Plasdone™ povidonesProduct Overview

High-performance polymersPlasdonepovidonepolymerspossessuniquephysicalandchemicalproperties, making them useful in a variety of pharmaceutical dosageforms.AseriesofsynthetichomopolymersofN-vinyl-2-pyrrolidone (Figure 1), Plasdone povidone polymers are highly adhesive, readily soluble in water and solvents, physiologically inert, nonionic,nontoxic,temperatureresistantandpHstable.Thisuniquecombination of properties is the result of the pyrrolidone ring, which imparts water solubility and solvent- and surfactant-like properties for high adhesion and interfacial activity.

Figure 1 Chemical structure of Plasdone povidone

BenefitsProvides excellent adhesive properties as a wet granulation tablet binder

Enhances solubility and bioavailability of drug actives

Inhibits crystallization of drug actives and inactive ingredients

Dissolves quickly in water

Modifies solution viscosity

Forms water-soluble bioadhesives and films

n

A. B.

Low and high molecular weights

Because physical and mechanical properties vary with a polymer’s molecular weight, Plasdone™ povidones are manufactured in a varietyofmolecularweightgradestobestmeettherequirementsofeachapplication.Ingeneral,asthemolecularweightofthepolymerincreases, the solution viscosity, glass transition temperature and adhesivepropertiesincrease.Asthemolecularweightdecreases,the rate of polymer dissolution, oral absorption and excretion increase. The average molecular weights for the commercial grades of Plasdone povidones measured by light scattering, are shown in Table 1.

Historically, it was difficult to determine the molecular weight of povidonepolymersdirectly.Thus,theK-valuewasadoptedtoclassify the various molecular weights of Plasdone povidones. The K-value,afunctionoftheaveragedegreeofpolymerizationandtheintrinsic viscosity of the polymer, is calculated from the kinematic viscosityofanaqueouspolymersolution.

Table 1 Plasdone K povidones are available in a range of molecular weights for use in pharmaceutical applications

Pyrogen-free options

For applications where pyrogens are of concern, Plasdone C povidones(Table2)aresuppliedwithlowendotoxinlevels.Thesegrades are preferred for parenteral and ophthalmic applications.

Table 2 Plasdone C povidones are “pyrogen-free “

Product Name K-Value

NominalMolecular

Weight (Mw)Typical Pyrogen Endotoxin Units

Plasdone C-12 povidone

10.2-13.8 4,000 0.5 max

Plasdone C-17 povidone

15.5-17.5 10,000 0.5 max

Plasdone C-30 povidone

29-32 58,000 0.5 max

Product K-Va

lue

Nom

inal

M

olec

ular

W

eigh

t (M

w)

Tg (⁰

C)

ApplicationsPlasdone K-12 povidone

10.2-13.8 4,000 120 Low viscosity, excellent solubilization/crystal inhibition properties for liquid-filled soft-gelatin capsules

Plasdone K-17 povidone

16-17.5 10,000 126

Plasdone K-25 povidone

24-26 34,000 160 Low viscosity, wet-granulation tablet binder (3-6% use level)

Plasdone K-29/32 povidone

29-32 58,000 164 Low viscosity, excellent wet-granulation tablet binder at 2-5% use level; excellent solubilization/crystal inhibition properties and fast dissolution for use in spray-dried and melt-extruded solid dispersions

Plasdone K-90 povidone

85-95 1,300,000 174 High viscosity, wet-granulation tablet binder; excellent tablet binder for high-dose, poorly compressible actives

Powders with good flow for ease of manufacturing

AllPlasdonepovidones,withtheexceptionofPlasdoneK-90povidones, are supplied as spray-dried powders with spherical particles that exhibit excellent flow properties and are well-suited forpowderblending.Asanexample,PlasdoneK-29/32povidoneparticles appear spherical when examined under a scanning electronmicroscope(Figure2A),whilePlasdoneK-90povidoneisaflakypowder(Figure2B).Typicalaverageparticlesizes,andtypicaltap and bulk densities for the various Plasdone povidone grades are reportedinTable3.

Figure 2 Plasdone povidone particle morphology

A.PlasdoneK-29/32povidoneisfree-flowingwithsphericalparticles

B.PlasdoneK-90povidoneisafine,free-flowing,flakypowder

Plasdone povidone K-12Plasdone povidone K-17Plasdone povidone K-25Plasdone povidone K-29/32Plasdone povidone K-90

100000

10000

1000

100

10

10 5 10 15 20

Concentration (% w/w)

Broo

kfiel

d Vi

scos

ity

(m∙P

as) a

t 25o C

High degree of compatibility

Plasdone povidones are compatible with a wide range of materials as demonstrated by their tolerance for pH changes and salts. The insensitivityofa5%aqueoussolutionofPlasdoneK-29/32povidoneto changes in pH is shown in Figure 4.

Figure 4 The viscosity of an aqueous Plasdone K-29/32 povidone solution is not affected by changes in pH

Furthermore,theappearanceandpropertiesofa1%aqueoussolutionofPlasdoneK-29/32povidoneareunaffectedbytheaddition of various salts, including aluminum sulfate, calcium chloride, sodium phosphate, ammonium chloride, sodium chloride and zinc sulfate – suggesting that Plasdone povidone will not interact with ionic drug actives or their salts.

Plasdone povidones have been found to be compatible in solution and in solid state with a wide variety of materials including carboxymethylcellulose (low-viscosity grade), ethylcellulose, methylcellulose, polyethylene glycol, polyvinyl alcohol, sodium alginate and sodium lauryl sulfate.

A long history of use Forover50years,Plasdonepovidoneshavebeenwidelyusedinavariety of pharmaceutical and dietary supplement dosage forms. PlasdonepovidonesconformtothecurrentUSP/NF,Ph.EurandJPEmonographs for povidone (Table 4).

ISP’sPlasdoneCandKpovidoneshavereceivedtheUnitedStatesPharmacopeia(USP)VerifiedPharmaceuticalIngredientMark.Inaddition,ISP’sPlasdoneCandKpovidoneproductsholdcertificatesofsuitabilityfromtheEuropeanDirectorateforQualityofMedicines(EDQM).PlasdonepovidonesarelistedintheUnitedStatesFoodandDrugAdministration’s(USFDA)InactiveIngredientGuide.ISPmaintainsaDrugMasterFilewiththeUSFDA.

Table 3 Plasdone™ povidone particles have excellent flow

Product Name

Typical Average

Particle Size (microns)*

Typical Tap Density(g cm-3)

Typical BulkDensity (g cm-3)

Plasdone K-12 povidone

50 0.54 0.42

Plasdone K-17 povidone

50 0.60 0.44

Plasdone K-25 povidone

60 0.49 0.38

Plasdone K-29/32 povidone

80 0.47 0.36

Plasdone K-90 povidone

200 0.46 0.32

10

8

6

4

2

01 4 7 9 1020.1

pHVi

scos

ity

of 5

% a

queo

us s

olut

ions

of

Plas

done

K-2

9/32

pov

idon

e at

room

tem

pera

ture

(cP)

*Resultsaretypicalmedian(D50)

Solubility and solution viscosityPlasdone povidones are completely soluble in water at room temperature. The maximum concentration of polymer soluble in water is limited only by the viscosity at a given concentration. The viscosityofanaqueoussolutiondependsonthemolecularweightofthepolymer(Figure3).

Inadditiontowater,Plasdonepovidonesaresolubleinawidevariety of organic solvents at room temperature. The viscosity of the solution is related to the viscosity of the solvent selected, the molecular weight of the polymer and concentration.

Figure 3 The higher molecular weight Plasdone K-90 povidone provides the highest aqueous solution viscosity

® Registered trademark, Ashland or its subsidiaries, registered in various countries™ Trademark, Ashland or its subsidiaries, registered in various countries* Trademark owned by a third party© 2009-2012, AshlandPC-11736

All statements, information and data presented herein are believed to be accurate and reliable, but are not to be taken as a guarantee, an express warranty, or an implied warranty of merchantability or fitness for a particular purpose, or representation, express or implied, for which Ashland Inc. and its subsidiaries assume legal responsibility.

Global Headquarters

Ashland Inc.50 East RiverCenter Blvd.P.O. Box 391Covington, KY 41012-0391 U.S.A.Tel: +1 859 815 3333

Ashland Specialty Ingredients8145 Blazer DriveWilmington, DE 19808 U.S.A.Tel: +1 877 546 2782

Regional CentersEurope — Switzerland Tel: +41 52 560 55 00Fax: +41 52 560 55 99

India — MaharastraTel: +91 22 61489696 Fax: +91 22 61712514 Asia Pacific — Singapore Tel.: +65 6775 5366 Fax: +65 6776 9690 Latin America — Mexico Tel.: +5255 5211 0111 Fax: +5255 5212 0883

pharmaceutical@ashland.com

ashland.com

ApplicationsPlasdone™ povidones are highly versatile excipients used in a wide range of pharmaceutical applications, including but not limited to:

• PlasdoneKpovidones,withtheirexcellentadhesivepropertiesandsolubility,arethepremier, high-performance tablet binders for wet granulation. Their use produces robust tablets with low friability and reproducible dissolution characteristics.

• Plasdonepovidonesimprovethesolubilityandenhancebioavailability,ofAPIs.Plasdonepovidones can improve the solubility of a drug through co-mixing, co-melting or co-precipitation to form solid dispersions.

• Inoralliquids,Plasdonepovidonesareusedasacrystalgrowthinhibitortopreventcrystallization of inactive ingredients that result in cap-blocking.

• Plasdonepovidonesstabilizesuspensions,dispersionsandemulsions.Plasdonepovidones absorb as a thin layer on the surface of the colloidal particles, thus preventing contact with other colloidal particles, effectively stabilizing the formulations.

• Plasdonepovidoneshavebeenshowntoenhancethesolubilityofactivesandproducehighly concentrated solutions that can be used to fill soft gelatin capsules.

• Whenaddedinophthalmicpreparations,Plasdonepovidonesincreasetheviscosityofdrug solutions and contact time with the eye and improve lubricant effectiveness.

• LowmolecularweightPlasdonepovidonesareusedassolubilizers,crystalgrowthinhibitors and dispersion aids in injectable products for human and veterinary drugs.

Product Name

Pharmacopeial Monograph

USP/NF Ph. Eur. JP/JPEPlasdone C-12 povidone NA1

Plasdone C-17 povidone (JPE)

Plasdone C-30 povidone

Plasdone K-12 povidone NA1

Plasdone K-17 povidone (JPE)

Plasdone K-25 povidone

Plasdone K-29/32 povidone

Plasdone K-90 povidone

Plasdone K-12

povidone

Plasdone K-17

povidone

Plasdone K-25

povidone

Plasdone K-29/32

povidone

Plasdone K-90

povidoneAppearance White to creamy white powder

% Moisture 5 max 5 max 5 max 5 max 5 max

pH (5% aqueous solution)

3-5 3-5 3-5 3-5 4-7

Vinyl Pyrrolidone (ppm) 5 max 5 max 5 max 5 max 10 max

% 2-pyrrolidone 0.99 max 3 max 3 max 3 max 0.99 max

Peroxide Content (ppm) 400 max 400 max 400 max 400 max 400 max

A toxicity and safety profile for Plasdone povidones is available on request. Table 4 Pharmacopeial monograph compliance

1 Currently,theJPmonographonlydefinespovidonegradeswithanominalK-valueofnotlessthan25andnotmorethan90.TheJPEdefinesanadditionalpovidonegradewithanominalK-valueof17.

Key product specifications

Complete product specifications are available on request.