Guidelines for Formulation Development and Process Technology for Enteric Coatings

1. Introduction

Many pharmaceutical dosage forms irritate the stomach due to their chemical properties. Others undergo chemical changes in the acidic gastric environment and through the action of enzymes, thus becoming less effective. The anionic EUDRAGIT® methacrylic acid copolymers can be used to provide enteric protection for such drug products and to provide gastrointestinal targeting by controlled drug release at the same time. 

2. Products

EUDRAGIT® L , EUDRAGIT® S, EUDRAGIT® FS

The EUDRAGIT® methacrylic acid copolymers of grades L, S and FS contain carboxylic groups and are thus anionic in character. Enteric coatings with these EUDRAGIT® grades release the active ingredient between pH 5.5 and >pH 7, allowing GI targeting from the small intestine to the colon. The release of active ingredients also depends on the thickness of the film coatings and the solubility characteristics of the active ingredient under physiological conditions. The different EUDRAGIT® polymers are available as aqueous dispersions, powders or organic solutions. EUDRAGIT® polymers can be applied as coatings to conventional solid oral dosage forms such as tablets, capsules and small particles.

EUDRAGIT®	Polymers:	Chemistry: Dissolution
L 30 D-55, L 100-55	Methacrylic acid, Ethyl acrylate	≥5.5
L 100, L 12,5	Methacrylic acid : Methyl methacrylate = 50 : 50	≥6.0
S 100, S 12,5	Methacrylic acid : Methyl methacrylate = 30 : 70	≥7.0
FS 30 D	Methacrylic acid, Methyl acrylate, Methyl methacrylate	≥7.0

3. Drug Considerations and Release Mechanisms

Dissolution of these films occurs with increasing pH due to the carboxylic acid groups. 

Release in the duodenum:

EUDRAGIT® L 100-55 or the aqueous dispersion EUDRAGIT® L 30 D-55 dissolve at pH values above 5.5.

Advantages: effective and stable enteric coatings with rapid dissolution in the upper region of the small intestine.

Release in the jejunum to ileum:

EUDRAGIT® L dissolves at pH values above 6.0. Mixtures of EUDRAGIT® L and EUDRAGIT® S dissolve in a pH range from 6.0 to 7.0.

Advantages: granulation of drug substances in powder form for controlled release.

Colonic delivery:

EUDRAGIT® S and EUDRAGIT® FS 30 D dissolve at pH 7.0.

Advantages: Safe pH-triggered colonic drug  delivery.

All polymer types can be mixed with each other in different ratios to some extent, thus making it possible to achieve drug release at intermediate values. The dissolution profiles established in vitro must be confirmed in clinical tests.

4. Auxiliary Excipient Recommendations Plasticizers

Plasticizers reduce the minimum film-forming temperatures as well as the glass transition temperature. The addition of a plasticizer such as triethyl citrate increases the flexibility of the film coatings. When hydrophilic plasticizers are used, it is sometimes advisable to include water in the spray suspension in order to avoid phase separation between polymer and plasticizer during film formation.

EUDRAGIT® L 30 D-55, EUDRAGIT® L 100-55 and organic solutions of EUDRAGIT® L 100 and EUDRAGIT® S 100 require 10 – 20% plasticizer based on dry polymer substance. Suitable plasticizers include triethyl citrate, dibutyl sebacate, polyethylene  glycol and propylene glycol.

Aqueous, redispersed EUDRAGIT® L 100 and EUDRAGIT® S 100 require 50 – 70% plasticizer based on dry polymer substance. Triethyl citrate is recommended. Other, usual plasticizers will not have the required effect on the minimum film-forming temperature of those aqueous latex systems.

EUDRAGIT® FS 30 D is a flexible polymer that has good film formation properties and requires no plasticizer!

In some cases, small amounts of plasticizer will enhance the film flexibility and improve performance. For example, for the compression of enteric-coated particles, increased flexibility of coatings is required in order to avoid film damage during compression. Recommended amounts of plasticizers are 5% based on dry polymer substance. In other cases, the core formulation or active ingredient may lead to curing effects. This should be tested by post-drying studies for safety‘s sake.

Glidants

Polymer solutions and dispersions go through a tacky phase during drying. To avoid agglomeration of the cores and to prevent the film coatings from becoming sticky, glidants are added to the spray suspensions. Talc: >25 – 100%, preferably 50% based on the dry polymer substance Glycerol monostearate: 2 – 20%, preferably 5% based on the dry polymer substance

Pigments

Pigments can be incorporated into the formulation. Suitable  pigments are titanium

dioxide as a white pigment, aluminium lakes, and iron oxide pigments. Partial neutralization of the polymer is recommended before adding lakes or iron oxides to latex dispersions, such as EUDRAGIT® L 30 D-55, in order to stabilize the physical stability of spray suspensions. Incorporated pigments (e.g. titanium dioxide, color lakes) may increase the permeability of the coating and require higher amounts of polymer

5. Processing Conditions

EUDRAGIT® polymers can be applied as film coatings to all conventional, solid oral dosage forms such as tablets, capsules, and small particles. The polymers can also be used as binders to prepare pellets, granules and sustained-release tablets. Polymers may be directly processed from aqueous latex dispersions or solutions in organic solvents (e.g., alcohols, acetone). The powders EUDRAGIT® L 100-55, L 100, and S 100 can be used for film coating applications as aqueous

dispersions or as organic solutions. Aqueous dispersions can be prepared by stirring the EUDRAGIT® powder into water and adding alkali to partially neutralize the carboxylic acid groups of the polymer, resulting in the formation of a colloidal dispersion.

For enteric coatings, 4 to 6 mg polymer are applied per cm2 of tablet surface, or 10 to 30% by weight on particles such as pellets, granules or crystals with sizes in the range of about 0.5 to 1.2 mm. The required polymer quantity may vary according to surface texture, mechanical stability or solubility of the active pharmaceutical ingredient.

For aqueous coating suspensions 20 - 25% solids content are recommended, for organic preparations the solids content should be around 10%.

	Fluid bed particle coating	Pan coater
Bed temperature aqueous dispersion	20-30°C	30 – 35°C
Product temperature organic solution	approx. 25°C	approx. 30°C

6. Test Methods

In-vitro tests such as dissolution and disintegration will generally involve two-stage testing: initially in an acid phase (e.g. 0.1 N HCl), followed by testing in a suitable buffer  (e.g. pH 6.8 or 7.4 phosphate buffer).

Reference : Evonik Industries