Technical Information Soluble Kollidon January 2004


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Technical Information
January 2004 Supersedes issue of February 2001 Register 2
® = Registered trademark of BASF Aktiengesellschaft

Soluble Kollidon® grades
Soluble polyvinylpyrrolidone (Povidone Ph.Eur, USP, JP) for the pharmaceutical industry

Fine Chemicals

Contents
2

1 Introduction 1.1 General 1.2 Synonyms 1.3 Range and product numbers
2 Specifications and stability 2.1 Specifications 2.2 Pharmacopoeias 2.3 Microbial status, absence of pyrogens 2.4 Residual solvents 2.5 Stability, storage 2.6 Packaging
3 Physical and chemical properties 3.1 Description 3.2 Solubility 3.3 Hygroscopicity 3.4 Viscosity 3.5 Particle-size distribution 3.6 Bulk density 3.7 Stability in solutions, sterilization 3.8 Complexation, chemical interactions 3.9 Molecular weight 3.10 Safety Data Sheets
4 Applications 4.1 General 4.2 Binder for tablets 4.3 Solubilization 4.4 Coprecipitation, comilling 4.5 Stabilizer for suspensions 4.6 Thickening agent 4.7 Ophthalmics 4.8 Sugar-coating 4.9 Film-coating 4.10 Miscellaneous applications 4.11 Food products
5 Toxicological data
6 Note

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1 Introduction
1.1 General
1.2 Synonyms 1.3 Range

The foundations of modern acetylene chemistry were laid by Reppe at BASF. One of the many products to emerge from this work was soluble polyvinylpyrrolidone, which is obtained by radical polymerization of N-vinylpyrrolidone

N

O

N

O

N

O

… CH CH2 CH CH2 CH CH2 … Monomer unit: 111.14

Because of its solubility in water and in many organic solvents, its high binding power and ability to form complexes, soluble polyvinylpyrrolidone occupies a special position among the synthetic colloids.

Separate Technical Data Sheets are available for the insoluble Kollidon grades (crospovidone) and for Kollidon VA 64, a copolymer of N-vinylpyrrolidone and vinyl acetate (copovidone).

More information on Kollidon than can be provided in this brochure may be found in the book, “Kollidon, Polyvinylpyrrolidone for the Pharmaceutical Industry” 7th edition 2003, also available as CD-ROM.

Soluble polyvinylpyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(1-vinyl-2-pyrrolidone) and PVP.

As the requirements differ considerably in the various fields of application, it has been found necessary to create two product lines: the Kollidon grades for pharmaceutical products and the Luviskol® grades for cosmetics and technical applications.

The Kollidon range consists of the following products:

PBG-Number

Kollidon 12 PF

10 011 265

Kollidon 17 PF

10 010 750

Kollidon 25

10 000 996

Kollidon 30

10 066 831

Kollidon 90 F

10 096 088

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2 Specifications and stability

2.1 Specifications

All the soluble grades of Kollidon are of pharmaceutical purity and meet the following specifications:

Table 1 Specifications of the soluble grades of Kollidon

Colour (10% in water)
Clarity (10% in water) K-value Nitrogen content Water (Karl Fischer), % pH value (5 % in water) Vinylpyrrolidone (HPLC), ppm Sulfated ash, % Aldehyde, ppm Heavy metals, ppm Hydrazine, ppm Peroxides (as H2O2), ppm Microbial status (see Table 3) Endotoxins (Ph.Eur.) (6% solution)
Residual solvents (Ph. Eur. 5.4)
2-pyrrolidone

KolIidon 12 PF
lighter than B6/BY6/R6 clear 10.2–13.8 11.5–12.8 ≤ 5.0 3.0–5.0 ≤ 5 ≤ 0.1 ≤ 500 ≤ 10 ≤ 1 ≤ 400 passes test ≤ 6 I.U./ml (≤ 0.1 I.U./mg) ≤ 0.5% 2-propanol ≤ 1.0%

KolIidon 17 PF
lighter than B6/BY6/R6 clear 15.3–18.0 12.0–12.8 ≤ 5.0 3.0–5.0 ≤ 5 ≤ 0.1 ≤ 500 ≤ 10 ≤ 1 ≤ 400 passes test ≤ 6 I.U./ml (≤ 0.1 I.U./mg) ≤ 0.5% 2-propanol ≤ 1.0%

KolIidon 25
lighter than B6/BY6/R6 clear 22.5–27.0 12.0 – 12.8 ≤ 5.0 3.0–5.0 ≤ 10 ≤ 0.1 ≤ 500 ≤ 10 ≤ 1 ≤ 400 passes test not tested
≤ 0.5% formic acid ≤ 3.0%

KolIidon 30
lighter than B6/BY6/R6 clear 27.0–32.4 12.0 – 12.8 ≤ 5.0 3.0–5.0 ≤ 10 ≤ 0.1 ≤ 500 ≤ 10 ≤ 1 ≤ 400 passes test not tested
≤ 0.5% formic acid ≤ 3.0%

KolIidon 90 F
lighter than B6/BY6/R6 clear 81.0–96.3 12.0 – 12.8 ≤ 5.0 4.0–7.0 ≤ 10 ≤ 0.1 ≤ 500 ≤ 10 ≤ 1 ≤ 400 passes test not tested
≤ 0.5% formic acid ≤ 1.0%

All the physical and chemical properties are determined by the methods in the European Pharmacopoeia or the USP.

2.2 Pharmacopoeias

All the Kollidon grades meet the requirements of the current harmonized monographs for povidone in the following pharmacopoeias:

Table 2 Soluble Kollidon in the Pharmacopoeias

Product name

Ph. Eur.

USP/NF

JP/JPE

Kollidon 12 PF

+

+

n. a.

Kollidon 17 PF

+

+

+

Kollidon 25

+

+

+

Kollidon 30

+

+

+

Kollidon 90 F

+

+

+

n. a. = not available

2.3 Microbial status, endotoxins

The microbial status is determined by Ph. Eur. 4 methods 2.6.12 and 2.6.13. The limits given in the European Pharmacopoeia (Table 3) apply to all the soluble Kollidon grades.
Table 3 Microbial purity requirements (Ph. Eur. 4, 5.1.4, Categories 2 + 3A)
– Max. 102 aerobic bacteria and fungi/g – No Escherichia coli/g – Max. 10 Enterobacteriaceae and other gram-negative bacteria/g – No Pseudomonas aeruginosa/g – No Staphylococcus aureus/g
Kollidon 12 PF and Kollidon 17 PF are tested for bacterial endotoxins by Method 2.6.14 in the 4th edition of the European Pharmacopoeia. A 6% solution of Kollidon in isotonic sodium chloride solution is tested.

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2.4 Residual solvents 2.5 Stability and storage
2.6 Packaging

The Kollidon grades fulfill the requirements of the ICH guidelines (Class 3, Ph. Eur. 5.4)
The soluble Kollidon grades retain the properties given in the specifications over a period of more than three years, if they are stored in the unopened original containers at room temperature (20–25 °C). Kollidon 90 F is an exception in that, under these conditions, its stability can be guaranteed, as its K value gradually decreases.
If Kollidon 90 F is kept refrigerated, its K value decreases more slowly.
Kollidon must be stored tightly closed and protected from light at max. 25 °C.
Kollidon 12 PF and Kollidon 17 PF: 50-kg PE drum with PE inliner.
Kollidon 90 F: 25-kg carton with welded PE/aluminium inliner.
Kollidon 25 and Kollidon 30: until 2001: 50-kg drum with PE inliner from August 2001: 25-kg carton with welded PE/aluminium inliner.

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3 Physical and chemical properties

3.1 Description

All grades of Kollidon are supplied in the form of an almost white free-flowing powder. They have a slight characteristic odour and are practically tasteless.

3.2 Solubility

The solubility of Kollidon varies considerably from one solvent to another. In Table 4 below, “soluble” signifies that a solution of at least 10% can be prepared, and “insoluble” signifies that the solubility is less than 1%.
Table 4 Solubility of Kollidon

Soluble in:

chloroform cyclohexanol ethanol abs. glycerine isopropanol methanol methylene chloride

n-butanol n-propanol polyethylene glycol 400 (= Lutrol® E 400) propylene glycol triethanolamine water

Insoluble in:

cyclohexane diethyl ether ethyl acetate liquid paraffin

pentane carbon tetrachloride toluene xylene

3.3 Hygroscopicity

The hygroscopic nature of Kollidon is important in many applications. There is hardly any difference between the individual grades so that the same curve applies to all (Fig. 1).

Fig. 1 Hygroscopicity of soluble Kollidon 6

3.4 Viscosity

Fig. 2 shows the relationship between the viscosity of aqueous solutions of the different grades of Kollidon and their concentration.

3.5 Particle-size distribution

Fig. 2 Viscosity of Kollidon solutions (Ubbelohde viscometer, 25 °C)

In the pharmaceutical technology of solid dosage forms, particularly in the direct compression of tablets, the particle-size distribution of the solid ingredients used is a factor of some significance.
The following table gives some typical particle-size distribution values (determined in an air-jet sieve; 5 min, 20 mbar):

Table 5 Particle-size distribution, %

< 50

Kollidon 25/30

approx. 10

Kollidon 90 F

max. 10

> 250 max. 5 max. 20

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3.6 Bulk density
3.7 Stability in solution, sterilization
3.8 Complexation, chemical interactions
3.9 Molecular weight
3.10 Safety Data Sheets
4 Applications
4.1 General

The bulk density of Kollidon is determined according to Ph. Eur. 4, Section 2.9.16.

Table 6 Bulk density of the Kollidon grades

Kollidon 12 PF

400–600 g/l

Kollidon 17 PF

400–600 g/l

Kollidon 25/30

400–600 g/l

Kollidon 90 F

400–550 g/l

Aqueous solutions of povidone have no buffering action. If left to stand, and particularly if heated, they take on a slight yellowish colour. The yellowing can be diminished by adding a reducing agent, e. g. sodium metabisulfite or cystein. Local legislation on the use of sodium metabisulfite in parenterals must be observed.
For sterilization purposes, 0.01–0.1% sodium metabisulfite or 0.05–0.1% cystein, as a proportion of the Kollidon, is added to the solution which is then heated in the absence of air.
Povidone can form fairly stable association compounds or complexes with a number of active substances. The best known example is PVP-iodine which is the subject of a separate leaflet.

The ability of Kollidon to form a water-soluble complex with insoluble active substances can be used in pharmaceuticals to improve the release rate and solubility of drugs (see Sections 4.3 and 4.4).
There are a few substances such as the polyphenols that form stronger complexes that can precipitate in neutral or acidic media. This effect can be used in the removal of polyphenols and anthocyanogens from solutions or beverages. However, insoluble polyvinylpyrrolidone (Kollidon CL) is most suitable for this purpose.
It must be noted that if povidone is combined with strongly alkaline substances such as lithium carbonate or sodium hydroxide it can crosslink and become insoluble, particularly at elevated temperatures. In extreme cases, this can increase the viscosity of liquid presentation forms and delay bioavailability in solid presentation forms.

With polymers generally, the average molecular weight can be expressed in three forms: weight, number and viscosity average.

The molecular weight of povidone is usually expressed as the K-value, from which it is possible to calculate the viscosity average molecular weight (Mv).
However, the weight average molecular weight (Mw) is found more frequently in the literature. It is determined by methods such as light scattering that measure the weight of the molecules.

The following Mw values were determined for different grades of Kollidon in recent measurements.

Kollidon 12 PF

2 000 –

3 000

Kollidon 17 PF

7 000 –

11 000

Kollidon 25

28 000 –

34 000

Kollidon 30

44 000 –

54 000

Kollidon 90 F

1 000 000 – 1 500 000

Earlier measurements of Mw that were not quite so accurate gave values of 40,000 for Kollidon 30 and 700,000 for Kollidon 90, for example.

Safety Data Sheets for the individual grades of Kollidon are available on request.

The main applications of the soluble Kollidon grades are summarised in Table 7. 8

4.2 Tablet binders

Table 7: Main applications of the soluble Kollidon grades

Binder

Tablets, capsules, granules

Bioavailability enhancement Tablets, capsules, granules, pellets, suppositories, transdermal systems

Film formation

Opthalmic solutions, tablets, medical plastics

Solubilization

Oral, parenteral and topical solutions

Taste masking

Oral solutions

Lyophilising agent

Injection preparations, oral lyophilisates

Stabilisation of suspensions Oral and parenteral suspensions, instant beverage powders and granules

Hydrophylization

Medical plastics, retard preparations, suspensions

Adhesives

Transdermal systems, adhesive gels

Drug stabilisation

Enzymes in diagnostics

Toxicity reduction

Injection preparations

The adhesive, film-forming, dispersing and thickening properties of the soluble Kollidon grades are used in tablet production, sugar coating, film coating and in the preparation of other dosage forms. The improvement in the solubility of active ingredients brought about by complexation or association, and the thickening effect find use mainly in the manufacture of liquid presentation forms.

The grade of Kollidon that is selected depends mainly on its molecular weight, as this dictates the viscosity, binding effect, the complexation capacity and how readily it is eliminated from the body.

A detailed description of the applications is to be found in the book, “Kollidon, polyvinylpyrrolidone for the Pharmaceutical Industry” (BASF, MEFM09015e, 2003 edition).

Kollidon 25, 30 and 90 F
Kollidon 25, 30 and 90 F give hard, free-flowing granules for tablet making with a low proportion of fines and high binding strength. For Kollidon 25 and 30, the quantity required lies between 2% and 5% of the tablet weight. For Kollidon 90 F, less than 2% is generally required, because of its great binding capacity. The high viscosity of binder solutions made with Kollidon 90 F sometimes requires certain precautions to ensure that the granules are evenly wetted. Granulators or spraying machines that have a strong mixing action are helpful.
The addition of polyethylene glycol 400 (Lutrol E 400) as a plasticizer or the replacement of the povidone with Kollidon VA 64 is often helpful if the granules are too brittle.
Kollidon 25, 30 and 90 F are also suitable for the direct compression of tablets without granulation (prior to 1993, Kollidon 90 was unsuitable for this purpose because of its particle size). This technique requires a certain relative humidity, as the powder mixture must have a certain moisture content to bind properly. If Kollidon is used in addition to microcrystalline cellulose, it not only makes the tablets harder but also gives them stronger edges. For best results in direct compression, all the excipients should have a certain moisture content. This applies to starch, microcrystalline cellulose and lactose monohydrate as fillers.
It can be seen from Fig. 3 that there is hardly any difference in the hardness of lactose placebo tablets made with Kollidon 25 and Kollidon 30. However, the same quantity (3 % of the tablet weight) of Kollidon 90 F almost doubles the hardness, compared with Kollidon 25.

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4.3 Solubilization

Fig. 3 Lactose monohydrate tablets with 3% Kollidon (wet granulation)

Kollidon is also suitable as a binder for modern processes such as fluidized-bed granulation. Thanks to their relatively low viscosity, solutions of Kollidon 25 and Kollidon 30 can be prepared relatively quickly, and sprayed easily, to quickly give hard dust-free uniform granules. If the spray includes pigments, Kollidon improves their distribution.

A typical formulation for wet granulation with Kollidon 30 is given below in Table 8 for alpha-methyldopa tablets. The formulation was tried out on a laboratory scale.

Table 8 Alpha-methyldopa tablets and cores (275 mg)

I Alpha-methyldopa

275 g

Lactose monohydrate

55 g

II Kollidon 30

15 g

Isopropanol

80 ml

III Kollidon CL

8 g

Magnesium stearate

2 g

Granulate mixture I with solution II, dry, sieve, mix with the ingredients in III and compress into tablets on a rotary tablet press with medium force (approx. 15 kN).

The tablets produced in the laboratory had the following properties:

Weight (measured)

361 mg

Diameter:

12 mm

Hardness:

118 N

Disintegration time (gastric juice):

5 min

Friability:

0 %

Dissolution acc. to USP in 0.1 N hydrochloric acid:

15 min: 77% 30 min: 98%

Some examples are given as in Table 9 of typical drugs that can be solubilized with soluble Kollidon.

Table 9 Some of the active ingredients that can be solubilized with soluble Kollidon

Acetaminophen (paracetamol) Allopurinol Amoxicillin Chloramphenicol Clonazepam Coumarin Diclofenac-Na Doxycycline Furaltadone Hydroflumethiazide Nitrofural

Oxytetracycline Reserpine Rifampicin Sulfadimethoxine Sulfamethazine Sulfamoxole Sulfathiazole Tranilast Trimethoprim Tyrothricin

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Technical Information Soluble Kollidon January 2004