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Pharma Ingredients & Services

Technical Information

June 2011 Supersedes issue dated January 2011

03_101002e-02/ of 16

Kollicoat® Smartseal 30 D

® = Registered trademark of BASF group

03_101002e-02 June 2011 of 16 Kollicoat® Smartseal 30 D

Contents

1. Introduction 3

1.1 General 3

1.2 Structural formula 3

1.3 Trivial names 3

2. PRD-No. 3

3. Specification & properties 3

3.1 Specification 3

3.2 Regulatoy status 3

3.3 Physico-chemical properties 3

4. Application and Processing 4

4.1 Taste masking 4

4.2 Moisture protection 4

4.3 Properties of isolated films 5

5. Processing 5

5.1 General handling recommendations 5

5.2 Selection of a plasticizer 5

5.3 Addition of an antioxidant 6

5.4 Preparation of the coating suspension 6

5.5 Cleaning recommendations 6

6. Formulation examples 7

6.1 Caffeine tablets 7

6.2 Caffeine pellets 9

6.3 Theophylline granules 10

6.4 Acetaminophen crystals 12

6.5 Moisture protection (Sorbitol tablets) 14

7. Packaging 14

8. Storage 15

9. Stability 15

10. Toxicology 15


1. Introduction

1.1 General Kollicoat Smartseal 30 D is an aqueous dispersion of a film forming polymer for taste masking and moisture barrier applications. The functionality of the polymer ensures effective protection from unpleasant taste and humidity as well as a quick release of the active ingredients in the stomach. Kollicoat Smartseal 30 D offers superior protection with a reduced amount of applied coating as well as extensive economies with lean and efficient operations.

1.2 Structural formula

OO

N

COCO

CH3

CH3 CH3

CH2

CH2

CH2

CH2

H5C2 C2H5m = 7; n = 3

m n* *

1.3 Trivial names Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion

2. PRD-No.* 30492630 * BASF’s commercial product numbers.

3. Specification & properties

Description Kollicoat Smartseal 30 D is an aqueaous polymer dispersion with a solids con-centration of approx. 30%. It contains methyl methacrylate and diethyl amino ethyl methacrylate copolymer stabilized with approx. 0.6% macrogol cetostearyl ether and 0.8% sodium lauryl sulfate. It comes as a milky white to yellowish liquid with a faint characteristic odor.

3.1 Specification See separate document: “Standard Specification (not for regulatory puroses available via BASF’s WorldAccount: http://worldaccount.basf.com (registered access).

3.2 Regulatory status Type IV US-DMF and type V US DMF are available.

3.3 Physico-chemical properties

Molecular weight The weight average molecular weight determined with size exclusion chromatography (SEC) – light scattering is approx. 200 000 dalton.

Solubility Kollicoat Smartseal 30 D is miscible with water while retaining its milky white appearance and low viscosity. When hydrophilic organic solvents are added, the polymer precipitates at first, but dissolves after continuous stirring: Acetone: Miscible at a ratio of 1:3, dissolves after 2 hrs (solution is cloudy)

Ethanol: Miscible at a ratio of 1:3, dissolves after 2.5 hrs (solution has a yellowish color)

Isopropanol: Miscible at a ratio of 1:3, dissolves after 3.5 hrs (solution has a yellowish color).

Glass transition temperature The Tg is approx. 63 °C.

Minimum film forming temperature The MFT measured with a heating block is approximately 57 °C (Due to the high lipophilicity of the polymer water cannot act as a plasticizer).

Particle size The mean particle size, determined with laser scattering, is approximately 150 nm.


4. Application and Processing

4.1 Taste masking The premise for an effective protection from unpleasant taste is the insolubility of the film coating in the saliva (pH 6.8 – 7.2). Kollicoat Smartseal 30 D is insoluble in neutral or basic media for more than 2 hours. Due to the defined number of tertiary amino groups, the polymer dissolves under protonation in acidic media of pH 5.5 and below. This pH-dependent solubility ensures an effective protection in the mouth and a quick release of active ingredients in the stomach. A coating level of 2 – 6 mg / cm² is recommended for taste masking applications.

Dis

solv

ing

time

[min

/100

µm

]

60.0

50.0

40.0

30.0

20.0

10.0

0.0

4.4 min

8.6 min 10.5 min

> 120 min > 120 min

pH 1.1 pH 1.2 pH 4.5 pH 5.8 pH 6.8

Figure 1: Dissolving time of isolated films

4.2 Moisture protection Film coatings with low vapor permeability can delay the moisture uptake of sensitive cores. The complete insensitivity to water determines the effective moisture barrier functionality of Kollicoat Smartseal 30 D. A coating level of 5 – 20 mg/cm² is recommended for moisture barrier applications.

Wat

er c

onte

n [%

]

30 40 50 60 70 80 90 100

1009080706050403020100

Desorption

SorptionRel. humidity [%]

Figure: 2 Sorption isotherm


4.3 Properties of isolated films Protective properties of Kollicoat Smartseal 30 D can be optimized by the selection of lipophilic plasticizers and pigments. Figure 3 shows the water vapor permeability of isolated films that are plasticized with 15% triethyl citrate (w/w based on the polymer).

Vapo

r pe

rmea

bilit

y [g

/(m2 *

d)/1

00 µ

m]

80

70

60

50

40

30

20

10

0

DIN EN ISO 7783-2/50 – 93% r.h.15% TEC rel. polymer, sprayed films

0% talc 10% talc 20% talc 30% talc 40% talc

Figure 3: Impact of talc on the vapor permeability

5. Processing

5.1 General handling recommendations

As with all aqueous polymer dispersions (latex) some factors could result in an irreversible coagulation that precludes further use of the product: • Exposure to frost. • Addition of acidic ingredients should be avoided because of potential interaction

with the functional goups of the polymer.

However, Kollicoat Smartseal 30 D is comparably stable so that it is possible to add certain plasticizers directly and without prior dilution into the dispersion.

5.2 Selection of a plasticizer Due to the high minimum film forming temperature (~ 57 °C) and due to the relatively brittle nature of the polymer, it is necessary to add a plasticizer. The following plasticizers are suitable in a concentration of 13 – 15% (w/w based on the polymer). • Triethyl citrate (TEC). • Acetyltributyl citrate (ATBC) in combination with docusate sodium (DS). • Dibutyl sebacate (DBS) and docusate sodium (DS) • Tributyl citrate (TBC) and acetyltriethyl citrate (ATEC); which have no history of use

in human oral dosage forms.

The addition of plasticizers leads to a strong decline of the minimum film forming temperature.

Min

imum

film

form

ing

tem

pera

ture

[°C

]

60

50

40

30

20

10

0

Concentration of plasticizer and surfactant [% rel.to polymer]0 5 10 13 15 20

Tributyl citrateAcetyltriethyl citrateTriethyl citrateAcetlytributyl citrat + docusate sodium 2%Dibutyl sebacate + docusate sodium 2%

Figure 4: Impact of plasticizers on the MFT


Plasticizers have an impact on the mechanical properties of the films. Figure 5 shows that the recommended plasticizer concentration of 13 – 15% (w/w based on the polymer) increases the elongation at break to approximately 100%.

Elo

ngat

ion

at b

reak

[%] 300

250

200

150

100

50

010 15 20 25

Plasticizer content rel. to polymer [%]

Triethyl citrate

Tributyl citrate

Acetyltriethyl citrate

casted films

Figure 5: Impact of plasticizers on the mechanical properties

5.3 Addition of an antioxidant The addition of antioxidants stabilizes the aminoester moiety of the polymer. Yello-wing and a delayed dissolution of the polymer after exposure to light or elevated temperatures can be avoided by adding 1.0 – 2.5% (w/w) of butylated hydro xy-toluene (BHT) (based on polymer weight). Tablet formulations require an antioxidant, to ensure an undelayed dissolution after storage. Pellet or particle coatings can be formulated without antioxidants.

5.4 Preparation of the coating suspension

Step 1: Dissolving of the lipophilic antioxidant. Dissolve the lipophilic antioxidant in the plasticizer (TBC, TEC or ATEC). Elevated temperatures of approx. 50 °C can speed up the process. Step 2: Dispersion of pigments. Disperse the pigments in water with an high shear mixer. (Hydrophilic antioxidants, such as sodium carbonate are added and dissolved in step 2.) Step 3: Addition of Kollicoat Smartseal 30 D and subsequently the mixture of BHT and plasticizer directly into the pigment suspension. Stirr for 2 hours and then pass through a 200 µm sieve. Stir for two hours.

Step 1 Step 2 Step 3

*Plasticizer & additives

Pigments

Kollic

oat

TEC &BHT

1

2*

Figure 6: Preparation of the coating suspension

5.5 Cleaning recommendations As the polymer is readily soluble in weak acids, coating equipment can be cleaned easily from residues of Kollicoat Smartseal 30 D based formulations. Acidic pre-parations, such as aqueous solutions of acetic acid, formic acid or citric acid, or commercially available cleaning agents are recommended for cleaning.


6. Formulation examples

6.1 Caffeine tablets

Composition of tablets Cores: Caffeine 30%, Ludipress® 58%, microcrystalline cellulose: 12%, Magnesium stearate: 0.3%, round, convex , Ø 9 mm

Composition of spray suspension Ingredients Content [%]

Kollicoat Smartseal 30 D 33.48%

Tributyl citrate (TBC) 1.31% (13% rel. to polymer)

Butylated hydroxytoluene (BHT) 0.25% (2.5% rel. to polymer)

Talc 8.00

Colorant 0.40

Water 56.56

Total 100

Solids content in the spray suspension Polymer content in the dried film

20.00 50.2

Process parameters Machine Accela Cota, 24''

Inlet air temperature 60 °C

Batch size 7 kg

Product temperature 30 – 33 °C

Spraying rate 35 g / min

Nozzle diameter 1 mm

Spray pressure 1.5 bar

Final drying 45 °C (product temperature)

Coating level (taste masking) 4.5 mg/cm² ~ 2.8% weight gain


uncoated cores & 1 mg/cm2 coating level

2 mg/cm2 coating level


4 & 5 mg/cm2 coating level

Time [min]

Dru

g re

leas

e [%

]

120

100

80

60

40

20

00 10 20 30 40 50 60

Figure 7 a: Caffeine tablets: Dissolution at pH 6.8

Dru

g re

leas

e [%

]uncoated cores & 1– 4 mg/cm2 coating level


Time [min]

120

100

80

60

40

20

00 10 20 30 40 50 60

Figure 7 b: Caffeine tablets: Dissolution at pH 1.2 A homogenious coating and an effective taste masking can be achieved at coating levels of 4 mg/cm².

6.2 Caffeine pellets

uncoated 1.5 mg/cm² coating level

3.0 mg/cm² coating level 4.5 mg/cm² coating level

6.0 mg/cm² coating level

Figure 8


Composition of pellets Caffeine: 20%, lactose (powder) 38.5%, microcrystalline cellulose: 38.5%, Kollidon® CL-F: 3%; Ø: 0.7 – 1.4 mm



Tributyl citrate (TBC) 1.5% (15% rel to polymer)

Butylated hydroxytoluene (BHT) 0.1% (1% rel. to polymer)

Talc 8.00

Colorant 0.40

Water 56.67

Total 100


20.00 50.0

Process parameters Machine Aeromatic Strea1, Wurster insert


Batch size 0.5 kg


Spraying rate 9 g/min

Nozzle diameter 0.8 mm


Final drying 55 °C, ~10 min (until outlet air has 45 °C)

Blending 0.2% colloidal silica for 10 min in a Turbula blender

Coating level (taste masking) 1.5 – 6.0 mg / cm² ~6.4 – 25.8% weight gain

Time [min]

Dru

g re

leas

e [%

]

1101009080706050403020100

0 20 40 60 80 100 120

uncoated pellets

1.5 mg/cm2 coating level

3.0, 4.5 & 6.0 mg/cm2 coating level

Figure 9 a: Caffeine pellets: Dissolution at pH 6.8


Time [min]

Dru

g re

leas

e [%

]

1101009080706050403020100

0 20 40 60 80 100 120

uncoated cores

1.5, 3.0, 4.5 & 6.0 mg/cm2 coating level

PP: phosphate buffer pH 6.8

Figure 9 b: Caffeine pellets: Dissolution at pH 1.2

6.3 Theophylline granules

Composition of cores Theophylline granules Ø 0.2 – 0.7 mm.



Tributyl citrate (TBC) 1.5% (15% rel to polymer)

Butylated hydroxytoluene (BHT) 0.1% (1% rel. to polymer)

Talc 8.00

Colorant 0.40

Water 56.67

Total 100


20.00 50.0

Process parameters Machine Ventilus 1 with IPC1 (Innojet)

Inlet air temperature 55 – 65 °C

Inlet air volume 45 m³ / h

Batch size 0.25 kg

Outlet air temperature 30 – 34 °C

Spraying rate 5 – 10 g / min

Nozzle diameter IRN2-V 1.0 mm


Blending 0.2% colloidal silica for 10 min in a Turbula blender

Coating level (taste masking) 8 – 28% weight gain

Taste masking can be achieved with 18% weight gain.


Example granules: Theophylline (0.2 – 0.7mm)

uncoated 8% weight gain

18% weight gain 28% weight gain

Figure 10: Microscopic pictures of coated and uncoated theophylline granules

Dru

g re

leas

e [%

]

uncoated granules

8% weight gain

Time [min]

120

100

80

60

40

20

0

0 30 60 90 120

18% weight gain

28% weight gain

Figure 11 a: Theophylline granules: Dissolution at pH 6.8

Dru

g re

leas

e [%

]

uncoated granules

Time [min]

120

100

80

60

40

20

00 30 60 90 120

8, 18 & 28 % weight gain

Figure 11 b: Theophylline granules: Dissolution at pH 1.2


6.4 Acetaminophen crystals

Composition of cores Acetaminophen crystals Ø approximately 0.3 mm.



Triethyl citrate (TEC) 1.51% (15% rel. to polymer)

Talc 8.00

Colorant 0.40

Water 56.47

Total 100


20.00 50.4

Process parameters Machine Aeromatic Strea1, top spray


Batch size 0.5 kg


Spraying rate 6 g / min



Final drying 55 °C, ~10 min (until outlet air has 40 °C)

Coating level 7.5 – 30% weight gain

Blending 0.2% colloidal silica for 10 minutes

Example crystals: Acetaminophen

uncoated 7.5% weight gain

22.5% weight gain 15% weight gain

30% weight gain

Figure 12: Microscopic pictures of coated and uncoated acetaminophen crystals


Dru

g re

leas

e [%

]

Time [min]

1009080706050403020100

110

0 20 40 60 80 100 120

uncoated crystals

7.5% weight gain

15.0 & 22.5% weight gain

30.0% weight gain

Figure 13 a: Acetaminophen crytsals: Dissolution at pH 6.8

Dru

g re

leas

e [%

]

Time [min]

90

110

80706050403020100

0 20 40 60 80 100 120

uncoated crystals and coated crystals(7.5, 15, 22.5 & 30.0% weight gain)

100

Figure 13 b: Acetaminophen crytsals: Dissolution at pH 1.2


6.5 Moisture protection (Sorbitol tablets)

Sorbitol tablets are highly hygroscopic and were therefore chosen as model to evaluate moisture barrier functionality of the coating.

Composition of tablets Cores: Sorbitol (Neosorb® P 60 W): 49.75%, Ludipress® 49.75%, Magnesium stearate: 0.5%, round, convex , Ø 9 mm; Hardness: 110 N



Tributyl citrate (TBC) 1.35% (13.0% rel. to polymer)

Butylated hydroxytoluene (BHT) 0.26% (2.5% rel. to polymer)

Talc 8.00

Colorant 56.67

Water 100

Total 20.0


52.0

Process parameters Machine Perforated pan coater Glatt GC 300


Batch size 1.5 kg

Product temperature 40 °C

Spraying rate 11g/min



Final drying 40 °C, 15 min (product temperature)

Coating level up to 20 mg/cm²

Moi

stur

e up

take

[%]

0 10 20 30 40 50 60 70

25

20

15

10

5

0

Time [d]

3 mg/cm²

0 mg/cm²

4.5 mg/cm²

6 mg/cm²

9 mg/cm²

12 mg/cm²

20 mg/cm²

Figure 14: Moisture uptake of sorbitol tablets during storage at 30 °C and 70% relative humidity

Kollicoat Smartseal 30 D based formulations can significantly reduce moisture uptake during storage. The barrier effect increases with higher coating levels.


7. Packaging 25 kg container (Art #50138477).

8. Storage Protect from frost and store at ambient / room temperature.

9. Stability At least 30 months in the unopened original container. On exposure to elevated temperature and if foaming occurs after moderate shaking during transport, white film flakes are formed and will appear on top of the dispersion.

10. Toxicology The safety of Kollicoat Smartseal 30 D as film coating agent for medicinal products is supported by a comprehensive non-clinical program. A summary is available on request. A detailed report can be shared as part of a non-disclosure agreement.

Note This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. June 2011


BASF SE - Nutrition & Health - Pharma Ingredients & Services - 68623 Lampertheim - www.pharma-ingredients.basf.com

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