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Copovidone Excipient | Uses, Suppliers, and Specifications

Copidone, also known as Vinylpyrrolidone-vinyl acetate or Copolyvidone, is a synthetic random copolymer of 1-vinyl-2-pyrrolidone and viny acetate. It is obtained by free-radical polymerisation of 6 parts of vinylpyrrolidone and 4 parts of vinyl acetate. Copovidone is supplied in fine particle form and appears as a white to yellowish powder with a faint taste and odour.

Synonyms and Trade Names: Copovidone; Copolyvidone; Vinylpyrrolidone-vinyl acetate copolymer; Copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 3:2 by mass; Copolyvidone; Poly (1-vinylpyrrolidone-co-vinyl acetate); Polyvinylpyrrolidone-vinyl Acetate Copolymer; PVP/VA; PVP/VA Copolymer; Kollidon VA 64; Plasdone® Crospovidone

Pharmacopoeial Compliance: USP-NF; Ph. Eur; B.P; IP; J.P.E

Uses and Applications: Granulation Aid; Dry Binder; Film Forming Polymer; Moisture Barrier Polymer; Matrix Former; and Solid Dispersions Polymer

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Copovidone - JH Nanhang

Kollidone® VA 64 - BASF

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Kollidone® VA 64 Fine - BASF

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Description

Copovidone, which is also known as Vinylpyrrolidone-vinyl acetate or Copolyvidone, is acetic acid ethenyl ester polymer with 1-etheny1-2 pyrrolidinone. It is a synthetic random copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio (by weight) of 6:3. In the USP-NF and Ph.Eur Copovidone is defined as a copolymer of 1-ethenylpyrrolidin-2-one and ethenyl acetate in the mass proportion of 3:2. It is an analogue of Povidone, and corresponds to the general chemical formula shown below:

(C6H9NO)n (C4H6O2)m (111.1)n + (86.1)m (the ratio of n to m is approximately n = 1.2m).

Copovidone’s (average) molecular weight is usually expressed as a K-value. The K-value of Kollidon®  VA 64 (BASF) is nominally 28, with a range of 25.2-30.8 while the K-value for Plasdone® S 630 (Ashland) is specified to be between 25.4 and 34.2. K-values are calculated from the kinematic viscosity of a 1% aqueous solution. From this information, the molecular weight can be calculated using the formula below:

M = 22.22 (K + 0.075K2)1.65.

Copovidone, together with the other polyvinylpyrrolidone polymers (e.g Povidone and Crospovidone) are some of the many materials that were first commercialised by BASF in the early 1930s as part of the company’s acetylene chemistry programme (started and led by the chemist, Walter Reppe). Over the course of several decades, Pyrrolidones have been adapted and applied across multiple fields, including pharmaceuticals, cosmetics, and food owing to versatility, solubility and consistency in their many performance attributes.

The method used to synthesise Copovidone is very much similar to that used by Povidone, that is, the Reppe process is used to produce Polyvinylpyrrolidone, which is then copolymerised with Vinyl acetate. However, as the Vinyl acetate is insoluble in water the reaction is carried out in an organic solvent rather than water. The presence of Vinyl acetate in the molecule renders Copovidone more hydrophobic compared with Povidone and also makes its films less brittle. Indeed, it was the desire to improve upon Povidone’s technological attributes that motivated the development of povidone derivatives.

Compared with Povidone, Copovidone is more versatile as an excipient. It also exhibits greater plasticity and gives granules and powder mixtures flexibility to deform thereby reducing tendencies to undergo capping and lamination during tabletting. Copovidone is supplied as a white to white-yellow amorphous, finely divided powder.

Chemical Structure & Identifiers


Chemical Name Acetic acid ethenyl ester, polymer with 1-etheny1-2 pyrrolidinone
CAS Registry Number [25086-89-9]
Empirical Formula (C6H9NO)n  (C4H6O2)m (111.1)n + (86.1)m

The ratio of n to m is approximately n = 1.2m

Molecular Weight Molecular weights of 45,000-70,000 have been determined for Koliidon VA 64. The average molecular weight of Copovidone is usually expressed as a K-value.

The K-value of Kollidon VA 64 is nominally 28, with a range of 25.2-30.8. The K-value of Plasdone® S 630 is specified between 25.4 and 34.2. K-values are calculated from the kinematic viscosity of a 1% aqueous. Molecular weight can be calculated with the formula

M = 22.22 (K + 0.075K2)1.65

The Ph.Eur and USP-NF describe Copovidone as a copolymer of 1-ethenylpyrrolidin-2-one and ethenyl acetate in the ratio (by mass) of 3:2

EINECS Number 607-540-1
FDA UNII Code D9C330MD8B

Regulatory Status

Copovidone is an approved pharmaceutical excipient. It is listed in the USP-NF, PhEur, B.P, and J.P.E. Copovidone is also included in the US FDA Inactive Ingredients Database. A specification for Copovidone is included in the Food Chemicals Codex.

Physicochemical Properties

Physical form Solid, powder
Appearance White, cream to yellowish finely divided powder
pH value 3.0-7.0
pKa -1.4 (Computed)
Log P -1.1
Bulk density Standard grades: 0.20-0.30 g/ml

Fine grades: 0.08-0.15 g/ml

Tapped density Standard grades: 0.30-0.45 g/ml
Density (true) 1.1 g/ml
Flashpoint 215 0C
Flowability Poorly flowing to relatively free-flowing powder
Glass transition temperature 100 – 110 0C
Hygroscopicity Absorbs <10% weight at 50% RH
K-value -630 Dependent on the supplier/grade. For Plasdone®, K value = 25 – 35
Melting point 140 0C
Solubility Soluble in water (179g/l). Soluble in ethanol, isopropyl alcohol, propylene glycol and glycerol (a 10% w/w solution can be easily prepared)
Viscosity (Brookfield) Viscosity of aqueous solutions varies with concentration and molecular weight of the polymer. A 5% w/v solution has a viscosity of 4-5 mPas (25 oC)

Pharmacopeoeal Specifications

USP-NF Ph.Eur B.P
Official name Copovidone Copovidone Copovidone
Authorised use Excipient Excipient Excipient
Identification specified specified Specified
Characters White or yellowish- white, hygroscopic powder White or yellowish-white hygroscopic powder White or yellowish-white hygroscopic powder
Identification A

B

C

A

B

C

A

B

C

Solution S specified specified specified
Appearance of solution specified specified Specified
Aldehydes ≤500 ppm ≤500ppm ≤500ppm
Peroxides ≤400 ppm ≤400 ppm ≤400 ppm
Monomers ≤0.1% ≤0.1% ≤0.1%
Impurity A ≤0.5% ≤0.5% ≤0.5%
Hydrazine ≤ 1 µg/g ≤1 ppm ≤1 ppm
Heavy metals ≤10ppm ≤20 ppm ≤20 ppm
Sulphated ash ≤0.1% ≤0.1% ≤0.1%
Loss on drying ≤5% ≤5% ≤5%
Residue on ignition ≤0.1% n/a n/a
Assay specified specified specified
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

Copovidone was developed as an improvement over Povidone (binder). Its favourable technical properties, namely better flowability, lower hygroscopicity, spherical particle shape, plasticity, lower glass-transition temperature, and hydrophobic–hydrophilic balance, rendered Copovidone highly advantageous in direct compression and roller-compaction tabletting operations. While Copovidone is still used as a dry binder (for direct compression and roller compression), its main utility is as a matrix former for the development of solid dispersions, film former (especially in the formulation of moisture-barrier coatings), and as a matrice former for sustained-release solid dosage forms.

1). Binder in Tablets 

Copovidone performs superbly as a dry binder for direct compression applications. It is particularly preferred for formulations susceptible to capping due to its plasticity. Finer grades have demonstrated superior binding performance compared with either Povidone and Cellulose-based polymers. Formulations developed with Copovidone show a direct relationship between tablet hardness, friability, porosity and disintegration with the applied compaction force.

2). Binder in Wet Granulation

The high solubility of Copovidone in water and standard granulation liquids makes it as an ideal binder in wet granulation operations. It may be added either as a solution or in the form of a dry powder followed by the addition of the granulating solvent or a combination of both. Copovidone, owing to its low hygroscopicity, allows greater predictable granulation endpoints and its granules have a much less propensity to stick to tooling, even when conducted under less favourable conditions.

3). Roller Compression

Copovidone has been shown to be particularly well-suited for use in roller compaction. It is an excipient of choice when particle size distribution and particle shape considerations are critical during roller compression process design. Owing to its spherical shape and fine size Copovidone gives better surface coverage and develops multiple bridges that lead to hard tablets with a reduced friability.

4). Film-Coating Film Former

Copovidone is a film former and it soluble membranes whose solubility is independent of pH. Copovidone films are also less hygroscopic, but more flexible compared with those formed by Povidone. For best results, it’s used in combination with other film-forming polymers that are less hygroscopic. Due to its flexibility, a plasticizer is not required.

5). Polymer for Amorphous Solid Dispersions

Copovidone is a suitable polymer for developing amorphous solid dispersions that are both kinetically and thermodynamically stable. Both spray-drying and hot melt extrusion approaches can be reliably used.

6). Other Uses

  • Inhibition of crystallisation of APIs in liquid soft-gel formulations
  • Sugar coating applications (to improve adhesion)
  • Subcoating of tablets (film coating)

Safety and Precautions

Copovidone has been used in pharmaceuticals for several decades as an excipient. It is generally regarded as nontoxic raw material. The US FDA now considers it GRAS (Self Affirmed) and has approved its use in food and nutritional supplements. It has no irritating or sensitizing effects on the skin. The safety of Copovidone as an excipient in solid oral dosage forms is evidenced by several non-clinical studies. These studies have demonstrated the absence of any significant toxicological effects (in animal models), resulting in no-observed-adverse-effect levels of 2800 mg/kg body-weight/day in rats and 2500mg/kg body-weight/day in dogs.

Toxicology: LD50 (rat. oral): >0.63g/kg. Carcinogenicity: Not evidenced

Stability and Storage Conditions

Copovidone is stable and should be stored in a well-closed container in a cool, dry place. The standard shelf life is given as 24 months. However, when Copovidone is exposed to high moisture levels, its stability may be reduced. Correct storage of the raw material is therefore highly advised.

In order to minimise any adverse effects, observance of SHEQ precautions consistent with operational circumstances and the quantity of material handled is advised. The use of eye protection, gloves, and a dust mask is also advised.

Sustainability and Environmental Impact

A Sustainability Score for Copovidone has not yet been computed.

Manufacturers & Suppliers

BASF Corporation

  • KOLLIDON® VA 64
  • KOLLIDON® VA64 FINE

Ashland Inc

  • PLASDONE® S630

JH Nanhang

  • COPOVIDONE

Additional Resources (Downloads)

References and Literature Used

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