Kollicoat EMM 30 D

Kollicoat® EMM 30 D

® = Registered trademark of BASF Aktiengesellschaft

Ethyl acrylate-methyl methacrylate copolymer for sustained-release pharmaceutical formulations

Technical Information

August 2004Supersedes issue dated January 2004

MEMP 030723e-02/ of 12

Excipients

Acties

Contract Manufacturing

Value Added

ContentsPage

1 Introduction 3

1.1 General Information 3

1.2 Chemical structure 3

1.3 Trivial names 3

1.3 Commercial formulation 3

2 Specifications and properties 3

2.1 Description 3

2.2 Physical and chemical properties 3

2.3 Pharmacopoeias 4

3 Application and processing 4

3.1 Processing notes 4

3.2 Propranolol sustained-release pellets 6

3.3 Ibuprofen sustained-release pellets 8

3.4 Production of caffeine sustained-release granules 9

3.5 General notes for the production of a spray suspension 10

3.6 Additional applications 10

4 Storage 11

5 Stability 11

6 PBG No. 11

7 Packaging 11

MEMP 030723e-02 August 2004 of 12 Kollicoat® EMM 30 D

1 Introduction

1.1 General Information Kollicoat® EMM 30 D is a copolymer based on ethyl acrylate and methyl methacrylate. It has a neutral character. The polymer is suitable for the produc-tion of sustained-release formulations and transdermal therapeutic systems. It has a strong, pH-independent sustained-release effect. Moreover, it can also be used for taste masking.

1.2 Chemical structure

The ratio of ethyl acrylate : methyl methacrylate is approximately 2 : 1. Kollicoat® EMM 30 D is a neutral ester dispersion without functional groups. The average molecular weight is approximately 800,000.

1.3 Triial names Polyacrylate dispersion 30% (Ph. Eur.), Ethyl Acrylate-Methyl Methacrylate Copolymer Emulsion (JPE)

1.4 Commercial formulation Kollicoat® EMM 30 D is an aqueous dispersion with a 30% solids content. The cloudy white, low-viscosity product has a weak, characteristic odour.

2 Specifications and properties

2.1 Description The dispersion contains 1.5% Nonoxynol 100 as an emulsifier. Kollicoat® EMM 30 D is a neutral ester dispersion which forms water-insoluble films.

2.2 Physical and chemical properties

Identity: passes test

Film formation: passes test

Solubility: passes test

Relative density: 1.037–1.047

Viscosity: max. 50 mPas

Coagulate content: max. 0.5%

Solids content: 28.5–31.5%

Sulphated ash: max. 0.2%

Heavy metals: max. 20 ppm

Arsenic: max. 2 ppm

Monomers: max. 100 ppm

Microbial status: passes test

Solubility Kollicoat® EMM 30 D can be mixed with water in any proportion while retaining its cloudy white appearance. Mixing the product with acetone, ethanol or isopropyl alcohol at a ratio of 1 : 5 results in a weakly opalescent, viscous solution. When organic solvents are added, the polymer initially precipitates out; however, it redissolves on addition of more solvent. Kollicoat® EMM 30 D is not soluble in diluted alkaline solutions. The cloudy white appearance of the dispersion is preserved.

Film formation When the product is poured out onto a glass plate, a clear film is formed after evaporation of the water.

Viscosity Viscosity is determined according to DIN EN ISO 3219 at a shear rate of 250 s-1 and 23 °C.


Coagulate content 100 g of the substance is filtered through a 90 µm screen. The residue is dried to constant weight in the drying cabinet at 105°.

Microbial status The test of microbial status is carried out according to Ph. Eur., Category 3. If not specified otherwise, the determination methods are taken from the current European Pharmacopoeia.

2.3 Pharmacopoeias Kollicoat® EMM 30 D meets the requirements of the monograph Polyacrylate Dispersion 30% (Ph. Eur.) and Ethyl Acrylate-Methyl Methacrylate Copolymer Dispersion (JPE).

3. Application and processing

3.1 Processing notes Certain external factors can cause aqueous dispersions to coagulate, rendering them unfit for use. These factors are: • The addition of finely dispersed pigments • High shear gradients when stirring and grinding • The addition of emulsifiers, stabilisers, or wetting agents • Changes in pH • Organic solvents • Foam formation Foam formation during processing can be prevented by adding a silicone anti-foam such as Pharsil 21046. Kollicoat® EMM is a soft polymer, which makes the use of a plasticizer unnecessary. The product forms very flexible, extensible films. Cores containing substances that are water-sensitive or incompatible with the sustained release coating should first be given a subcoating. A coating weight of 0.2–2.0 mg/cm2 is required, depending on the polymer used. A subcoating film of an organic solution is recommended for water-sensitive active ingredients. Kollidon® VA 64 is suggested as a polymer for a subcoating. It is recommended to subsequently dry the pellets. If the pellets, granules or crystals are surrounded by a nonporous membrane, very effective sustained-release is achieved. In order to adjust the release charac-teristics of the active ingredients in sustained-release forms, additions of pore-forming agents are necessary. The best control can be achieved with water-soluble polymers or slightly swelling water-insoluble polymers. The permeability of the water-insoluble films can be varied • by the thickness of the coating • by the use of pore-forming agents (HPMC, microcrystalline cellulose PH 105).

The quantity depends on the release profile desired.

The layer thickness should not fall below 1.5 mg/cm2 ( approximately 15 µm), since otherwise film defects and bursting may be expected. Kollicoat® EMM 30 D is a polymer with relatively high tack. Auxiliary agents are necessary to reduce the tack and to improve processing when it is processed as a coating. Previously, talc was generally used for this purpose. More recent studies have shown that the use of fine microcrystalline cellulose or hydroxypropyl methylcellu-lose can greatly reduce the tack. At the same time, the inlet air temperature and the spraying rate can be increased, which makes it possible to noticeably accel-erate the coating process. At the same time, these substances have the advan-tage that they can also act as a pore-forming agent and give stable release char-acteristics throughout the storage time.


The formulations with microcrystalline cellulose and HPMC indicated in the examples are intended as starting formulations for developing formulations. BASF typical formulations Compositions of the spray suspensions

Kollicoat® EMM 30 D (solids)

[%]

Microcrystalline cellulose PH 105

[%]

HPMC (Pharmacoat® 603)

[%]

Talc

[%]

1 Sparingly soluble active ingredients (< 1%), low tack

7.50 7.50 3.50

2 Sparingly soluble to soluble active ingredients (< 10% solubility)

see 3.3 see 3.4

9.75 4.50 0.75 3.50

3 Soluble to readily soluble active ingredients ( 10%)

see 3.2 11.80 0.75 6.00

4 Readily soluble active ingredients ( 20%) – strong sustained-release effect

12.50 12.50

��Influence�of�various�auxiliary�agents�on�release�control�and�tack��Formulation No. 2 is the most suitable because of its very low tack. The spraying conditions depend on the formulations and the equipment. Normally, the temperature settings are as follows: • Inlet air temperature: 30–65°C • Outlet air temperature: 20–35°C • Product temperature: 20–35°C The minimum film-forming temperature (MFT) is less than 10 °C. Thermal aftertreatment (curing) of the coated pellets is frequently unnecessary.


3.2 Propranolol sustained- release pellets

Composition of the pellets: 20% propranolol-HCl, 51.7% Avicel® PH 101, 25.8% lactose, 2.5% Kollidon® VA 64

Composition of the spray suspension

The�formulation�is�designed�for�3�kg�pellets�(diameter�0.7–1.4�mm)

Parts by weight [g]

Proportion [%]

Polymer suspension

Kollicoat® EMM 30 D 895.5 39.3 (11.8 polymer)

Pharmacoat® 603 16.1 0.7

Water 501.2 42.5

Pigment suspension

Kollidon® 30 11.4 0.5

Titanium dioxide 11.4 0.5

Sicovit® Red 30 11.4 0.5

Talc 136.7 6.0

Water 694.3 10.0

2278.0 100.0

Production of the spray suspension Polymer�suspension: Pharmacoat® 603 is first added to the specified quantity of water. Kollicoat® EMM 30 D is added with stirring. Pigment�suspension: Kollidon® 30 is dissolved in the specified quantity of water. Sicovit® Red 30, titanium dioxide and talc are added with powerful stirring and homogenised by means of a corundum disc mill. Spray�suspension: The pigment suspension is introduced into the polymer suspension with stirring. The mixture must be stirred in order to prevent sedimentation during the spray-ing process.

Machine parameters Machine: Hüttlin HKC 5TJ coater

Batch size: 3 kg

Inlet air temperature: 45°C

Outlet air temperature: 27°C

Product temperature: 29°C

Air flow: 320 m3/hr.

Atomizing pressure: 0.6 bar

Spraying rate: 38 g/min.

Quantity applied 3 mg/cm2

Spraying time: 60 min.

Afterdrying: 45°C/3 min. The spray suspension is continuously sprayed onto the fluidized, prewarmed pellets in the Hüttlin coater. The above formulation can also be used in fluidized-bed coating machines. Both the bottom spray method and the top spray method can be used.


The coating weight of 3 mg/cm2 in this case was calculated from the surface area of the above pellets. Since the particle size distribution and the surface structure influence the required polymer quantity, a calculation of the surface area is recommended in order to estimate the quantity to be applied. The concentration of pore-forming agents and tack reducers influence the inlet air temperature and product temperature that can be used. The higher the concentrations of these substances are, the higher the corresponding temperatures that can be used.

�Release�of�propranolol�sustained-release�pellets�


3.3 Ibuprofen sustained- release pellets

Composition of the pellets: 60.0% ibuprofen, 2.5% Kollidon® VA 64, 37.5% Avicel® PH 101 A 70 : 30 subcoating of 1 mg/cm2 Pharmacoat® 603/talc is applied to the pellets.


The�formulation�is�designed�for�2.3�kg�pellets�(*�0.7–1.5�mm)

Parts by weight [g]

Proportion [%]

Polymer suspension

Kollicoat® EMM 30 D 540.2 32.50 ( 9.75 polymer)


Avicel® PH 105 74.8 4.50

Water 785.2 47.25

Pigment suspension

Kollidon® 30 8.3 0.5



Talc 58.2 3.5

Water 166.2 10.0

1662 100.0

The spray suspension is produced by analogy to the previous formulation.

Machine parameters Machine: Hüttlin HKC 5TJ pellet coater

Batch size: 2.3 kg

Inlet air temperature: 48°C

Outlet air temperature: 34°C

Product temperature: 38°C

Air flow: 375 m3/hr.

Atomizing pressure: 0.6 bar

Spraying rate: 28 g/min.

Coating weight 2 mg/cm2

Spraying time: 60 min.

Drying: 48°C/3 min.

As the ibuprofen pellets become highly charged during coating, the coater must be well earthed.


Release�of�ibuprofen�sustained-release�pellets�

3.4 Production of caffeine sustained-release granules


The�formulation�is�designed�for�500�g�granules�(diameter�0.6–1.8�mm)

Parts by weight [g]

Proportion [%]

Polymer suspension

Kollicoat® EMM 30 D 237.25 32.5

( 9.75 polymer)


Avicel® PH 105 32.85 4.50

Water 344.92 47.25

Pigment suspension

Kollidon® 30 3.65 0.5



Talc 25.55 3.5

Water 73.00 10.0

730.00 100.0

The spray suspension is prepared in the same way as the previous formulation.


Machine parameters Machine: WSG Aeromatic Strea 1, Wurster insert

Lot size: 500 g

Inlet air temperature: 45 °C

Outlet air temperature: 25 °C

Atomizing pressure: 1 bar

Coating weight: 4 mg/cm2

Spraying time: approximately 60 min including 3 min. drying time

Release�of�caffeine�sustained-release�granules�

3.5 General notes for the production of a spray suspension

Due to the different solubilities of the active ingredients and the different release rates they give as a result, the choice of pore-forming agent is very important in the production of spray suspensions. The figures shown in the chart are based on our experience.

3.6 Additional applications Kollicoat® EMM 30 D can be used as an odour, taste or moisture barrier, or to protect active ingredients against interaction with other substances (protective coating, subcoating). By granulating active ingredients in a fluidized bed, for instance, and subse-quent compressing, it is possible to produce matrix sustained-release tablets. The production of transdermal systems is also possible.


4. Storage Above freezing and not over 30°C.

5. Stability At least 18 months in the unopened original containers at room temperature. Under the effects of heat or frost as well as foaming, aqueous dispersions can form coagulates which make them unsuitable for further use. Since the product has a neutral pH, care must be taken not to introduce contamination into the product, due to the risk of microbial growth. Opened containers must be used up as quickly as possible, or preserved with sodium hypochlorite solution (5 ppm active chlorine).

6. PBG No. 10 213 678

7. Packaging 25 l polyethylene containers.

Note The data contained in this publication are based on our current knowledge and experience. In view of the many factors that may affect processing and application of our product, these data do not relieve processors from carrying out their own investigations and tests; neither do these data imply any guarantee of certain properties, nor the suitability of the product for a specific purpose. Any descriptions, drawings, photographs, data, proportions, weights etc. given herein may change without prior information and do not constitute the agreed contractual quality of the product. It is the responsibility of the recipient of our products to ensure that any proprietary rights and existing laws and legislation are observed. August 2004


BASF AktiengesellschaftFine Chemicals Division - Pharma Solutions - 67117 Limburgerhof - www.pharma-solutions.basf.com


Kollicoat EMM 30 D

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