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Polyvinylpyrrolidone (PVP) – One of the Most Widely UsedExcipients in Pharmaceuticals: An OverviewBy: Hubertus Folttmann, PhD, and Anisul Quadir, PhD, MBA

TThe chemistry of acetylene,developed at BASF in the1920s by Walter Reppe,

opened up numerous applicationpossibilities, especially in the youngfield of plastics. In 1938, the yearNylon and Perlon were discovered,BASF succeeded in using acetylenechemistry to develop a highlyinteresting derivative: by reactingacetylene with pyrrolidone,vinylpyrrolidone was obtained, whichin turn was used to formpolyvinylpyrrolidone (PVP). Theprocess patent was granted on January1, 1939.

It soon became apparent that PVPwas an all-around talent. It is readilysoluble in water, physiologicallycompatible, non-toxic, essentiallychemically inert, temperature-resistant,pH-stable, non-ionic, and colorless.This remarkable combination ofproperties predestined its use innumerous applications in medicine,pharmaceutical technology, cosmetics,and in the technical industry. Even asearly as 1939, PVP was used as aplasma expander and was widely usedin this form during World War II.During the 1950s, PVP replaced theschellac hitherto used in hair sprays.This article, however, deals with theapplications of PVP in thepharmaceutical industry.

POLYVINYLPYRROLIDONE(POVIDONE)

Structure, Properties & ProductRange

Soluble PVP products are obtainedby the radical polymerization ofvinylpyrrolidone, giving the structure inFigure 2. Drying is carried out either byspray- or drum-drying. This results in awhite-to-yellow-white powder. SolublePVP in aqueous solution has a veryslight taste of its own.

The soluble PVP products ofpharmaceutical quality are designatedas Povidone in the USP. Today’s range

comprises products of different K-values. The K-value characterizes themean molecular weight (eg, PovidoneK 12, Povidone K 17, Povidone K 25,Povidone K 30, and Povidone K 90).BASF markets these products underthe brand name Kollidon®; ISP ismarketed as Plasdone®. As theseproducts are widely used, they aremonographed in numerouspharmacopoeias, eg, Ph Eur, USP, andJP/JPE. Table 1 lists the currentpharmacopoeial requirements.

One of the outstanding propertiesof the soluble PVP products is theiruniversal solubility in hydrophylic andhydrophobic solvents. Povidone, for

F I G U R E 1

Reppe’s Synthesis of N-vinylpyrrolidone

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example, is practically infinitely soluble instandard pharmaceutical solvents,although at high concentrations, thesolution becomes highly viscous. Themean molecular weight of the Povidonegrades is characterized by the K-value inthe European and US pharmacopoeias. Itis always included as part of thetradename and is calculated from therelative viscosity in water. Povidone ishygroscopic, a particular advantage in itsmain application as a tablet binding agent.

The following MW values (weightaverage molecular weight) weredetermined for different grades ofPovidone in recent measurements:Povidone K 12 (2000-3000),

Povidone K 17 (7000-11000),Povidone K 25 (28000-34000), PovidoneK 30 (44000-54000), and Povidone K 90(1000000-1500000). With the exceptionof very few particles, the particle sizedistribution of the products is within therange 50 µm to 250 µm. The bulk densityis approximately 400-600 g/l.

Povidone can form fairly stableassociation compounds or complexeswith a number of active substances. Thebest-known example is PVP-iodine, oneof the most important disinfectants incurrent use. The ability of Povidone toform a water-soluble complex withinsoluble active substances can be used inpharmaceuticals to improve the releaserate and solubility of drugs. It must benoted, however, that if Povidone iscombined with strongly alkalinesubstances, such as lithium carbonate orsodium hydroxide, it can cross-link andbecome insoluble, particularly at elevatedtemperatures. In extreme cases, this canincrease the viscosity of liquidpresentation forms and delaybioavailability in solid forms.

Povidone possesses the followingproperties that make it ideal for numerousapplications in drug manufacture:

• Solubility in all conventionalsolvents

• Adhesive and binding powers

• Film formation

• Affinity to hydrophilic andhydrophobic surfaces

• Ability to form complexes

• Availability in different meanmolecular weights

• Thickening properties

The main applications of Povidone(including functions and dosage forms) inthe pharmaceutical industry can be seen inTable 2.

As a Binder in Tablets, Granulates& Capsules

The main application area forPovidone K 25, K 30, and K 90 is as abinder in tablets and granulates (Table 3).The binding effect is achieved both in wetand dry granulation and in direct tabletcompression.

While Povidone K 25 and K 30 arevery similar, the binding effect ofPovidone K 90 is considerably greater;this means that only about half theconcentration of Povidone K 90 needs tobe used. Due to their excellent solubilityin water, the Povidone grades, in spite oftheir excellent binding qualities, havehardly any negative effect on the

disintegration time of the tablets. Wetgranulation with Povidone K 25, K 30, orK 90 results generally in hard granulateswith excellent flow properties. Povidonecan be used with all current granulationtechniques. Povidone K 25 and K 30 aresuitable for the manufacture ofeffervescent tablets as they, due to theirhigh degree of solubility, rapidly formclear solutions. Interesting applicationsfor K 25, K 30, and K 90 as binders arethe wet granulation of excipients fordirect tablet compression (eg, Ludipress®,Kollidon® SR) and the granulation ofdirectly compressible active substancesfor tablets. Active substances marketed inpre-granulated form for direct tabletcompression are usually those substancesthat are difficult to compress or that aresubject to hydrolysis. Typical examplesare vitamins and acetaminophen.

Apart from wet granulation, thePovidone grades are also used in drygranulation (eg, drum compression) or indirect tablet compression. However, fordirect tablet compression, the moreplastic and less hygroscopic Copovidoneis the more suitable.

Specifications of the Povidone grades

Povidone K 12 Povidone K 17 Povidone K 25 Povidone K 30 Povidone K 90

Colour (10% in water) lighter than lighter than lighter than lighter than lighter thanB6/BY6/R6 B6/BY6/R6 B6/BY6/R6 B6/BY6/R6 B6/BY6/R6

Clarity (10% in water) clear clear clear clear clear

K-value 10.2-13.8 15.3-18.0 22.5-27.0 27.0-32.4 81.0-96.3

Nitrogen content (%) 11.5-12.8 12.0-12.8 12.0-12.8 12.0-12.8 12.0-12.8

Water (Karl Fischer, %) ≤ 5.0 ≤ 5.0 ≤ 5.0 ≤ 5.0 ≤ 5.0

pH value (5% in water) 3.0-5.0 3.0-5.0 3.0-5.0 3.0-5.0 4.0-7.0

Vinylpyrrolidone (ppm, HPLC) ≤ 10.0 ≤ 10.0 ≤ 10.0 ≤ 10.0 ≤ 10.0

Sulfated ash (%) ≤ 0.1 ≤ 0.1 ≤ 0.1 ≤ 0.1 ≤ 0.1

Aldehyde (ppm) ≤ 500 ≤ 500 ≤ 500 ≤ 500 ≤ 500

Heavy metals (ppm) ≤ 10.0 ≤ 10.0 ≤ 10.0 ≤ 10.0 ≤ 10.0

Hydrazine (ppm) ≤ 1.0 ≤ 1.0 ≤ 1.0 ≤ 1.0 ≤ 1.0

Peroxides (ppm H2O2) ≤ 400 ≤ 400 ≤ 400 ≤ 400 ≤ 400

Microbial status (see Table 3) passes test passes test passes test passes test passes test

Endotoxins (Ph.Eur.) ≤ 6 I.U./ml ≤ 6 I.U./ml not tested not tested not tested(6% solution) (≤ 0.1 I.U./mg) (≤ 0.1 I.U./mg)

Residual solvents ≤ 0.5% ≤ 0.5% ≤ 0.5% ≤ 0.5% ≤ 0.5%(Ph. Eur. 5.4) 2-propanol 2-propanol formic acid formic acid formic acid

2-pyrrolidone (%) ≤ 3.0 ≤ 3.0 ≤ 3.0 ≤ 3.0 ≤ 3.0

T A B L E 1

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Toshiba

Highlight

Improvement of the Release &Bioavailability of Active Substances

Two problems are frequentlyencountered with many active substances:their low degree of solubility in water andtheir limited bioavailability. One simplemethod to improve solubility is to add asolubilizer such as Povidone. With manyactive substances, Povidone forms solublecomplexes. In some cases, a physicalmixture of an API and Povidone is quiteadequate. Apart from that, severalmethods have been used to increase thesurface interface between active substanceand solubilizer. In such cases, soliddispersions or solid solutions are suitable.In solid dispersions, the active substanceis embedded in a hydrophilic carrier (eg,

Povidone), possibly in fine crystallineform. In solid solutions, the activesubstance is in an amorphous, molecular-disperse form within the matrix(Povidone). Povidone is suitable for themanufacture of solid dispersions or solidsolutions as it possesses hydrophylicproperties, is available in variousmolecular weights and viscosities, formswater-soluble complexes with many activesubstances, and is almost universallysoluble.

Suitable processes include mixing,co-milling, or melt-extrusion of thePovidone-drug mixture, co-precipitation,granulation onto a carrier, or spray-dryinga solution containing the drug andPovidone. Numerous drugs are available

on the market as solid dispersions or solidsolutions. In some cases, a positiveinfluence on bioavailability is described inthe literature. The most frequently testeddrug mentioned is most likely Nifedipine.

The low-molecular grades, PovidoneK 12 and K 17, are used as solubilizingagents, dispersants, and crystallizationinhibitors, particularly for injectables.This application is used in particular forantibiotics in solution or in lyophylizedform. Povidones with higher K-valuesmay not be administered parenterally as,due to their high molecular weights, theycannot be excreted by the kidneys andhence accumulate within the body. Theuse of Povidone grades K 12 and K 17 assolubilizers in parenteral applications is afrequent one for veterinary drugs;however, it has not been approved for usein humans in all countries.

Povidone K 25 and K 30 can be usedas solubilizers in preparations for oral ortopical applications in the same way asPovidone K 12 and K 17 are used ininjectables. One typical example is theformulation of acetaminophen syrup, inwhich Povidone K 25 increases thesolubility of the drug and also reduces itsbitter taste.

Other Applications

STABILIZER OF SUSPENSIONS: ThePovidone grades can be used insuspensions, dry granulates, and drysyrups as physical stabilizers. The mostimportant function of these hydrophylicpolymers in such cases is as a protectivecolloid; the individual solid particles arerendered hydrophylic and separatedsterically. In this way, dispersibility isimproved and the sediment volume can beincreased. A further general function ofPovidone is that it can preventcrystallization of the dissolved activesubstance by forming soluble complexeswith it. The low-molecular Povidones K12 and K 17 can also be used to stabilizeparenteral suspensions.

OPHTHALMIC PREPARATIONS: Becauseof its solubilizing, film-forming, and

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F I G U R E 2

The Chemical Structure of Polyvinylpyrrolidone (Povidone)

Function Dosage Form

Binder Tablets, Capsules & Granules

Bioavailability Enhancer Tablets, Capsules, Granules, Pellets, Suppositories & Transdermal Systems

Film Former Ophthalmic Solutions, Tablet Cores & Medical Plastics

Solubilizer Oral, Parenteral & Topical Solutions

Taste-Masker Oral Solutions & Chewable Tablets

Lyophilization Agent Injectables & Oral Lyophilizates

Suspension Stabilizer Suspensions, Instant Granules & Dry Syrups

Hydrophilizer Medical Plastics, Sustained Release Forms & Suspensions

Adhesive Transdermal Systems & Adhesive Gels

Stabilizer Enzymes in Diagnostics & Different Drug Forms

Toxicity Reducer Injectables, Oral Preparations, etc

T A B L E 2

Main Applications of Povidone


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thickening properties, Povidone is usedin ophthalmic preparations. This ensuresthat the preparation remains in the eyefor a certain amount of time to lubricateit or to solubilize the active ingredient.This application requires between 2%and 10% Povidone. The bioavailabilityof some APIs in ophthalmic preparationscan be improved by adding Povidone.Povidone is also used in cleaning fluidsfor contact lenses.

SUGAR COATING: In sugar coating,Povidone K 25 or K 30 is mostly useddue to their following properties:

• Prevention of micro-cracks on thecoating

• Adhesion of the sugar coating ontothe core when hydrophobic activesubstances are being used

• Homogeneous distribution of thepigment or lacqueur in the coating

• Stabilization of the sugarsuspension

• Slower and more homogeneouscrystallization of the sugar

The prevention of micro-cracks isextremely important if large batches areto be prepared or if rapid drying isimportant. As most active substances arehydrophobic, Povidone helps to preventthe sugar coating from cracking.

FILM COATING: Due to its alreadymentioned film-forming and adhesiveproperties in sugar coating and its abilityto form dispersions with pigments,Povidone is also used in film coating.However, it is never used as the sole film-former due to its hygroscopicity.Povidone, when added to other solublefilm coatings increases the dissolutionspeeds of the other film-formers,resulting in the disintegration of the tabletand the release of active substance beingaccelerated.

MISCELLANEOUS APPLICATIONS: Apartfrom the aforementioned applications, the

soluble grades of Povidone can be usedfor the following purposes:

• As adhesives in gels (eg, dentures)

• Stabilization of nitroglycerine intransdermal systems

• Regulation of the release of activesubstances in controlled-releasepreparations and transdermalsystems

• Hydrophilization and poreformation in plastics for medicalapplications (eg, hollow fibers)

• Reduction of the toxicity of certainactive substances

• Cryoprotection, lyophilization

• Enzyme stabilization (eg,diagnostics)

• Vitamin stabilization

CONCLUSION

The unique properties of Povidone,such as its high solubility in solvents ofdiffering polarities, its solubilizing andfilm-forming abilities, its suspension andemulsion-stabilizing effects and, last butnot least, its binding properties, make itone of the most important excipients inpharmaceutical technology. Scientistskeep working on numerous alternativeapplications of Povidone.

MORE LITERATURE

Bühler V. Kollidon® Polyvinylpyrrolidone for the

Pharmaceutical Industry. 9th ed. BASF SE;2008.

Technical Information. Soluble Kollidon® Grades.

BASF;June 2007.

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Dr. HubertusFolttmannis a pharmacistby education.After 12 yearsof experience indifferentfunctions in thepharmaceuticalindustry, he

joined BASF in 1998. His currentposition at BASF SE is the Head ofGlobal Marketing, PharmaceuticalExcipients. His areas of expertiseinclude binders, disintegrants,coatings, and solubilizers. He can bereached by email [email protected].

Dr. AnisulQuadir is theTechnicalDevelopmentManager ofBASFCorporation inRoxbury, NJ. Heearned his PhDin Pharmaceutics

from the University of Rhode Islandand his MBA from Rutgers Universityat New Jersey. In his currentposition, he leads the BASF CareChemicals, North Americadevelopment group for newapplications of pharmaceuticalexcipients and to provide technicalsupport to the pharmaceuticalindustry.The group developed varioustechnologies like taste-masking,intra-oral film, soft gelatin coatings,floating technology, and drugsolubilization, which can be used indifferent drug delivery systems.Before joining BASF, he worked atAmerican Cyanamid and CatalyticaPharmaceuticals as a DevelopmentScientist. He has been invited by theFDA to speak about the developmentof high-functionality excipients, isauthor of seven publications in peer-reviewed journals, and holds 5patents. He can be reached by emailat [email protected].

B I O G R A P H I E SPovidone Grade Concentration in

Tablets/Granules

Povidone K 25 2%-5%Povidone K 30 2%-5%Povidone K 90 1%-3%

T A B L E 3

Usual Concentrations as a Binder


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