICOAT MAE – EFFECTIVENESS AND ECONOMY IN ENTERIC COATINGProc. 2nd World Meeting APGI/APV, Paris, 25/28 May 1998

Process parameters in coating and subsequent treatment accordingto technical data sheets.

ProcessParameter

Inlet airtemperature [oC]

Producttemperature [oC]

Rate of spraying[g/min]

Drying

Heat treatment[min/oC]

CAP Kollicoat® HPMCP HPMCP HPMCASMAE

aqueous aqueous aqueous organic aqueous

78 50 70 60 70

32–33 35–38 32 36 33–35

60 30 30 60 40

5 minutes at 50 oC

60/60 No heat treatment 30/60

Composition of the spray dispersions according to technical data sheets.

Ingredients[%]

Film-former

Ammonia (30%)

Ethanol

Kollidon® 30

Sodium laurylsulfate

Iron oxide red

Talc

Titanium dioxide

Triacetin

Triethyl citrate

Tween 80

Water

CAP Kollicoat® HPMCP HPMCP HPMCASMAE

aqueous aqueous aqueous organic aqueous

11.04 15.00 9.70 5.00 7.00

1.80

79.19

0.50

0.21

0.26 0.50 0.33 0.17 0.24

2.00 2.50 1.50 2.10

0.26 0.50 0.33 0.17 0.24

3.35 1.00

1.50 1.96

0.10

84.99 80.00 84.34 13.97 88.25

The Result10

The acid permeationresults show that to

achieve resistance togastric juice, different

minimum film thick-nesses are required for

each film-forming agent.To achieve adequate

resistance towardsgastric juice, a coating

of only 5.5 mg/cm2 isrequired with Kollicoat®,which is just as little as

with the HPMCPproduct in an organic

solution. Taking intoaccount the different

coating weightsrequired to achievegood resistance to

gastric juice theproduction times are

as shown below.

■ After 1 hour■ After 2 hours

Increase in weight of film-coated tablets (8.0mg/cm2) in gastric juice.

The degree of resistance to gastric juice was determined from theincrease in weight of film-coated tablets during resistance test.

The different processing times in the preparation of spray suspensionsare not taken into account here. More time and effort are always requiredto prepare suspensions from powders than to mix in an aqueousdispersion such as Kollicoat® MAE. Furthermore unlike the cellulosederivatives, which undergo degradation to release phthalic acid, succinicacid and/or acetic acid, Kollicoat® MAE is highly stable against hydrolysis.

■ Heat treatment time (min.)■ Drying time (min.)■ Spraying time (min.)

Production times for maximum resistance to gastric juice or a coatweight of 11.0 mg/cm2.

pro

du

ctio

n t

ime

[min

.]

HPMCPorganic

Kollicoat® MAEaqueous

HPMCASaqueous

CAPaqueous

HPMCPaqueous

120

100

80

60

40

20

0

5

5

5 5

5

4430

86 78

40

60

30

incr

ease

in w

eig

ht

[%]

HPMCPorganic

Kollicoat® MAEaqueous

HPMCASaqueous

CAPaqueous

HPMCPaqueous

2.15 2.24

20.32

24.24

34.9840

35

30

25

20

15

10

5

0

3.66 3.91

33.76

25.41

35.63

11The Summary

The major advantages of theproduct are:

■ Batch size of ca. 26 MT resultsin reduced analysis costs (advantage ~0.20 EUR/kg)

■ Better gastric resistance than cellulose derivatives

■ Identical to market leader Eudragit L 30 D-55

■ Kollicoat® MAE 100 P is partly neutralized and thus no caustic soda is to be handled in production

■ Better gastric resistance than cellulose derivatives

■ Same chemistry as market leader Eudragit L 100-55, but already neutralized

Kollicoat® MAE pro-duces enteric coatingsof excellent qualitymore easily and atlower cost than film-forming agents basedon cellulose derivatives.

Kollicoat® MAE 30 DP andKollicoat® MAE 100 P are firstchoice enteric coating agentswhich

■ allow an easy preparation of the spray suspension

■ shorten the coating process as the concentration of the film-former in the spray sus-pension is high and the amountof film-former needed is little

■ form films with a smooth shiny surface, even when mixed with large quantities of pigments

■ provide reliable and highly stable resistance to gastric juice

■ are purely aqueous dispersions and not burdened with the disadvantages of organic solvents

Kollicoat® MAE 30 DP andKollicoat® MAE 100 P aresupported by BASF's worldwidenetwork of technical expertise.

Please complete,copy and fax to us,or detach the postcardand send it to us.

Please send thefollowing information.

■ Technical information onKollicoat® MAE grades.

■ Sample ofKollicoat® MAE 30 DP 0.5 kg.

■ Sample ofKollicoat® MAE 100 P 0.5 kg.

■ Please contact me, I wouldlike to know more aboutKollicoat® MAE.

Fax Reply

Local contact:

+49-621-60-2 86 25or Headquarter Germany:

■ Technical informationon Kollicoat® IR White.

■ Technical informationon Kollicoat® Protect.

■ Technical information onKollicoat® IR.

■ “What’s Your Coat Name?”CD-ROM.

■ Newsletter “ExAct”(Excipients & Actives for Pharma).

Reply card

BASFAktiengesellschaftStrategic MarketingPharma ExcipientsMEM/PE – Li 55467117 LimburgerhofGermany

Please writein block letters.

Thank you.

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Pleaseapply

postagestamp.

We look forward toanswering anyquestions you mayhave. Please fill in thepostcard, detach itand return it to theaddress overleaf.

Please send thefollowing information.

■ Technical information onKollicoat® MAE grades.

■ Sample ofKollicoat® MAE 30 DP 0.5 kg.

■ Sample ofKollicoat® MAE 100 P 0.5 kg.

■ Please contact me, I wouldlike to know more aboutKollicoat® MAE.

■ Technical informationon Kollicoat® IR White.

■ Technical informationon Kollicoat® Protect.

■ Technical information onKollicoat® IR.

■ “What’s Your Coat Name?”CD-ROM.

■ Newsletter “ExAct”(Excipients & Actives for Pharma).

AsiaBASF Asia PacificRegional HQPharma SolutionsDr. Danilo MercadoBASF East Asia RegionalHeadquarters Ltd.45th Floor, Jardine House,No.1 Connaught Place,Central, Hong KongPhone: +852 2731 1588Fax.: +852 2734 9638mercadd@basf-east-asia.com.hk

EuropeBASF AktiengesellschaftMEE/HP – J 550Mr. Peter HoffmannD-67056 LudwigshafenGermanyPhone: +49/621 60 7 69 28Fax: +49/621 60 7 69 40peter.01.hoffmann@basf-ag.de

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www.pharma-solutions.basf.com

Pleasecontactyour localBASFcompanyor oneof thefollowingregionalcenters:

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BASF offers more thancGMP quality and supplysafety: technical expertise.Our technical serviceis always at your side.

BASF wishes to createa prosperous and sustain-able future with you as ourcustomer – and partner.

■ Excipients

■ Actives

■ ContractManufacturing

■ Value Added

pharmaSOLUTIONS

Lutrol® gradesRange of PEGs(Lutrol E range)and poloxamers(Lutrol F range)for a wide varietyof pharmaceuticaldosage forms.Soluphor® P2-pyrrolidone.Cremophor®

grades andSolutol® HS 15Range of differentethoxylatedemulsifiers andsolubilizerssuitable for topical,oral and parenteralformulations.

■ ActivesIbuprofenCaffeineTheophyllineEphedrinesPseudoephedrinesPVP-IodineTretinoinIsotretinoinDopamineDobutamineOxymetazolineXylometazolineSelegiline

Vitamins

■ ContractManufacturing

■ Value Added

BASF – the world’s leading chemical company – can look back onwell over 135 years of success and has attained an outstandingposition as a reliable partner.

Our portfolio for the pharmaceutical industry comprises acomprehensive range of major and new active ingredients andexcipient brands.

■ ExcipientsKollidon® gradesGroup of Povidoneand Copovidoneproducts suitablemainly as tabletbinders,Crospovidone as tablet disintegrant and dissolution enhancer.Kollidon® SRMatrix sustainedrelease polymer.Kollicoat® gradesRange of aqueousbased film formers,cost efficient andecological.Ludipress® gradesDirect tablettingaids for fasterproduct develop-ment and speedierprocessing.