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Methacrylic Acid-Ethyl Acrylate Copolymer Excipient | Uses, Suppliers, and Specifications

Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) is a synthetic anionic copolymer of methacrylic acid and ethyl acrylate (molecular weight 320,000 g/mol) for use as an enteric coating (trigger pH 5.5). It is commonly known as EUDRAGIT® L100-55 (Evonik) or KOLLICOAT MAE 100P (BASF). Methacrylic acid-Ethyl acrylate copolymer (1:1) is obtained by free-radical polymerisation of acrylate and methacrylate derivatives and is supplied as a free-flowing powder with a faint acrylic odour.

Synonyms and Trade Names: Methacrylic Acid–Ethyl Acrylate Copolymer (1:1) is also known as Poly(methacrylic Acid Ethyl Acrylate) 1:1; Acrylates Copolymer; Methacrylic Acid Copolymer, Type C; Methacrylic Acid Copolymer LD; EUDRAGIT® L100-55; Kollicoat® MAE 100 P; Acryl-EZE; ACRYCOAT L100-55

Pharmacopoeial Compliance: USP-NF; Ph.Eur; JP; IP

Uses and Applications: Enteric Polymer; Film Forming Agent; Tablet Binder; and Tablet Coating Agent

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EUDRAGIT® L 100-55 - Evonik Operations (Degussa)

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ACRYCOAT® L 100-55 - Corel Pharma PVT

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Kollicoat® MAE 100P - BASF Corporation

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Description

Methacrylic Acid–Ethyl Acrylate Copolymer (1:1) is a synthetic anionic polymethacrylate copolymer derived from esters of acrylic and methacrylic acid. It contains between 46% and 56% m/m methacrylic acid units, and has a mean relative molecular mass of approximately 320 000, and the ratio of carboxylic groups to ester groups is 1:1. The presence of carboxylic acid groups in its structure renders Methacrylic Acid–Ethyl Acrylate Copolymer (1:1)  insoluble in acidic media but soluble in neutral to alkaline fluids, making it ideal for use as an enteric film coating agent. It is supplied as a solid substance in form of a white, free-flowing powder with a faint characteristic odour.

Poly(methacrylate) copolymers have a long history of use in the pharmaceutical industry. They were first introduced in 1955 following on from the work of the famed scientist, Otto Rohm (Rohm & Haas), who also invented PLEXIGLASS®, a material that is chemically related to and shares many chemical properties with poly(methacrylate) copolymers. Their introduction marked a step-change in the field of drug delivery and pharmaceutical technology owing to their reproducibility and versatility compared with naturally derived polymers based on cellulose.

Basics of Poly(methacrylate) Copolymers

The structural basis of all Poly(methacrylate) copolymers, such as Methacrylic Acid–Ethyl Acrylate Copolymer, is Methacrylic acid, an alpha, beta-unsaturated monocarboxylic acid, that is, acrylic acid having the hydrogen at C2 substituted by a methyl group:

To synthesise poly(methacrylate) polymers, acrylic and methacrylic acid esters are combined via free radical polymerisation. Long polymer chains are then formed by chain grow reactions from various acrylate or methacrylate derivatives. The polymerisation reaction can be performed in a solvent, bulk, suspension or emulsion:

Variations in chain lengths can be obtained via termination and transfer reactions, while the functional properties of methacrylic copolymers and the final polymers are adjusted by selecting from a variety of monomers. Generally, non-functional comonomers determine the polymer’s properties while functional comonomers determine the solution profile.

Classification of Poly(methacrylate) Copolymers

Depending on the functional group attached to the polymer chain backbone, poly(methacrylate) copolymers can be broadly categorised into two groups:

  1. Based on the charge on the polymer’s molecule into three main categories, namely cationic polymethacrylates; anionic polymethacrylate, and neutral polymethacrylates
  2. Based on solubility and permeability in digestive fluids into two main categories, namely soluble through salt formation with alkaline (L, S, FS) or acidic (E) groups

In reality, significant overlap exists and the ideal method for classifying poly(methacrylate) copolymers is to use both schemes as shown below:

Anionic Polymers

Anionic poly(methacrylate) polymers contain -COOH (methacrylic acid) functional groups, which allows them to dissociate and dissolve at the higher pH of the small intestine and colon. These polymers offer enteric protection to many active ingredients in oral solid formulations in the gastric environment and can trigger drug release at a selected pH for targeted drug delivery. They are available in a wide range of physical forms (aqueous dispersions, organic solvent, granules, and fine powders).

Cationic Polymers

Cationic polymethacrylate polymers are based on dimethyl aminoethyl methacrylate, butyl methacrylate, and methyl methacrylate residues. These grades are cationic and soluble in gastric fluid below pH 5 but become swellable and permeable, but not soluble, above pH 5. For this reason, cationic poly(methacrylate) copolymers can be used for taste-masking and moisture-protection applications. They are available in a wide range of physical forms, including aqueous dispersions, organic solvents, granules, and fine powders.

Neutral Polymers

Neutral poly(methacrylate) copolymers are further divided into two broad groups:

  1. The first group consists of copolymers of ethyl acrylate, methyl methacrylate, and low content of methacrylic acid ester with quaternary ammonium groups. The ammonium groups are present as salts (with Chloride), rendering these molecules neutral. In aqueous media, while insoluble, these copolymers swell to different degrees and are permeable. The degree of permeability is dependent on the number of quaternary ammonium groups. They can be used to sustain drug release (matrix formulation or coatings) and are available in a wide range of physical forms (aqueous dispersions, organic solvent, granules, and fine powders).
  2. The second category is based on copolymers of ethyl acrylate and methyl methacrylate (2:1), however, they do not contain ionic groups and, therefore, only swell in aqueous media independently of pH without dissolving. These grades are generally available as aqueous dispersions with solid content at 30% and 40% respectively (eg, Eudragit NE 30 D and Eudragit NE 40 D). Films prepared from these are insoluble in water but will swell and become permeable when they are in contact with water and exhibit pH-independent drug permeability. Such neutral polymethacrylate aqueous dispersions can be used for controlled-release coatings and wet-granulation binders.

A summary of the various poly(methacrylate) copolymer grades, their names and their application scope in pharmaceuticals is shown in the table below:

 

Chemical Structure & Identifiers

R = COOH

Alkyl = -CH2CH3


Chemical Name Poly(methacrylic acid co-methyl methacrylate) 1:1
CAS Registration Number [25212-88-8]
Empirical Formula n/a
Molecular weight 250 000
EC Number n/a
UNII Code (FDA) T967IEU43C

Regulatory Status

Methacrylic Acid–Ethyl Acrylate Copolymer (1:1) is an approved pharmaceutical excipient. It is listed in the Ph.Eur (Methacrylic Acid–Ethyl acrylate copolymer (1:1)), USP-NF (Methacrylic Acid Copoymer, Type C) and the J.P.E (Methacylic Acid Copolymer LD). It is included in the US FDA Inactive Ingredients Database.  It is also approved for food use in the EU (E1207).

Physicochemical Properties

Physical state Solid
Appearance White fine powder
Acid value (mg KOH/g DS) 300-330
pKa No data
Log P No data
Poured density 0.350-0.42  g/cm3
Tapped density 0.418-0.452 g/cm3
Density (true) 0.820-0.850 g/cm3 depending on grade/supplier
Solubility Insoluble in water and acids. Soluble in Acetone, Ethanol, Ethyl acetate, Sodium hydroxide solutions & intestinal fluids above pH 5.5
Viscosity (dynamic) 10-200 cP

Pharmacopeoeal Specifications

Test USP-NF Ph.Eur B.P
Name Methacrylic acid and ethyl acrylate copolymer Methacrylic acid-ethyl acrylate copolymer 1:1 Methacrylic acid-ethyl acrylate copolymer 1:1
Authorised use Excipient Excipient Excipient
Definition specified specified specified
Characters White, free-flowing powder White, free-flowing powder White, free-flowing powder
Identification A

B

A

B

A

B

Appearance of a film n/a specified specified
Viscosity 100-200 mPa.s 100-200 mPa.s 100-200 mPa.s
Ethyl acrylate and methacrylic acid n/a ≤0.1% ≤0.1%
Heavy Metals ≤0.002% n/a n/a
Loss on Drying ≤4.0% ≤5.0% ≤5.0%
Sulphated Ash n/a ≤0.4% ≤0.4%
Assay 46-50.6% (methacrylic acid units) 46-50.6% (methacrylic acid units) 46-50.6% (methacrylic acid units)
Labelling specified n/a n/a

Key: n/a Specification is not listed

*All claims with respect to conformity are subject to our Terms and Conditions. No express or implied warranty is made for specific properties or fitness for any particular application or purpose.

Applications in Pharmaceutical Formulations or Technology

Methacrylic Acid–Ethyl Acrylate Copolymer (1:1) is an enteric film forming  agent and tablet binder. It is used in oral capsule and tablet formulations as film-coating agents. Methacrylic Acid–Ethyl Acrylate copolymer (1:1) may additionally be used to form the matrix tablet systems. The benefits of using Methacrylic Acid –Ethyl acrylate copolymer (1:1) are:

  • pH-dependent drug release
  • protection of active ingredients that are sensitive to gastric fluids
  • protection against mucosal irritation by intolerable formulation
  • targeted delivery to the ileum

Note that for enteric applications, there are several anionic Poly(methacrylate) copolymers that possess carboxyl groups in varying amounts, and therefore, suitable for use, either alone or in combination with Methacrylic Acid-Ethyl Acrylate copolymer (1:1), as enteric coatings. When the dissolution pH is reached, the polymers dissolve by salt formation, allowing the drug substance to be released in the GI tract.

Pharmacopoeial name Brand Solubility Release site
Methacrylic acid-ethyl acrylate copolymer (1:1) EUDRAGIT®L30 D-55

EUDRAGIT®L 100-55

≥pH 5.5 Duodenum
Methacrylic acid-methyl acrylate copolymer (1:1) EUDRAGIT® L 100

EUDRAGIT® L 12.5

≥pH 6.0 Jejunum
Methacrylic acid-methyl acrylate copolymer (1:2) EUDRAGIT® S 100

EUDRAGIT® S 12.5

≥pH 7.0 Ileum/colon
Poly(methyl acrylate-co-methyl methacylate-co-methacrylic acid) 7:3:1 EUDRAGIT® FS30D ≥Ph 7.0 Ileum/colon

If the interest is in simple enteric coatings that dissolve quickly in the small intestine, the aqueous dispersion, Methacrylic acid-ethyl acrylate copolymer (1:1) 30% dispersion or or the same polymer in spray-dried form, Methacrylic acid-ethyl acrylate copolymer (1:1) are more than adequate. If the drug is to be released lower down in the small intestines, poly(methacrylate) copolymers with higher trigger pH, such as Methacrylic acid-methyl acrylate copolymer (1:1) or Methacrylic acid-methyl acrylate copolymer (1:2) can be used in different mixtures to create specific dissolution profiles.

For release in the colon, grades with dissolution pH of 7 are used. Methacrylic acid-methyl acrylate copolymer (1:2) (e.g EUDRAGIT® S), is the choice for coating tablets while the Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (e.g EUDRAGIT® FS 30D) is recommended for coating multiparticulates due to its greater flexibility.

Preparation of a coating dispersion in water by redispersion of Methacrylic acid-ethyl acrylate copolymer (1:1)

Methacrylic Acid-Ethyl Acrylate copolymer (1:1) is the dry substance of Methacrylic Acid-Ethyl Acrylate copolymer (1:1) 30% dispersion in a re-dispersible form. The redispersion is achieved by the addition of small amount of alkali or organic bases to produce an aqueous suspension of the powder. In this process, about 6 mol-% of the carboxyl groups in the polymer are neutralised; the resistance to gastric juice of the resulting polymer remains unimpaired. The resulting dispersion exhibits similar properties and can be used much the same way as Methacrylic acid-ethyl acrylate copolymer (1:1) 30% dispersion.

Dispersing procedure

A simple stirrer is more than adequate for this task, which can be accomplished at moderate speed. The powder should be added into the water and stirred in a sufficiently moderate speed to prevent sedimentation, being careful not to introduce air.

The following formulation is for 1 kg (sufficient for 10 kg)

Eudragit L 100-55 300 g 30.0 %
1 N Sodium hydroxide solution 100 g 0.4 %
Water 600 g 69.6%
1000 g 100.0 %

The sodium hydroxide solution can be prepared by dissolving 4g of sodium hydroxide pellets in water. 600 g of water is poured into a 2-litre vessel, and 300 g of Eudragit L 100-55 is stirred in portions, ensuring that the powder is thoroughly wetted and no lumps are formed. After stirring for 5–10 mins, the sodium hydroxide is added dropwise and stirred for 5 mins.

Stirring is continued for approx. 30 mins. After this time, a latex-like dispersion is formed, recognised by the formation of a milk-like consistency. This should be filtered by passing it through a 0.25 mm sieve. In the event of foam formation, 2-3 drops of Simethicone-based antifoaming emulsion can be added.

Supplementary ingredients, such as plasticizers, pigments (Titanium dioxide) and anti-tacking agents (Talc) can then be added in much the same way as Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) 30% Dispersion (e.g Eudragit L30 D-55).

Safety and Precautions

Methacrylic Acid–Ethyl Acrylate Copolymer (1:1) is a long-established synthetic polymer that is widely used as an enteric film-coating material in oral pharmaceutical formulations. It is not absorbed or metabolised by the body following oral ingestion. For this reason, it is generally regarded as non-toxic and non-irritant material when used as intended in the specified dosage ranges. A daily intake of 2-200 mg/kg body weight (depending on polymer type) has been set by authorities based on data from chronic oral toxicity studies in animal models.

Toxicology: LD50 (rat, SC): 75g/kg; Carcinogenicity – Not shown.

Stability and Storage Conditions

Methacrylic acid–ethyl acrylate copolymer (1:1) is stable at temperatures <30 °C. Shelf life is assigned as 24-36 months when stored in accordance with the manufacturer’s recommendations. Storage at elevated temperature tends to make powders clump, although this does not affect the quality of the material and any formed clumps are easily disaggregated.

Care should be taken when handling Methacrylic acid copolymers in the workplace. Acute and chronic adverse effects have been reported in individuals who routinely handle closely related substances (Methyl methacrylate and poly(methyl methacrylate). In several countries, the workplace exposure limit for Methyl methacrylate has been set at 208 mg/m3 (50ppm) long-term (8-hour TWA), and 416mg/m3 (100ppm) short-term.

Observe applicable SHEQ protocols when processing Methacrylic acid-ethyl acrylate copolymer. PPE (eye protection, gloves, and a dust mask or respirator) is recommended. Adequate ventilation and procedures to reduce dust formation should be should be in place for the safety of everyone else.

Click here to read more about recommended storage conditions for EUDRAGIT L100-D and EUDRAGIT L30 D-55 aqueous dispersions here:

EUDRAGIT® L100-55 Storage Stability Information Sheet (Evonik)

Sustainability and Environmental Impact

A sustainability score for Methacrylic Acid–Ethyl acrylate copolymer (1:1) has not been provided.

Manufacturers & Suppliers

Evonik Operations GmbH (ex DEGUSSA/Rohm)

  • EUDRAGIT® L100-55

Corel Pharma Tech 

  • ACRYCOAT® L100-55

BASF Corporation

  • Kollicoat® MAE 100 P

Additional Resources (Downloads)

References and Literature Used

FAQS

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