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BASF Fine Chemicals No. 2, July 1999

Excipients & Actives for Pharma

60th Anniversaryof Povidone page 1

Calendar page 1

Great 60 Yearsof Polyvinyl-pyrrolidone page 2–4

KollidonY –A Review onits Use inGranulation page 5–13

Toxicologyof Polyvinyl-pyrrolidone page 14

News page 15

Preview page 16

Contact page 16

60th Anniversary ofPovidoneDear reader,In 1939 Professor Reppe did the invention of Povidoneas part of the acetylene chemistry, well-known underthe expression “Reppe Chemistry". Professor Reppetogether with chemists like Dr. Fikentscher, Dr. Herrle,Dr. Sanner and Mr. Denzinger and generations ofyoung chemists in polymer research continued todevelop types of PVP-based polymers or at leastimproved the existing ones up to now.

Parallel to the research chemistry, production ofPovidone underwent also an evolution processresulting in GMP-like production sites in Ludwigs-hafen and Geismar.

Names, which supported these efforts have beenDr. Penning, Dr. Dall, Dr. Gellrich, Dr. Schröder andon the quality control side Dr. Schmötzer, Mr. Miersch,Dr. Lamprecht and Dr. Filges support the Povidone linewith new analytical methods or introduced new labstandards.

Last but not least two groups responsible for marke-ting and technical support were part of the successof Povidone. Mr. Zöllner, Mr. Löffler, Mr. Görgens,Mr. Jenke, Mr. Lappas in marketing and on thetechnical side Dr. Rutz, Dr. Seelert, Dr. Schwarz,Dr. Bühler, Mr. Reich and Dr. Lang were part of thepositive development of this product line.

At the beginning there was this brilliant idea called“Reppe chemistry", but to develop all the differentaspects of this idea, it took all the skills of chemists,salesmen, pharmacists over a long period of time toreach the status of Povidone nowadays.

Team work and dedication for a production line wereresponsible for the success and will also help Povi-done to be a winner in the decades coming up.

Yours sincerely,

BASF AktiengesellschaftMarketing PharmaIngredients

Dr. Lang

Publisher:

BASF Aktiengesellschaft

Editorial staff:

Dr. Volker Bühler, Dr. Hubertus Folttmann,

Dr. Karl Kolter, Dr. Siegfried Lang,

Birgit Wesche

Concept/Layout:

MLW KommunikationsForm

GmbH Werbeagentur, Mannheim

Print:

Frotscher Druck, Darmstadt

imprint

2nd to 4th November, 1999

CPhl, Pharmaceutical Ingredients Worldwide

Frankfurt*

14th to 19th November, 1999

AAPS (American Association of

Pharmaceutical Scientists) Annual Meeting

New Orleans*

18th to 19th November, 1999

Asian Conference and Exhibition

on Controlled Release

Hong Kong

7th to 10th December, 1999

PharmaIndustria ’99 (Exhibition on raw

materials, semi-finished drugs and medicines

in bulk to the Russian market)

Moscow

3rd to 6th April, 2000

3rd World Meeting on Pharmaceutics,

Biopharmaceutics and Pharmaceutical

Technology

Berlin*

* BASF will be represented.

Calendar

BASF ExAct page 2 – No. 2, July 1999

Great 60 Years of PolyvinylpyrrolidoneChemistry and physicochemical properties of Povidone.H. Witteler, M. Gotsche

Introduction

As a water-soluble polymer Polyvinylpyrrolidone,also named Povidone or PVP, has a large numberof commercial uses. The polymer derives itssuccess from its low toxicity, biocompatibility, filmforming and adhesive characteristics, complexingability to proton donors, and a low osmoticpressure. Due to this exceptional combination ofproperties, PVP finds diverse applications inpharmaceutical and cosmetic products, food,adhesives and textile auxiliaries.

Looking back, PVP is one of the numerous productsof Reppe's acetylene chemistry. By reaction of acety-lene with formaldehyde 1,4-butine diol is formed. After

Pharmaceutical QualityPovidone Grades.

(Table 1)

Prof. Walter Reppe,father of acetylene

chemistry, explains thesynthesis of polyvinyl-pyrrolidone. Kollidon

was already used as atrademark for pharma

quality.

hydrogenation to 1,4-butane diol, γ-butyrolactone isobtained by oxidative cyclization. The conversion withammonia to pyrrolidone is finally followed by additionof acetylene generating N-vinylpyrrolidone (NVP)(Figure 1). The first polymerization product of N-vinylpyrrolidone was patented in 1939. On its 60th

anniversary, PVP is still under investigation and thenumber of applications is still growing. Moreover, PVPis a perfect example of “Verbund” (integrated manu-facturing) in the chemical industry. “Verbund” of pro-duction facilities for basic chemicals, intermediatesand polymerization technology has made PVP a greatsuccess for both BASF and our customers.

Synthesis and Properties of PVPN-Vinylpyrrolidone is usually polymerized by radicalpolymerization. Cationic polymerization with BF3 leadsonly to oligomers. The polymerization can be con-ducted in solution or in bulk.The radical polymerization of NVP in organic solventsleads to low or medium molecular weight products,due to the fact, that the solvent may act as a chaintransfer agent. The higher molecular weight polymerscan be produced by solution polymerization in waterusing hydrogen peroxide as initiator. The polymeriza-tion is usually conducted at pH 7 to prevent a hydro-lysis of the monomer. The molecular weight is regu-lated by the concentration of hydrogen peroxide.Under these conditions the polymers contain hydroxylend groups from the starting hydroxy radicals. In mostcases an aldehyde function is found as the secondend group, which is formed during chain termination,followed by the elimination of pyrrolidone (Figure 2).

PVP typically is characterized by its K-Value. The K-Value is related to the weight average of the molecularweight and is obtained from viscosimetric measure-ments. Since the K-Value plays a dominant role in theproperties of PVP, it is usually part of the name of PVP

Complex formationconstants of a number

of drugs and othersubstances with soluble

Kollidon grades(D. Horn, W. Ditter,

J. Pharm. Sci. 71, 1021-26 (1982)).

(Table 2)

Substance Complex formationconstant in L/mol

Acetaminophen 1.5

Acetylsalicylic acid 0.7

Benzoic acid 0.9

Chloramphenicol 0.4

Methotrimeprazine 3.2

Methylparaben 1.8

Phenol 0.8

Resorcinol 2.4

Salicylamid 1.3

Salicylic acid 1.5

Sorbic acid 0.5

Sulfamoxole 0.3

Sulfathiazole 0.4

Trimethoprim 0.2

Pharmaceutical Quality Average MolecularPVP Grades Weight, Mw/g mol-1

Kollidon 12 PF )1 2000–3000

Kollidon 17 PF )1 7000–11000

Kollidon 25 28000–34000

Kollidon 30 44000–54000

Kollidon 90F 1000000–1500000

)1 PF = pyrogen-free

No complexation occurs between PVP and hydrogenperoxide in aqueous solutions. Still, in dried, an-hydrous form complex formation is proven by IR-spectroscopy. Powders of PVP-H2O2 offer a versatilevehicle for the application of H2O2 in many appli-cations due to their stability and the ease in handlingas compared to aqueous solutions of H2O2. Possibleapplications cover disinfectants, topical formulations,and many others.

CopolymerizationSolution polymerization in water is also used for thecopolymerization of NVP with different monomers toalter or to improve the properties of the PVP. Copoly-mers with vinyl acetate (VA) are usually prepared inwater leading to more hydrophobic polymers thanPVP. In order to obtain a homogenous copolymercomposition, vinyl acetate is added gradually to thereaction mixture. Kollidon VA 64 (Copovidone) is a

copolymer of 60 wt. % N-vinylpyrrolidone and 40 wt.% vinyl acetate. Like PVP, it is soluble in a variety ofsolvents ranging from water to 1-butanol, but unlikePVP it is much less hygroscopic. For film-coating oftablets, moisture uptake is of disadvantage, and herea less hygroscopic copolymer of N-vinylpyrrolidone isof advantage. Applications of PVP/VA range fromgalenic (coatings, binders, polymer/excipient extru-sion) to cosmetics (film former in hair spray formula-tions). Copovidone is listed in the European Pharma-copoeia and Japanese Pharmaceutical Excipients. AUSA-NF draft monograph was published in 1998(Figure 4).

Crosslinked PolymersThere are different ways used for the preparation ofcrosslinked PVP. Slightly crosslinked PVP is obtainedby treatment of linear PVP with hydrazine or hydro-gene peroxide or by γ-irradiation of the linear polymer.

page 3 – No. 2, July 1999 BASF ExAct

grades (e.g. Kollidon K 30: PVP with a K-Value of 30).Commercial PVP grades have K-Values as high as 90.15 percent of PVP K 90 in aqueous solution boosts theviscosity of water from 1 mPa s to more than 5000 mPa sand consequently, this type of PVP may be used as athickener in various types of formulations (Table 1).The most frequently used Povidone grades are Kolli-don 12 PF, 17 PF, 25 and 30. The qualitative identifica-tion is provided by the infrared spectrum. At the sametime the infrared spectrum allows the study of com-plex formation of PVP with organic and inorganicmolecules (see below). Quantitative determination ofsoluble PVP grades may be carried out by photometryof the PVP-iodine complex. This also points into thedirection of an important application.

PVP is a hygroscopic substance. When used as abinder, the hygroscopic character of PVP is of greatimportance and plays a role in the binding properties.Besides intrinsic physical properties, the particle sizedistribution has a marked effect on application proper-ties. Pharma quality means that all Kollidon gradesfulfill the requirements of the important pharmaco-poeias like USP, Ph. Eur. and JPE.

Complex Formation with soluble PVPDue to their chemical structure, namely the amidebond, PVP forms a variety of complexes with otherchemical compounds including pharmacologicalactives. For these compounds, complexation results ineither enhanced solubility, improved bioavailability orincreased stability. Complexation is a technique toobtain formulations that dissolve quickly in water fromactives that are usually difficult to formulate in water.Here, the most prominent example is the com-plexation of iodine in water. The solubility of the disin-fectant iodine in water is poor and for this reason inthe past the increased solubility of the potassiumtriiodide was used to overcome this hurdle. But, tinc-ture of iodine – a mixture of potassium iodide andiodine in water and ethanol – contains considerableamounts of free iodine. Free iodine leads to unwantedside effects like strong staining and itching when usedin wound disinfection. PVP provides the tool to dis-solve iodine in water while maintaining an extremelylow level of free iodine. Here, very small doses ofiodine – as low as 1 ppm in a solution that contains1% of iodine – are supplied from a complex of PVPwith HI3 (Figure 3).

Typical complexes of organic molecules with PVP aremuch weaker than the PVP-iodine complex. Com-plexation is effective at a high concentration of PVPthat is typical of the formulated drug. At typical gastro-intestinal concentration, complexation can be neglec-ted. Still, formulation with PVP is a versatile tool to im-prove solubility or dissolution rate of both liquid andsolid dosage forms. This effect is based on the abilityto form solid solutions with a solute, e.g. an activeingredient and thus prevent it from crystallizing. Theabsence of crystallinity leads to improved dissolution.(Y. Nozawa et al., Pharm. Acta Helv. 60, 175 (1985);M.M. Devilliers et al., Int. J. Pharm. 163, 219 (1998))(Table 2).

Formation of alde-hyde end groups in

NVP-polymerization inwater.

(Figure 2)

HO–––CH2–C––––––CH2–C·H

N O N ·OH + O

n

HO–––CH2–C––––––CH2–CH––OH

N O N

n

O

HO–––CH2–C––––––CH2–C

N O

n

O

H +HN O

N ONN

O OH

I3

Structure of thePVP-HI3 complex.

(Figure 3)

Synthesis ofN-vinylpyrrolidone.

(Figure 1)

– H20

C–H + HC CH + H–C HOCH2–C C–CH2OH

HOCH2 –CH2–CH2–CH2OH

H

O

H

+2 H2 – 2 H2

O

O O

+ NH3 HC CHHN O

H2C CH N O

BASF ExAct page 4 – No. 2, July 1999

balanced aqueous solubility properties, Kollidongrades have been found to provide a comprehensiveand universal base for various types of drugs. Aftermelt extrusion, the active drug can be present in theextrudate in one or two forms: as a crystal suspendedin the hardened Kollidon matrix, or as a moleculedissolved in the polymer during the melting phaseand remaining dissolved in the finished product – a“solid solution". Melt extrusion technology paves theway for benefits in therapy (Figure 5):

specifically designed controlled-release for-mulations (both instant and sustained release)

formulation with improved bioavailability for compounds with low aqueous solubility.

Miscellaneous ApplicationsFurther pharmaceutical, biomedical and biochemicalapplications cover protein isolation and protein stabi-lization (J. F. Carpenter et al., ACS Symp. Ser. 567, 134-47 (1994)), gene therapy (K. Anwer et al., Human GeneTherapy 9, 659 (1998)), cancer therapy (R. Katoh et al.,Oncology Reports 5, 103 (1998)), and reproductionbiology (J. L. Titterington, J. Robinson, Human Repro-duction 11, 2697 (1996)). Besides pharmaceuticaluses, technical grades of PVP are used throughout theindustry. Applications cover cosmetics and toileteries,beverage filtration, photographic products, dyeingapplications and inks, detergents, dispersions, sus-pensions and emulsions, adhesives, paints andcoatings, and paper manufacturing.

Properties of insolublePVP grades.

(Table 3)

Hygroscopicity ofKollidon VA 64 and

Kollidon 25, 30 or 90 Ffor comparison, after

7 days at 25 °C.(Figure 4)

More densely crosslinked PVP is prepared by copoly-merization of N-vinylpyrrolidone with bifunctional mo-nomers. Because of the combination of high wateruptake and insolubility, swelling is observed withcrosslinked PVP when exposed to water while solublePVP simply dissolves.The popcorn polymerization – bulk polymerization ofN-vinylpyrrolidone either in presence of alkali metalhydroxide above 100°C or in presence of smallamounts of bifunctional monomers at 100°C – leadsto highly crosslinked PVP particles with a specific sur-face area of a few square meters per gram. This pop-corn PVP, Crospovidone, finds important use as tabletdisintegrant, as an agent for clarifying beverages andas active ingredient for stomach and gastrointestinaldiseases. In contrast to soluble PVP, complexes ofcrosslinked PVP with high complexation constants en-able the extraction of the complexed molecule. Theusefulness of crosslinked PVP for gastrointestinal dis-eases is based on the following properties:

formation of a protective layer on the mucous membranes

adsorption of gas adsorption of water, swellability complexation of toxins of microbial origin

Complex formation of crosslinked PVP with tannin isof interest both in pharmacology and in beveragetechnology (K. J. Siebert, P. Y. Lynn, J. Am. Soc. Brew.Chem. 56, 24 (1998); D. Horn, W. Ditter, J. Pharm. Sci.71, 1021 (1982)). Tannin is a biopolymer with poly-phenol structures. The complexation constant oftannin with Kollidon CL is >1000 L mol-1 (in 0.1 Nhydrochloric acid).

Particle size distribution plays a more crucial role forthe application properties of crosslinked PVP as com-pared to soluble grades. The properties of Kollidongrades as a disintegrant for tablets vary with particlesize (Table 3) (V. Bühler, Polyvinylpyrrolidone for thepharmaceutical industry, BASF, Ludwigshafen 1996).In tablets obtained from Kollidon by compression thedisintegration time decreases with the particle size ofthe PVP used for the formulation. Like soluble PVP,Kollidon CL-M is capable of stabilizing suspensions,such as antibiotics, antacids, vitamin preparations andtopical formulations.Lately, it has been demonstrated, that pH-controlleddrug release is possible from PVP/Polyacrylic acidinterpenetrating networks (J. F. Yaung, T. K. Kwei, J.Appl. Polym. Sci. 69, 921 (1998)). Radiation curedhydrogels of PVP, polyethylene glycol, and agar havemany desirable properties for using as wounddressings (A. B. Lugao et al., Radiat. Phys. Chem. 52,319 (1998)).

Polymer/Drug Melt ExtrusionAs a result of close collaboration over the past tenyears, Knoll AG and its parent company BASF havedeveloped a patent-protected novel pharmaceuticalmanufacturing technology: drug is incorporated bymelt extrusion in a matrix consisting of a pharma-ceutical polymer. Due to its thermoplasticity and

Monitoring(in-process sensors)

Polymer, Excipient, Drug(Feeder system)

Conveying, Mixing, Melting (Extruder)

Shaping(Calender,Cutting system)

Polymer/Drug MeltExtrusion. Product is

either tablet, granulate,pellet, sheet ...

(Figure 5)

Property Dimension Kollidon Kollidon Crospo-CL CL-M vidone M

Particle Size < 15µm > 90%(air jet screen, < 50µm < 60% > 90%5min, 20mbar) < 250µm > 96%

Bulk density g cm-3 0.30–0.40 0.15–0.25 0.31–0.41

Specific surface m2 g-1 app. 1 3–6 app. 2area (det.according Ph.Eur. 2, V 5.5.3)

Swelling pressure kPa app. 55 app. 30of lightly com-pacted PVP inwater

Rel. humidity [%]

60

40

20

0

0 20 40 60 80

� Kollidon 25, 30, 90 F

� Kollidon VA 64Wat

er a

bso

rptio

n, [

%]

page 5 – No. 2, July 1999 BASF ExAct

Historical Background

Polyvinylpyrrolidone (Povidone), which is oneof the products resulting from Reppe's studiesof acetylene chemistry, was patented in 1939.Originally it was introduced as a blood plasmaexpander and was widely used during the secondworld war. This application was cancelled lateron due to the fact that medium molecular weightPovidone (K-25 - K-30) is not able to pass thekidney barrier completely. But nevertheless theunique properties of Povidone like high solubilityin solvents of differing polarity, solubilizing andfilm forming ability, suspension and emulsionstabilizing effects and last but not least its bindingproperties make it one of the most importantexcipients in phamaceutical technology.

Besides the parenteral application early reviews(Lesser 1954, Greenfield 1956, Ferraris 1959) deal withuses like complexation, sustained release action,emulsion and foam stabilizer, applications in cosmetic(Greenfield 1957) and printing industry as well as awater removable adhesive. Although a hint on tabletbinding properties is given by Lesser (Lesser 1954),the first paper about the use in tablet formulations waspublished by Lehrman (Lehrman 1958) who found thataqueous Povidone solutions in a concentration rangefrom 5 to 25% were in comparison to acacia muci-lage, starch paste and syrup an “acceptable" bindingagent. The amount of binder used was described as“quantum satis" to reach granular consistency, noabsolute figures were presented. Next a Germanpharmacist described the use of Povidone to preparecharcoal tablets (Köhler 1961), lozenges (Köhler1962a) and its application in sugar coating of tablets(Köhler 1962). Later on the use of Povidone as a con-stituent for pills (Kàlmàn 1963) was recommended.A review by Prescott (Prescott 1965) states that Povi-done can be used with success as a dry binder in di-rect compression, in aqueous and non aqueous bin-ding solutions for granulation as a film forming sub-stance, a stabilizer for aspirin and as a clarifier for wine.

Today Povidone is the most commonly used binder intableting and has replaced natural materials like gumacacia, gelatin, traganth and others as well as many ofthe semisynthetic cellulose derivatives. It is available indifferent grades making an optimum choice possible.For further details of Povidone properties see the ex-tensive review of Bühler (Bühler 1993).

Basic considerationsGranulation is done for a number of purposes: toenhance compressibility and compactability, to in-

KollidonY (Polyvinylpyrrolidone)A Review on its Use in GranulationProf. Dr. Peter C. Schmidt, Dept. of Pharmaceutical Technology, Eberhard-Karls-Universität Tübingen

crease flowability of the bulk and to reduce dust in thetableting mixture. According to Rumpf (Rumpf 1974)the following forces of increasing order can be in-volved in the binding between particles: van der Waalsforces, electrostatic forces, liquid bridges, binder con-taining bridges, salt and solid bridges. Van der Waalsand electrostatic forces as well as solid bridges act

mainly in dry powder compaction while liquid bridgeswith or without a polymer as a binder are the domina-ting mechanisms in conventional and fluidized bedgranulation. The parameters influencing the formationof a bridge between two particles are presented infigure 1.

In the first step the solvent or the binder containingsolution has to wet the surface of the solids to begranulated. The wetting depends on the surface ten-sion of the solid and the liquid and on the interfacialtension between solid and liquid. The amount of liquidnecessary to wet the whole surface of the solids de-pends on the surface area and porosity of the material.Finally the solubility of the solids in the solvent or thebinder solution will influence the formation of liquidbridges. When the binder, in most cases an organicpolymer, is mixed together with the other ingredientsas a powder and moistened afterwards by the solvent,the dissolution rate of the binder in the solvent duringthe granulation process will also influence the proper-ties of the resulting granules. In these cases the typeof equipment used for granulation will become veryimportant.

The correlations between the solid , the solvent andthe binder can be visualized as a triangular phasediagram as shown in figure 2.

The corners of the triangle represent the solids, thesolvent and the binder respectively. Along the linesolids/dry binder, where the solvent content is zero,roller compaction and direct compression are located.A solvent granulation without using a binder takesplace along the line solids/solvent. At any place withinthe triangle a ternary system comprising of solids,solvent and binder is existing. The working area forpractical purposes is marked in the upper region ofthe triangle. The aim of a granulation process is togranulate the material with a minimum of binder. In aconventional granulation process the amount of sol-vent is limited by the solubility of both the binder andthe solids, because an over-moistening effect leadingto a suspension has to be avoided. In fluidized bedgranulation, where the solvent is continuously re-moved, it is possible to incorporate more binder es-pecially when the binder forms high viscous solutions.These two situations are depicted in figure 3.

The conventional granulation is a “closed system"where the addition of liquid is limited. In a fluidized bedgranulator an unlimited solvent supply is possible andtherefore a high amount of binder could be incor-porated by the addition of a binder solution. In con-ventional granulation normally less than 30% of a

Solids (actives andexcipients) 100%

Working area

Roller compaction/direct compression

Dry binder100%

Solventgranulation

Solvent100%

20% Solutionof a binder

The formation of a binder bridge between twoparticles depends on: the particle's surface, itsporosity and wettability, the solubility of the ingre-dients being granulated in the solvent or bindersolution and on the dissolution rate of the binder.(Figure 1)

Phase triangle showing the relations between thesolids, the solvent and the binder in a conventionalgranulation process. As an example working pointrepresenting 60% solids, 32% solvent and 8%binder is given.(Figure 2)

BASF ExAct page 6 – No. 2, July 1999

liquid depending on the properties of the solids couldbe added before over-moistening takes place. Bin-ders forming high viscous solutions, e.g. tragacanth orsodium alginate, can therefore be incorporated only inan amount of up to 3 to 5% based on the solid contentof the granulate.Soluble Povidone is available in five different gradesas shown in table 1 (Bühler 1993, p.36).

The molecular weight MV which is taken from viscositymeasurements shows for all types a range accordingto the European Pharmacopoeia. The low molecularweight types are designed for parenteral use due tothe fact, that they pass the kidney barrier. In earliertimes the main product in granulation was Kollidon 25,but is now replaced by Kollidon 30 and Kollidon 90 F.Several attempts were made to differentiate betweenthe binding behaviour of different types of Povidone

and to compare Povidone with other binders used ingranulation. Cutt et al. (Cutt et al. 1986) investigatedthe binding effiency of Povidone, Methocel E 15 , ahydroxypropyl methylcellulose (HPMC) and Byco Cgelatin, a hydrolized gelatin, in a model system com-prising of glass beads of a mean diameter of 26 and40 µm respectively. They found a uniform binder dis-tribution throughout all granulations. Povidone show-ed the lowest granule friability, formed stronger gra-nules compared to HPMC but not as strong as Bycogelatin. The granule strength was slightly lower whenthe glass beads were coated with a hydrophobic layerof dimethylsilane. Horisawa et al. (Horisawa et al. 1993)granulated glass beads of 152 µm in a kneader usingPovidone K-30, Povidone K-90, two types of hydroxy-propyl cellulose, two different hydroxypropyl methyl-celluloses, one sodium carboxymethylcellulose andlactose for comparison. After granulating the glass

beads one part of the resulting granules was dried for3 h at 60°C, the other one was compressed into moldsand the molds were dried for 12 h at 60°C. Thestrength of the agglomerates and the molds, measu-red using a special equipment, is shown in figure 4.

For agglomerates and for molds Povidone K-90showed the highest strength values followed byPovidone K-30, the cellulose derivatives and lactoseindicating the high binding efficiency of Povidone.When silicon treated glass beads were used thestrength values were in general lower but of the sameorder showing the importance of wetting as a first stepin granulation. These findings are supported by Danjo(Danjo 1993) who found a similar ranking when usinglactose as an excipient and preparing granules byextrusion, fluidized bed and conventional granulation.Jäger and Bauer (Jäger and Bauer 1984) foundcoarser granules with high molecular Povidone. Theauthors recommend polymer blends to adapt theparticle size distribution to a desired value.

Mode of incorporation of Povidone in granulesThe binder can be incorporated into granules by threedifferent methods:

by dry granulation using a roller compactor by mixing the binder with the actives and

excipients and subsequent moistening with a solvent preferably water

by granulating the powder mass using a binder solution

Dry granulation does not require any solvent and isadvantageous whenever stability problems arise witha drug in contact with water or other solvents. Nodrying operation is necessary, therefore the product isnot stressed by higher temperatures. It is a simpleprocess of high capacity. Nevertheless it is not fre-quently used in pharmacy for several reasons. Thegranules produced by a compaction process areirregular in shape, show a high friability and containoften quite a high amount of fines. Povidone, althoughrecommended as a dry binder has in the dry state lessbinding properties compared to e.g. Kollidon VA 64,a copolymer of vinyl pyrrolidone and vinyl acetate(Bühler 1993, pp. 129-222). In wet granulation thepowders are normally granulated using a bindersolution. This process involves a lot of parameters,the most important are:

properties of the powder mass like wetting behaviour, solubility and tendency to rapid“over-moistening".

amount of binder solution concentration of binder in the solution mode of application of the binder solution

like pouring or spraying type of granulating equipment time of kneading the moistened powder mass

in conventional granulation processes

The advantage of this type of process is that the binderis used in solution and the polymer is present in a

Differences between aconventional and afluidized bed granu-lation process. In bothcases the binder con-tent in the final granulescan easily kept constantwhen granulating withthe pure solvent. Whenusing binder solutionsthe binder contentvaries depending onthe amount of fluid andis nearly unlimited inthe case of fluidizedbed granulation.(Figure 3)

Table 1: Viscosity-average values of themolecular weight, Mvfor the soluble Kollidon grades, calculated from the K-value.

Agglomerate strengthand strength of moldsas a function of bindersolution added (ml/gpowder). Concentrationof binder solution: 10%(w/w) for polymers,saturated solution forlactose. Sample: un-treated glass beads.(Figure 4)

Mv calculated from Mv calculated from the K-the nominal K-Value value range given in Ph. Eur.

Kollidon 12 PF 3900 2600–5500

Kollidon 17 PF 9300 7100–11000

Kollidon 25 25700 19300–31100

Kollidon 30 42500 31700–51400

Kollidon 90 F 1100000 790000–1350000

Bindersolution

Solids

Solvent

Solids plus drybinder

High shear mixer

Moist granules

Drying unit

Dry granules

Bindersolution

Solids

Solvent

Solids plus drybinder

Continuoussolvent

evaporation

Fluidized bed granulator

Dry granules

Conventional Granulation Fluidized Bed Granulation

Agglo

mer

ate

stre

ngth

[kg

/cm

2]

Str

ength

of

mold

s [k

g/c

m2]

Proportion of binding solution added [ml/g]

40

30

20

10

0

30

20

10

00,00 0,05 0,10 0,15 0,20 0,25 0,00 0,05 0,10 0,15 0,20 0,25

PovidoneK-30

PovidoneK-90

HPC-EFP

HPC-LFP

HPMCTC-5E

HPMCTC-5S

Na-CMC

Lactose

page 7 – No. 2, July 1999 BASF ExAct

molecular distribution developing highest bindingefficiency. On the other hand, a solution has to beprepared in advance and the amount of binder willvary within certain limits due to the fact that quite oftenthe amount of liquid required reach the end point ofthe granulation has to be adapted.

The third possibility is to mix the binder in the dry statewith the powder mass to be granulated and to moistenthe mixture using a solvent, which is preferably water.This method has the advantage that the amount ofbinder is constant and independent from the amountof liquid required for granulation. But the process hassome problems:

the amount of binder being dissolved depends on the nature of the binder itself, on the granulation time and type of equipment

only cold water soluble binders can be used the dissolution rate of the binder becomes an

important step in granulation.

Povidone offers excellent properties to be treatedaccording to this method. It is soluble to a high degreein various solvents at room temperature. The disso-lution rate is high enough to be partially or even com-pletely dissolved during the granulation process.Therefore it is of interest to compare the two methodsof binder addition.

D'Alonzo et al. (D'Alonzo et al. 1990) used a modelsystem consisting of microcrystalline cellulose andPovidone as binder to study the effect of binder con-centration and the method of addition on granulegrowth in a high shear mixer. The concentration rangeof Povidone was 1 to 5% which is recommended fortablet formulations, the amount of water to moisten1kg of microcrystalline cellulose was 1 litre. The gra-nulation time was kept constant for all experimentsand the process was followed by a resistancemeasurement at the impeller blade of the mixer, whichwas also used for end point detection. The meanparticle diameter of the resulting granules for bothmethods is shown in figure 5.

The granules prepared by the dry method indicate amore consistent behaviour in dependence of theamount of Povidone. Furthermore the authors statethat the percentage of fines was reduced. The resis-tance at the impeller blade was lower for the bindersolution compared to water indicating a lubricationeffect of the aqueous binder solution. In a secondpaper (Alkan and Ulusoy 1983) granulations of lac-tose, starch and Povidone are described. Again thedry addition method was compared to a binder solu-tion. The composition of the mixture was 80% lactose,12% starch and 8% Povidone. Granulation was donein a fluidized bed dryer. To granulate 400g of powder200ml of ethanol were used leading to a Povidoneconcentration of 16% when used as a binder solution.The particle size distribution of the resulting granuleswas log-normal, the mean particle diameter for the drymethod was 680 µm and for the granules preparedusing a binder solution 330 µm. Flowability was

similar for both granulations, friability was lower for thegranules prepared with Povidon in solution. A moreuniform distribution of Povidon in the granules wasfound for the binder added in solution. The authorscome to the conclusion that it is advantageous to addthe binder in solution.Comparing the two papers the results seem not to bein agreement. For the system microcrystalline cellu-lose/Povidone/water the dry method was recommen-ded while for lactose plus starch/Povidone/ethanolthe solution method was superior. But two aspectswere not considered in both papers: the properties ofthe excipients and the equipment. Microcrystallinecellulose absorbs high amounts of water beforeagglomeration starts while a mixture containing 80%of lactose and 12% of starch immediately starts agglo-meration. The granulation behaviour of the substan-ces is completely different. In addition the methodsused were not directly comparable. The mechanicalstress in a kneader is high compared to a fluidizedbed unit. Therefore the contact between binder, ex-cipients and water is more intensive in a mixer granu-lator leading to a dense packaging of the material anda better distribution of the liquid.

Voigt and Richter (Voigt and Richter 1988) and Richteret al. (Richter et al. 1989) compared the dry and thesolution method using the binders gelatin, Povidone,polyvinyl alcohol (PVA), hydroxypropyl methylcellulose(HPMC) and a hydrolized potato starch (SHP) to gra-nulate a starch/lactose (2:1) mixture in a fluidized bedgranulator. The mean particle diameter of the granuleswas smaller in all cases, when the dry method wasused and was nearly concentration independent,while with the solution method an increase of themean particle diameter with increasing amount ofbinder was observed. Gelatin and PVA gave hardertablets after solution granulation while Povidoneshowed no differences. This was explained by thehigh dissolution rate of Povidone during granulation.Again Povidone was recommended for the methodof dry binder addition and subsequent moistening.

Wan and Lim (Wan and Lim 1989) used the dry andthe solution method to granulate lactose and starchrespectively using 25g of Povidone per 400g ofmaterial in a fluidized bed dryer. They found larger

particle diameters for the dry method for lactose andno significant differences for starch. The higher waterabsorption of starch should again be responsible forthe differences between both substances.

To summarize these findings: Povidone is a valuablebinder when incorporated in a powder mixture as adry substance being granulated by the addition ofwater or an organic solvent. Due to its high dissolutionrate it is superior to other polymers like gelatin. Theexperimental conditions depend on the type of ma-terial to be granulated and on the equipment used.

Povidone as a binder in model systemsBasic investigations of the granulation process arequite often carried out using model formulations.Frequently used excipients in this field are lactose,starch, mixtures thereof, microcrystalline cellulose anddicalcium phosphate. Most of the work published inthe past was done with lactose or mixtures thereof withstarch. The following tables summarize work whichwas done with Povidone alone or in comparison toother binders. Investigations dealing with lactose aresummarized in tables 2 and 3, those with mixtures oflactose and starch are presented in table 4.

The results from fluidized bed granulation of lactosecan be summarized as follows:

higher molecular weights of Povidone lead to larger and stronger granules

the granule size is increased and the granule friability is decreased with increasing con-centration, spray rate and volume of the binder solution

tablet hardness is increased with increasing binder concentration

Table 3 presents the results with the lactose/Povidonesystem granulated in high shear mixers of differenttypes.

Due to the limited amount of liquid being used in thistype of granulation the binder concentration in thesolution is in general much higher compared tofluidized bed granulation. Concentrations rangingfrom 10 to 45% are usual. The amount of liquid should

� Wet Addition Method� Dry Addition Method

Povidone Concentration [% w/w]

650

600

550

500

450

400

3500 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n G

ranu

le S

ize,

d [

µm]

Influence of thePovidone concentrationafter addition of thebinder as a dry powderor a binder solutionrespectivily on themean granule size.(D'Alonzo et al. 1990)(Figure 5)

BASF ExAct page 8 – No. 2, July 1999

be chosen as large as possible because all experi-ments cited in table 3 indicate that there is a stronginfluence of the amount of liquid added on the pro-perties of the granules and later on on the tablets.Besides this the intensity and time of kneading shouldhave some substance dependent influence. Theparticle size of the powder and the type of solvent(water, ethanol or mixtures thereof) have less influ-ence.

The situation using mixtures of lactose and starch issummarized in table 4.

Wan and Lim (Wan and Lim 1991) investigated mix-tures of lactose and starch of different ratios in afluidized bed apparatus using Povidone K-25 as abinder. The binder was applied in different concen-trations and at different spray rates. The results indi-cate best granule properties when a ratio of lac-tose : starch of 3 :1 was used, while a ratio of 1:3 wasdifficult to granulate due to the small particle size of thestarch. In general the granulation of small particles ina fluidized bed apparatus is a problem because theparticles are partially exhausted by the air into the filterand sometimes do not take part in the granulationprocess. A 2 :1 mixture of lactose and maize starchwas granulated by Crimella et al. (Crimella et al. 1984)using five different types of equipment. They founddifferences in the granule and tablet properties andrecommended a combination of a high shear mixerfor granulation and a fluidized bed dryer for drying toobtain tablets within the desired specifications. Incontrast Held et al. (Held et al. 1993) found similartablet properties when comparing a formulation con-taining lactose, starch and 2.5% of nitrazepam usingcombinations of a planetary mixer, a high shear mixer,a tray dryer and a fluidized bed dryer in a factorialdesign experiment. They concluded that through acareful validation process identical products can beobtained even with differing equipment.

In a series of papers Vojnovic et al. (Vojnovic et al.1992, 1993 and 1995) optimized the operating con-ditions of two high shear mixers Roto J and Roto Pfrom Zanchetta, Italy. They used a powder mix con-taining 68.2% of lactose and 31.8% of corn starchwhich was granulated with a Povidone solution. Firsta central composite design using a Roto J granulatorwas carried out leading to the following optimumconditions for the granulation process:

moisture level: 17.45% impeller speed: 426.5 rpm granulation time: 8.01min.

Their second paper deals with the simultaneousoptimization of several response variables. Using thesame formulation the optimum zone of the 10-litremachine was determined and scaled up to a 50-litrehigh shear mixer. In the third paper the central com-posite design was optimized by an “a priori" approach.

Model granulations of lactose/Povidone using conventional mixing equipment. (Table 3)

Model granulations of lactose/Povidone using a fluidized bed granulator(Aeromatic-Strea 1, Aeromatic-Fielder, Bubendorf, Switzerland). (Table 2)

Model granulations of lactose and starch withPovidone as a binder. (Table 4)

Lactose Povidone Apparatus Parameters Results Literature-solution investigated

Solution� type � type� particle size (µm) � amount� amount � concentration

lactose Ph. Eur. VA-64 high speed mixer � method of liquid � granule growth is Holm et al.X50 = 52 up to 750 g Fielder-PMAT 25 VG addition controlled by the 19837.5 kg 10 % � liquid flow rate amount of binder

� impeller speed added and the� chopper speed impeller speed

lactose Ph. Eur. VA-64 high speed mixer � kneading time after � no influence of Holm et al.X50 = 52 up to 750 g Fielder-PMAT 25 VG liquid addition kneading time on 19847.5 kg 10 % � impeller speed granule growth (in

� chopper speed contrast to calciumphosphate)

lactose 100 mesh K-25 planetary mixer � mixtures of the two � no correlation bet- Tapper andX50 = 103 38–133 ml Kenwood 707 A lactose types ween surface area Lindberg1000 g 18.4–44.0 % (w/w) � concentration of of lactose and 1986

corresp. to 30 g binder solution volume ofgranulation fluid

lactose 350 mesh PovidoneX50 = 321000 g

α-lactose- K-25 planetary mixer � solvent type � tablet strength Wikberg andmonohydrate 90–300 ml Kenwood A 71 C (water/EtOH/water: increased with Alderborn– EtOH 0 50 : 50) increasing amount 19901000 g 16–45 % � amount of liquid of liquid in

granulation

Lactose Povidone-solution Parameters Results Literatureinvestigated

� type � type� particle size (µm) � amount� amount (g) � concentration (w/v)

lactose BP K-25 � amount of lactose � high influence of Povidone binder Wan and Lim84,7±3,84 200–600 � concentration of concentration on size of granules 1988200–500 1–10 % Povidone solution � low Povidone concentration, slow

� volume of spray rate, small volume of PovidonePovidone solution solution and a large lactose feed lead� spraying rate to small monosized granules

lactose powder (Pharma- K 90 � type of Povidone � particle size of granules is increased Wan et al.tose 200, DMV. Veghel, 150–300 � concentration and with K 120 1995The Netherlands) 1–3 % volume of binder � granule size is increased with

K 120 solution increasing concentration, spray rate400 150–300 � spraying rate and volume of binder solution

1–3 %

lactose monohydrate K 15, K 25, K 30 � type of Povidone � increase of molecular weight of Povi- Georga-(Merck) < 70 300 done results in an increase of granule kopoulus et al.70–150 150–250 10 % size and tensile strength of the tablets 19831000 and in a decrease of granule friability

Lactose Starch Ratio Povidone Granulation Parameters Results Litera--type -type lactose: -type -amount equipment investigated ture-particle size -particle size starch/feed -concentration

lactose BP maize starch BP 1 : 1/400 g K-25 Aeromatic Strea 1 � ratio of lactose/ � ratio 3:1>1:1> Wan and84.7±3.84 µm 16.3±1.43 µm 3 : 1/400 g 500 ml (solution) starch 1:3 with respect to Lim 1991

1 : 3/400 g 7 or 15 ml/min � binder conc. in larger granulesolution size and better� spray rate flow properties

lactose maize starch 2 : 1 K-25 1,5 % A: Glatt-WSG 5 � granule pro- tablets com- Crimella(tablet) B: planetary perties (humidity, pressed from et al.

mixer (Viani)/ apparent granules pre- 1984tray dryer density, porosity, pared by methodC: high shear angle of repose) D were superiormixer (Diosna P � tablet properties50)/ Glatt WSG 15 (hardness,D: high shear friability, dis-mixer (Diosna P integration)50)/ Glatt WSG 15E: Viani mixer/Glatt WSG 15

lactose, maize starch 3.26 : 1 K-30 2 %/5 % planetary mixer � factorial design comparable Held et al.German German (tablet) (Artofex RG 115) tablet 1993Pharma- Pharma- high shear mixer properties withcopoeia copoeia (Diosna P 50) different equip-

tray dryer fluid- ment afterized bed dryer validation

lactose, 200 corn starch 2.1 : 1 K-25 2 % (tablet) high shear mixers � surface high effect of Vojnovicmesh (DMV) X50=15µm Zanchetta Roto J response design moisture level, et al.X50=39µm and Roto P tray � simultaneous optimum con- 1992

dryer optimization ditions used 1993method for up scaling, 1995� experimental comparison ofdesign with predicted with“a priori” criterias results obtained

page 9 – No. 2, July 1999 BASF ExAct

Besides lactose and mixtures of lactose and starchsome papers deal with other excipients like dicalciumphosphate and microcrystalline cellulose as modelsubstances in granulation. Ritala et al. (Ritala et al.1986 and 1988) used a high shear mixer (FielderPMAT 25 VG) in basic investigations with dicalciumphosphate and the binders Povidone K-25, PovidoneK-90, two hydroxypropyl methylcelluloses MethocelE5 and E15, a hydrolized gelatin (Byco C or Protein S)and a poly(vinylpyrrolidone-vinylacetate) copolymer.Povidone K-90 and Protein S facilitated the granulegrowth leading to coarser granules. Avicel was usedto study the interactions of this microcrystalline cellu-lose with aqueous solutions of Povidone K-25 andhydroxypropyl methylcellulose (Pharmacoat 603)using a laboratory-scale, instrumented mixer torquerheometer. The authors found differences between thetwo binders which were explained by theories relatingbinder surface tension to granule properties.

Povidone in the granulation of active ingredientsIn model systems containing lactose, starch, mixturesthereof, microcrystalline cellulose or dicalcium phos-phate as excipients, the influence of different binderson the granule properties could be studied relativelyeasily. Except lactose these excipients are water in-soluble, the bonding between them and the binderdepends on their wetting behaviour, water uptake,swelling, and later on during compression of thetablets on their compression and compaction proper-ties. When adding an active ingredient the situationbecomes more difficult. Wetting and solubility as wellas its compressional behaviour will – depending onthe dosage – more less strongly influence the proper-ties of the resulting granules and tablets. Table 5summarizes those articles from literature which dealwith Povidone as a binder. The examples chosencover a range of pharmaceutical actives. It was not theintention to collect all papers published.

Acetaminophen is a high dosed drug which issparingly soluble in water and poorly compressible.Therefore it is a good example to test the capability ofbinders in granulation. Liu et al. (Liu et al. 1994) usedPovidone K-30 to develop a direct compressibleacetaminophen. In preliminary trials Povidone wasapplied at the three levels 2, 5, and 10% in the gra-nules via 5, 7.5 and 10% solutions using a GlattGPCG-1 (Glatt Air Techniques Inc., Binzen, Germany)fluidized bed granulator. It was found that in minimum5% of Povidone are required to give a free flowinggranulate. In an additional factorial experiment 5% ofPovidone were used in two spray concentrations of 5and 7.5% in solution. The other factors were spray rate,spray pressure and inlet air temperature. The batchsize was 500g. The validity of the model was provenby three replicates of one of the experiments. It wasconcluded that the inlet air temperature was not asignificant factor. Through the elimination of this factor,the system becomes a 23 factorial design with tworeplicates. Calculation of this model led to a granu-lation with 5% Povidone K-30 in the granules appliedas 7.5% solution. After the addition of 0.5% magne-sium stearate and 1 or 3% of crospovidone or sodium

starch glycolate respectively tablets were obtainedfulfilling all requirements of the USP. The same group(Chen et al. 1995) later on published a paper wherethey recommended the additional use of a surfactantlike sodium lauryl sulfate or Pluronic F-68 in combi-nation with Povidone in granulation to enhance thedissolution rate and the hardness of the resultingtablets.Becker et al. (Becker et al. 1997) compared a place-bo granulation and an acetaminophen containing oneusing a combination of a high shear mixer Diosna P10 (Dierks & Söhne, Osnabrück, Germany) and afludized bed dryer Strea 1 (Aeromatic-Fielder, Buben-dorf, Switzerland). They compared Povidone K-30, ahydroxypropyl methylcellulose (Cellulose HP-M 603),a pregelatinized starch (Lycatab PGS), a maltodextrin(Lycatab DSH) and a low substituted hydroxypropyl-cellulose (L-HPC, type 11). The binders were added aspowders and granulation was done with water.

Although they were able to detect differences betweenthe binders there was no formulation found leading toa tablet with sufficient properties. Here the question iswhether or not the mode of incorporation of the bin-ders into the granules plays an important role. Ebube

and co-workers(Ebube et al.1996) com-pared theinfluence ofacetaminophenas an exampleof a sparinglysoluble drug andpseudoephe-drine sulfateshowing a highwater solubility ontablet properties usinga hydroxypropyl methyl-cellulose and Povidone K-30 as binders. The drugs wereused alone and in combination in a matrix of thetwo binders of differing ratios. The total polymercontent was between 3.5 and 19.2% in the final matrix.The presence of the water soluble pseudoephedrinesignificantly influenced the properties of an aceta-minophen granulation by reducing the particle sizedistribution of the granules and the friability of the

Granulation of active ingredients using Povidone as a binder and special purposesof the investigations. (Table 5)

Active ingredient Povidone-type Main purpose of the investigation Literatureand concentration

Acetaminophen K-30; 2/5/10 % in Development of acetaminophen for direct compression Liu et al. 1994granul.5/7.5/10 % in soln.

Acetaminophen K-30; 2 and 5 % Development of acetaminophen for direct compression Chen et al. 1995

Acetaminophen K-30; 0/2/6/10 % Comparison of Povidone with other binders Becker et al. 1997

Acetaminophen/ K-29-32, blended with Effect of drug, formulation and process variables on granulation Ebube et al. 1996Pseudoephedrine HPMC; 3.4 to 19.2 % and compaction characteristics

Aminophylline not specified; 1/3/5 % Comparison of Povidone with corn starch and HPC Anjo et al. 1988

Aspirin K-90, 6 % Influence of solvent type (water/ethanol on granules and tablets) Wells and Walker1983

Caffeine anhydrous K-30; 2/3/4/5 % Investigation of the granulation process using artificial Kesavan andneural networks Peck 1996

Caffeine K-12/K-17/K-25/ Application of polymer blends in granulation Jäger und BauerK-90; 3 % 1984

Herbal drugs K-30/K-90; 5 % Effect of binder solution on physical properties of granules Seko et al. 1993

Hydrochlorothiazide K-30; 5 % Comparative evaluation of two pharmaceutical binders Symecko et al.1993

Metronidazole Povidone; M, 44000 Comparison of Povidone, gelatin and methylcellulose as binders Itiola and Pilpelfor metronidazole 1987

Naproxen K-25; 5 % Comparison of wet granulation and direct compression Tarimci and Satiro-glu-Tezcan 1995

Naproxen K-29-32; 5 % Action of “superdisintegrants” in Povidone based granulations Gordon et al. 1991

Phenytoin Povidone, M, 10000; Influence of mode of incorporation on dissolution rate Gabr et al. 19913.78/7.78/10/15 %

Piracetam Povidone; 3 % Influence of piracetam solubility on granule properties Fábregas andCucala 1987

Propranolol K-25/K-29-32/K-90/ Effect of Povidone solutions containing dissolved drug Wan et al. 1996hydrochloride K-120; 2/3/4/5/6/7 % on characteristics of granules

Ranitidine K-30; 5 % Influence of moisture and different binders on the properties Uzunarslan andhydrochloride of granules prepared from ranitidine Akbuga 1991

Salicylic acid/ K-29-32; 5 % Influence of wettability of insouble active ingredients on Jaijeoba andSulfanilamide Kaolin granule properties Spring 1980

Sulfadiazine K-90; 5/10/15 % Comparison of Povidone, acacia and gelatin as binders Nouh 1986for sulfadiazine

Sulfamethoxazole not spezified; 3 % Effect of type of binder on the properties of Agrawal andsulfamethoxazole tablets Prakasam 1988

Sulfathiazole not spezified; 5 % Influence of solvent type and drying method on granule Mandal 1995properties

Fluid bed granulation.

BASF ExAct page 10 – No. 2, July 1999

tablets, while the tablet hardness was increased. Thisbehaviour was explained by a change in the hydrationcharacteristics of the polymers by the addition of ahighly water soluble drug.

Aminophylline was granulated using Povidone, cornstarch and hydroxypropyl cellulose by Anjo and co-workers (Anjo et al. 1988). Povidone showed the bestdissolution rate and the lowest disintegration time atsufficient hardness values of the tablets. The influenceof binder vehicle upon granule and tablet propertieshas been studied by Wells and Walker (Wells andWalker 1983) in a model system containing aspirinand Povidone. Water and ethanol were chosen as sol-vents changing the solubility of aspirin from 4.66 mgper ml in pure water gradually to 133.6 mg per ml inpure ethanol. Using mixtures containing 25, 50 and75% ethanol besides the two pure solvents it waspossible to study the influence of a change in drugsolubility on the granule and tablet properties. Greatersolubility of the drug increases the granule size distri-bution and decreases the friability of the granules. Thedisintegration time was prolonged when using a sol-vent with a higher drug solubility.

Caffeine as a model drug was used by Kesavan andPeck (Kesavan and Peck 1996) to optimize a formulaby artificial neural networks. Their basic formulation isshown in table 6.

Besides the variation of the type of binder four con-centrations of Povidone ranging from 2 to 5%, themode of addition of binder in the dry state and as asolution and a high shear mixer as well as a fluidizedbed dryer were used. The granules were compressedinto tablets and hardness, friability, thickness, disinte-gration time and average tablet weight were deter-mined. A good correlation between predicted andobserved values was found for all granule and tabletparameters. In a second paper dealing with caffeineJäger and Bauer (Jäger and Bauer 1984) investiga-ted the influence of different types of Povidone inclu-ding K-12, K-17, K-25 and K-90 and mixtures thereof inthe preparation of granules and in subsequent table-ting. They came to the conclusion that the use of poly-mer blends containing K-25 and K-90 have superiorproperties compared to the single Povidone types.

Seko et al. (Seko et al. 1993) published a paper on thegranulation of crude drug powders comparing hydro-xypropyl cellulose, sodium carboxymethylcelluloseand the Povidone types K-30 and K-90. The followingpowdered drugs were used: Glycyrrhiza, Senna leaf,Rhubarb, Magnolia bark, Peony root and Cenidiumrhizome. The granulation was done by two methods:fluidized bed granulation using a Glatt CPCG-1 granu-lator and by agitation granulation using a Multiplexgranulator FM-MP-10. Different concentrations ofbinder solutions were applied.

The results were analyzed by multiple linear regres-sion yielding a regression equation for each responseparameter and both granulators. The physical pro-perties of the products of both, agitation and fluidized

bed granulation, are closely related to the amount andthe viscosity of the binder solution. Hydrochlorothia-zide was granulated comparing Lycatab DSH, a mal-todextrin, and Povidone K-30 (Symecko et al. 1993).The binder was added in the dry state and granulationwas carried out following the scheme shown infigure 6.

This is a typical scheme to prepare granules using thebinder in the dry state and moistening the powder mixduring the granulation with water. In these cases thebinder has to have a good water solubility combinedwith a high dissolution rate. The results obtained in thisinvestigation are summarized in table 7.

The granule and tablet properties for both binders aresimilar. The dissolution of hydrochlorothiazide is a littlebit faster for Povidone. The compression/hardness-profile of the two formulations is presented in figure 7,indicating a higher binding capacity for Povidone.Naproxen, a poorly water soluble nonsteroidal anti-

inflammatory agent, was compared in direct com-pression and granulation formulations by Tarimci andSatiroglu-Tezcan (Tarimci and Satiroglu-Tezcan 1995)using 5% Povidone K-25 as a binder. Although themechanical tablet properties were almost the same forboth preparation methods the authors detectedsignificant differences between direct compressionand granulation. All granulated formulations liberatethe active ingredient completely within 10 minuteswhile some of the direct compression formulationsshowed a prolonged drug dissolution. Gordon et al.(Gordon et al. 1993) investigated the influence of threeso called “super disintegrants" on the dissolution ofnaproxen from granulated tablets on storage underdifferent conditions and found that crospovidone andsodium starch glycolate were superior compared tocroscarmellose sodium. The way of incorporation ofthe disintegrants did not influence the drug dissolu-tion. The binder used for granulation was Povidone K29-32 in an amount of 5% in the final tablet dissolvedin water.

Formulation composi-tion of caffeine Tabletsaccording to Kesavan

and Peck (Kesavan andPeck 1996).

(Table 6)

Preparation scheme forhydrochlorothiazide

tablets using the binderin the dry state and

granulating with water(Symecko et al. 1993).

(Figure 6)

1. 10 min dry mixing

2. granulation with water 60mlin 1 min; stop for 30sand so on

3. end point detection by powerconsumption measurement

0.01 kgMagnesium

stearate

Hydrochlorothiazide: 0.2 kgBinder: 0.1 kg

Anhydrous lactose: 1.69 kg

Instrumented double planetary mixer

8-Mesh screen

Drying oven40°C [down to 0.1% loss on drying]

Turbula mixer 5min

Stokes B-2 instrumented rotarytablet press 3/8” flat face punches

Tablet weight: 315mgHardness: 6–8 kg

Composition % (w/w); range

Caffeine anhydrous USP 40.0

Lactose or dicalcium phosphate 47.5–44.5

Povidone K-30 2.0–5.0

Corn starch 10.0

Magnesium stearate 0.5

page 11 – No. 2, July 1999 BASF ExAct

Phenytoin was used as a model substance to investi-gate differences in the mode of drug incorporation intoa tablet by coprecipitation during granulation, copreci-pitation alone, solvent deposition and granulationusing a Povidone solution. Povidone, Mr 10000, in anethanolic solution in different concentrations was usedas a binder. The disintegration times of all tablet formu-lations were within the USP specifications althoughthere was an increase with increasing Povidone con-centration. On the other hand the dissolution of phe-nytoin was increased with increasing Povidone con-centration in general. Differences were found for theway of incorporation. Best results were obtained whenthe drug was dissolved together with Povidone inethanol and coprecipitation occured during granu-lation. The slowest dissolution rates were observedwhen a simple granulation with a Povidone solutionwas done.The influence of the solvent used in granulation on thedisintegration time of tablets during storage was in-vestigated with piracetam as an example for a highlywater soluble drug (Fábregas and Cucala 1987). Theauthors came to the conclusion that whenever a partof the drug is dissolved during granulation the dis-integration time of the tablets is prolonged on storageespecially under humid conditions. A similar influenceof drug was found for propranolol hydrochloride whenit was dissolved together with Povidone prior to granu-lation (Wan et al. 1996). Besides the drug influence theauthors found an increase in crushing strength of thetablets with increasing volume and concentration ofbinder used. High molecular Povidone resulted instronger tablets.

The effect of wetting ternary powder mixtures in gra-nulation was investigated by Jaiyeoba and Spring(Jaiyeoba and Spring 1980). As a basic mixture theyused a combination of lactose and boric acid indifferent proportions and an aqueous 5% Povidone K29-32 solution as a binder. The third component of theternary mixture was either kaolin, sulfanilamide orsalicylic acid added in an amount of 10%. The addi-tion of kaolin, which is very readily wetted by water,resulted in stronger granules. Sulfanilamide did notchange the granule strength due to its medium wetta-bility which lies between lactose and boric acid, whilesalicylic acid, which is not wetted by water, reducesthe granule strength significantly.

Sulfadiazine was granulated by the fluidized bed aswell as by a conventional method comparing gelatin,acacia and Povidone K-90 in concentrations of 5, 10and 15% based on the binder content in the finaltablet (Nouh 1986). It was found that in all casesfluidized bed granulation was superior compared tothe traditional method and that Povidone gave betterdisintegration times at the same hardness level com-pared to gelatin and acacia. The effect of starch, ethylcellulose, Povidone (type not specified) and acacia inan amount of 3% based on the dry basis on tabletproperties of sulfamethoxazole tablets was investi-gated by Agrawal and Prakasam (Agrawal and Praka-sam 1988). Although they obtained best flow proper-ties and lowest angle of repose with Povidone they

came to the following ranking of the binders: starch>ethyl cellulose>Povidone>acacia. In an investigationon the influence of microwave drying on granule andtablet properties Mandal (Mandal 1995) used Povi-done in a concentration of 5% in water, 50% waterand 50% ethanol and ethanol respectively to granu-late mixtures comprising of 45% starch, 45% lactoseand 10% sulfthiazole. There was no significant differ-ence between the microwave and the conventionaldrying method, but water based granules showed ahigher granule strength compared to 50% water/50%ethanol and pure ethanol.

SummaryLinear, soluble polyvinyl pyrrolidone (Povidone) wassynthetized in 1939 by Reppe. Its main application wasfirst as blood plasma expander. After the second worldwar other applications came up and in the field ofpharmaceutical technology one of the main pur-poses is up to now the use as a binder in granulation.At present five types K-12, K-17, K-25, K-30 and K-90,differing in their molecular weight, are available. Thelow molecular weight types K-12 and K-17 are used inparenterals while the higher ones are prefered in

peroral medicines. The binding properties of Povidoneincrease with increasing molecular weight. Thereforestrongest bonds between particles in granulation areformed by the high molecular weight type K-90. Onthe other hand this type shows the highest viscositywhich could be a limiting factor. The formation ofgranules is mainly influenced by the factors:

type of Povidone concentration of Povidone in the granulation fluid concentration of Povidone in the final tablet the mode of addition of the binder the equipment used in granulation the properties of the active ingredients being

granulated.

The type of Povidone determines the granule strengthtogether with the concentration. Higher molecularweight Povidone leads to a higher granule strength.Therefore Povidone K-90 quite often is preferred. Onthe other hand the use of high viscous solutions couldbe a limitation when only a certain amount of liquidcan be used. The concentration of Povidone in thegranulation fluid therefore varies between 10 and 40%

Granule and tabletproperties of hydro-chlorothiazide tablets(adapted fromSymecko et al. 1993).(Table 7)

Comparison of tablethardness againstmaximum compressionforce for the twobinders Lycatab DSH,a maltodextrin, andPovidone K-30, bothadded as powders ina concentration of 5%(Symecko et al. 1993).(Figure 7)

� Kollidon 30� Lycatab DSH

Max. Compression Force [kN]

12

10

8

6

4

2

00 5 10 15 20 25 30

Har

dne

ss [

kg]

Binder

Granules Lycatab DSH Kollidon 30

Flow rate (g/sec) 4.39 4.51

Granule friability 3.87 4.37(%)

Mean particle 201.7 143.9size (µm)

Tablets

Weight (mg) 315.5 313.1

Friability (%) 0.38 0.51

Disintegration 13.42 13.71time (min)

Hardness (kg) 7.63 7.45

Dissolution ∼ 40% ∼ 60%profile: 20 min

30 min ∼ 100% ∼ 100%

BASF ExAct page 12 – No. 2, July 1999

in conventional granulation while in fluidized bedgranulation the concentration normally is in a rangeof 5 to 10%. In the final tablet the concentration ofPovidone as a binder is between 3 to 5 and 10%.The binder could be added either as a dry powderfollowed by the addition of a solvent or as a bindersolution. The first method has the advantage that thereis always a constant amount of binder in the formu-lation, the disadvantage is that the binder in manycases is not completely dissolved and that thereforethe type of the equipment used and the processingtime become very important for the result of the gra-nulation process. In addition only could water solublebinders can be used in this process.

The use of a binder solution has the advantage thatthere is a molecular distribution of the binder leadingto the formation of the maximum number of bondsbetween particles. The disadvantage is that therecould be a variation in the amount of binder addeddue to the fact that the amount of fluid necessary forgranulation varies between different batches ofpowder. Therefore when using this method the rawmaterials have to be standardized with respect toparticle size or surface area.

The equipment has an additional influence in granu-lation. Today there are two different concepts in use:

the fluidized bed technology and the high shear mixer technology often combined

with a fluidized bed dryer.

The fluidized bed technology is a one step processwhere mixing of the powders moistening of the mate-rial, granulation and drying are carried out in the sameapparatus. The method has no restrictions with res-pect to the amount of binder added and yields highlycompressible granules due to its loose structure. Dis-advantages are the limited batch size and the timeconsuming process. The high shear technology offersa rapid method for mixing the powder, moistening andgranulation within a few minutes leading to a densermaterial compared to the fluidized bed technology.There is equipment ranging from small scale (below100 grams) to high capacity apparatus of several hun-dred kilograms available. The disadvantages are: theamount of binder added as a binder solution is limiteddue to the solubility and viscosity of the polymer usedfor granulation and drying is normally carried out in asecond unit quite often a fluidized bed dryer.

The presence of active ingredients can tremendouslyalter the properties of the granulation mixture. In gra-nulation the first step is the wetting of the material bythe granulating fluid. This can be facilitated by wettingagents. The solubility of the actives and excipients inthe granulation liquid will also influence the processand is quite often the determining factor when highlywater soluble drugs have to be granulated. In additiona recrystallization during drying can occur leading toa change in hardness, disintegration and dissolutionof the tablets prepared from these granules. Thesephysical changes occur during storage over a prolon-

(Milan) 25, 208-215 (1959) Gabr, K. E., El-Shaboury, M. H., Abd El-Gawad H.A., Hashem, F. M., Combining coprecipitation andsolvent deposition in formulation tablet. AlexandriaJ. Pharm. Sci. 5, 119-124 (1991) Georgakopoulos, P. P., Malamataris, S.,Dolamidis, G., The effects of using different gradesof PVP and gelatin as binders in the fluidized bedgranulation and tabletting of lactose. Pharmazie 38,240-243 (1983) Gordon, M. S., Rudraraju, V. S., Rhie, J. K.,Chowhan, Z. T., The effect of aging on thedissolution of wet granulated tablets containingsuper disintegrants. Int. J. Pharm. 97, 119-131 (1993) Greenfield, I., Polyvinylpyrrolidone, its manu-facture, properties and use in cosmetics. J. Soc.Cosmet. Chem. 8, 196-211 (1957) Greenfield, I., The manufacture and uses ofpolyvinylpyrrolidone. Ind. Chem. 32, 11-14 (1956) Held, K., Kopp, U., Kilchmann-Bohli, I., Sucker, H.,Einfluß unterschiedlicher Herstellungsmethoden aufdie physikalischen Eigenschaften von Tabletten.Pharm. Ind. 55, 171-175 (1993) Holm, P., Jungersen, O., Schaefer, T., Kristensen,H. G., Granulation in high speed mixers. Part 1:Effects of process variables during kneading.Pharm. Ind. 45, 806-811 (1983) Holm, P., Jungersen, O., Schaefer, T., Kristensen,H. G., Granulation in high speed mixers. Part 2:Effects of process variables during kneading.Pharm. Ind. 46, 97-101 (1984) Horisawa, E., Komura, A., Danjo, K., Otsuka, A.,Effect of binder characteristics on the strength ofagglomerates prepared by the wet method. Chem.Pharm. Bull. 41, 1428-1433 (1993) Itiola, O. A., Pilpel, N., Fundamental properties ofmetronidazole formulations in relation to tableting. J.Pharm. Pharmacol. 39, 644-647 (1987) Jäger, K.-F., Bauer, K. H., Verwendung von Poly-merblends aus Polyvinylpyrrolidonen zur Optimie-rung der Eigenschaften von Aufbaugranulaten undTabletten. Acta Pharm. Technol. 30, 85-92 (1984) Jaiyeoba, K. T., Spring, M. S., The granulation ofternary mixtures: the effect of the wettability of thepowders. J. Pharm. Pharmacol. 32, 386-388 (1980) Kálmán, K., A polivinilpirrolidon mint pulula-kötóanyag. Acta Pharm. Hung. 33, 271-274 (1963) Kesavan, J. G., Peck, G. E., Pharmaceuticalgranulation and tablet formulation using neuralnetworks. Pharm. Dev. Technol. 1, 391-404 (1996) Köhler, H. Rudolf, R., Versuche zur Herstellungvon Kohle-Tabletten. Dtsch. Apoth. Ztg. 101, 324-326(1961) Köhler, H., Oesterreich, J., Quark, B.,Pigmentfarben in Tablettenüberzügen. Dtsch. Apoth.Ztg. 102, 1-8 (1962b) Köhler, H., Versuche zur Herstellung von Mund-und Halstabletten. Dtsch. Apoth. Ztg. 102, 507-510(1962a) Lehrman, G. P., Skauen, D. M., A comparativestudy of polyvinylpyrrolidone and other bindingagents in tablet formulations. Drug Stand. 26, 170-175 (1958) Lesser, M. A., Povidone. Drug & Cosmet. Ind. 75,

ged period of time. Nevertheless today Povidone isbesides many other applications the most widely usedbinder in granulation.

AcknowledgementsThe author acknowledges the help of BASF inthe literature search and thanks Dr. Volker Bühler and Dr. Siegfried Lang, BASF, Ludwigshafen, for helpful discussions. Thanks should also be givento Mrs. Renate Beer, University of Tübingen, fortyping and revising the manuscript.

Literature

Agrawal, Y. K., Prakasam, K., Effect of binders onsulfamethoxazole tablets. J. Pharm. Sci. 77, 885-888(1988) Alkan, H., Ulusoy, A., Granulation in a fluidizedbed. I. Effect of addition of the binder in solution orin dry form. DOGA TU J. Med. and Pharm. 11, (1)1-7 (1987) Anjo, S., Suzuki, Y., Kondo, Y., Experimentalaminophylline tablets – Effect of various additives onhardness, disintegration time and dissolution. ByoinYakugacu 14, 312-316 (1988) Becker, D., Rigassi, T., Bauer-Brandl, A.,Effectiveness of binders in wet granulation: Acomparison using model formulations of differenttabletability. Drug Dev. Ind. Pharm. 23, 791-808(1997) Bühler, V., Kollidon-Polyvinylpyrrolidone for thepharmaceutical industry, 2nd ed. BASF Ludwigs-hafen (1993) Chen, S.-C., Lee, Y.-C., Sokoloski, T. D., Sheu,M.-T., The study of directly compressible acetamino-phen compositon with fluidized-bed granulation.Chin. Pharm. J. Taipei, 47, 221-233 (1995) Crimella, T., Delucchi, F., Gallazzi, A., Kauten, G.,Iamartino, P., Maccario, G., Pedrani, M., Rizzo, D.,Influenza di differenti procedimenti di granulazionead umido sulle caratteristiche tecnologiche deigranulati e delle compresse. Boll. Chim. Farm. 123,210-222 (1984) Cutt, T., Fell, J. T., Rue, P. J., Spring, M. S.,Granulation and compaction of a model system. I.Granule properties. Int. J. Pharm. 33, 81-87 (1986) D'Alonzo, G. D., O'Connor, R. E., Schwartz, J. B.,Effect of binder concentration and method ofaddition on granule growth in a high intensity mixer.Drug Dev. Ind. Pharm. 16, 1931-1944 (1990) Danjo, K., The relationship between tabletcompressibility and granule strength. Pharm. Tech.Japan, 9, 225-231 (1993) Ebube, N. K., Hikal, A. H., Wyandt, C. M., Beer,D. C., Miller, L. G., Jones, A. B., Effect of drug,formulation and process variables on granulationand compaction characteristics of heterogeneousmatrices: Part II. HPMC and PVP systems. Drug Dev.Ind. Pharm. 22, 561-567 (1996) Fábregas, J. L., Cucala, J., New approach toaqueous granulation of highly hydrosoluble drugs.Drug Dev. Ind. Pharm. 13, 1217-1227 (1987) Ferraris, E., Il polivinilpirrolidone. Mater. plast.

page 13 – No. 2, July 1999 BASF ExAct

32-33, 126-131 (1954) Liu, C.-H., Chen, S.-C., Lee, Y.-C., Sokoloski, T. D.,Sheu, M.-T., Directly compressible acetaminophencompositions prepared by fluidized-bed granulation.Drug Dev. Ind. Pharm. 20, 1911-1922 (1994) Mandal, T. K., Evaluation of microwave drying forpharmaceutical granulations. Drug Dev. Ind. Pharm.21, 1683-1688 (1995) Nouh, A. T. I., The effect of variations in concen-tration and type of binder on the physical character-istics of sulfadiazine tablets and granulations pre-pared by wet and fluidised-bed granulationmethod.Pharm. Ind. 48, 670-673 (1986) Parker, M. D., York, P., Rowe, R. C., Binder-substrate interactions in wet granulation. 1: Theeffect of binder characteristics. Int. J. Pharm. 64,207-216 (1990) Prescott, F., PVP for tablet making. Drug &Cosmet. Ind. 97, 497, 621-622 (1965) Richter, M., Rahn, H.-W., Voigt, R., Zum Einfluß derEinarbeitungstechnik von wasserlöslichen makro-molekularen Bindemitteln auf die Eigenschaften vonWirbelschichtgranulaten und der daraus herge-stellten Komprimate. Pharmazie 44, 43-46 (1989) Ritala, M., Holm, P., Schaefer, T., Kristensen,H. G., Influence of liquid bonding strength on powerconsumption during granulation in a high shearmixer. Drug Dev. Ind. Pharm. 14, 1041-1060 (1988) Ritala, M., Jungersen, O., Holm, P., Schaefer, T.,Kristensen, H. G., A comparison between binders inthe wet phase of granulation in a high shear mixer.Drug Dev. Ind. Pharm. 12, 1685-1700 (1986) Rumpf, H., Die Wissenschaft des Agglomerierens.Chem. Ing. Tech. 46, 1-46 (1974) Seko, N., Sunada, H., Danjo, K., Otsuka, A.,Yonezawa, Y., Matsui, N., Pharmaceutical prepara-tions of crude drug Powder. III. The effects of thephysical properties of the binder solution on thecharacteristics of the granule from the mixedpowders. Chem. Pharm. Bull. 41, 937-941 (1993) Symecko, C. W., Romero, A. J., Rhodes, C. T.,Comparative evaluation of two pharmaceuticalbinders in the wet granulation of hydrochloro-thiazide Lycatab DSH versus Kollidon 30. DrugDev. Ind. Pharm. 19, 1131-1141 (1993) Tapper, G.-I., Llindberg, N.-O., The granulation ofsome lactose qualities with different particle sizedistributions in a domestic-type mixer. Acta Pharm.Suec. 23, 47-56 (1986) Tarimci, N., Satiroglu-Tezcan, N., Design andevaluation of naproxen tablet formulationsprepared by wet granulation and directcompression methods. FABAD J. Pharm.Sci., 20, 1-6 (1995) Uzunarslan, K., Akbuga, J., The effect of mois-ture on the physical characteristics of ranitidinehydrochloride tablets prepared by differentbinders and techniques. Drug Dev. Ind. Pharm.17, 1067-1081 (1991) Voigt, R., Richter, M., Zum Einfluß wasser-löslicher makromolekularer Bindemittel aufdie Eigenschaften von Wirbelschichtgranulaten undder daraus hergestellten Komprimate. Pharmazie43, 191-194 (1988)

Vojnovic, D., Moneghini, M., Rubessa, F.,Experimental design for a granulation process with“a priori” criterias. Drug Dev. Ind. Pharm. 21, 823-831(1995) Vojnovic, D., Moneghini, M., Rubessa, F.,Zanchetta, A., Simultaneaus optimization of severalresponse variables in a granulation process. DrugDev. Ind. Pharm. 19, 1479-1496 (1993) Vojnovic, D., Selenati, P., Rubessa, F., Moneghini,M., Zanchetta, A., Wet granulation in a small scalehigh shear mixer. Drug Dev. Ind. Pharm. 18, 961-972(1992) Wan, L. S. C., Heng, P. W. S., Ling, B. L., Effect ofpolyvinylpyrrolidone solutions containing dissolveddrug on characteristics of lactose fluidized bedgranules. Int. J. Pharm. 141, 161-170 (1996) Wan, L. S. C., Heng, P. W. S., Ling, B. L., Fluidizedbed granulation with PVP K90 andPVP K120. Drug Dev. Ind. Pharm.21, 857-862 (1995) Wan, L. S. C., Lim, K. S.,Granulation of mixtures oflactose and starch by afluidized bed technique. S. T.P. Pharma Sci. 1, 285-293(1991) Wan, L. S. C., Lim, K.S., Mode of action of

polyvinylpyrrolidone as a binder on fluidized bedgranulation of lactose and starch granules. S. T. P.Pharma 5, 244-250 (1989) Wan, L. S. C., Lim, K. S., The effect of incorpora-ting polyvinylpyrrollidone as a binder on fluidisedbed granulations of lactose. S. T. P. Pharma 4, 560-571 (1988) Wells, J. I., Walker, C. V., The influence of granu-lating fluids upon granule and tablet properties: therole of secondary binding. Int. J. Pharm. 15, 97-111(1983) Wikberg, M., Alderborn, G., Compression cha-racteristics of granulated materials. III. The relation-ship between air permaeability and chemicalstrength of tablets of some lactose granulations. Int.J. Pharm. 63, 23-27 (1990).

BASF ExAct page 14 – No. 2, July 1999

General

Polyvinylpyrrolidone (Povidone) is a linear homo-polymer of 1-vinyl-2-pyrrolidone monomer used ina wide range of applications in the pharmaceuti-cal, food and cosmetic industry. Povidone gradesare available in different molecular weight ranges.The letter K and an appropriate number related tothe molecular weight are used to designate thedifferent Povidones. Numerous toxicological andkinetic studies with Povidones have been per-formed indicating the biological inertness of thecompound.

Absorption, Metabolism, Distribution, ExcretionThe absorption of Povidone from the gastrointestinaltract is very limited and proceeds primarily by fluid-phase pinocytosis. After injection, Povidone may bestored at the injection site or at distant sites (cutaneousstorage syndrome). The disappearance of Povidonefrom the bloodstream is inversely related to the mole-cular weight and involves an initial rapid removal oflow molecular weight materials by the kidney and aprolonged slower removal of higher molecular weightmaterial into lymph and tissues, primarily the reticulo-endothelial system tissues, including liver, spleen,bone marrow, bone and kidney. Tissue storagedisease in humans occurs only following parenteraladministration of large amounts of the higher mole-cular weight Povidones. Orally administered Povidoneis eleminated almost totally in the faeces; very little isfound in the bile or urine. Povidone is not metabolizedin the body.

Acute toxicity studiesStudies in rodents, dogs and primates have shownthat Povidone is a substance with a very low acutetoxicity. It is essentially impossible to kill animals byadministration of Povidone except by gross osmoticimbalance. Thus the LD50 of Povidone orally is repor-ted to exceed 100g/kg and to be around 10g/kg ormore intravenously or intraperitoneally. The onlyevidence of toxicity following oral administration isproduction of diarrhea with doses exceeding 0.5g/kgdue to the non-absorbed osmotic load in the gutlumen.

Subchronic toxicity studiesRepeat-dose oral studies in rodents and dogs haveshown that apart from diarrhea at high doses relatedto the bulk purgative actions of Povidone there is noevidence of any toxicity as judged by clinical chemis-try, hematology or histopathology. Occasional reduc-tions in weight gain have been observed with 10%Povidone in the diet, but this is probably related to

reduced food intake and diarrhea. There is someevidence of minimal absorption as judged by theappearance of cell inclusions in the mesenteric lymphnodes in one dog study, but this is probably not of anytoxicological significance. The no-adverse-effect levelin subchronic studies in rodents and dogs is around5g/kg/day.

Chronic toxicity/carcinogenicity studiesIn two well conducted chronic studies using PovidoneK25 and K90 at dose levels in the diet up to 10% and5%, respectively, over a 2 year period, there was noevidence of any substance-related toxicity in clinicalchemistry, hematology, urine analysis or histopatho-logy. There was no evidence of an carcinogenic effector evidence of Povidone storage in any organ. In lesswell reported chronic oral dog studies in whichPovidone K30 was administered in the diet for 1–2years, there was no evidence of treatment-relatedeffects other than some evidence of Povidone storagein the regional lymph nodes. There was no evidenceof any cumulative damage over the 2 years.

Parenteral toxicity studiesAfter parenteral administration, Povidone is well tolera-ted, with little evidence of local damage after single or5 injections. However, parenteral administration oflarge amounts has been reported to cause histaminerelease in the dog and Charolais cow, and other car-diovascular phenomena secondary to osmotic imba-lance. Histamine release is well-known for the caninefamily. Numerous studies on the chronic effects ofinjection of Povidone in rats have given conflictingresults, virtually all due to poorly designed and con-ducted studies. When well conducted studies havebeen carried out, there is no evidence of a carcino-genic effect from repeated parenteral administration.Repeated injection of Povidones, especially the largermolecular weight materials, e.g. K-30 and over, canresult in acculmulation of Povidone in the tissues. Thisis particularly so if the Povidone is injected into poorlyperfused sites. This has been demonstrated in ani-mals to lead to development of foreign body typesarcomas at the site of injection but with no meta-stases.

Mutagenicity studiesSeveral investigations of the mutagenic potential ofPovidone have been carried out, all of which indicatethat Povidone is without mutagenic activity. In theAmes test, Povidone K30 has given negative resultswith and without activation. Povidone K30 was alsofound to be non-mutagenic in the mouse lymphomaassay with and without metabolic activation. In vivo,the dominant lethal test and a cytogenetic in the bone

Toxicology of PolyvinylpyrrolidoneA comprehensive summary of the toxicological properties of Povidone.St. Schulte

marrow of Chinese hamsters gave no indication of agenotoxic or clastogenic activity from Povidone K30.

Developmental toxicity studiesFour studies have been performed, two in the rat andtwo in the rabbit, using Povidone with four differentmolecular weight distributions. Povidone K30 andPovidone K90 were given in the diet during the first 20days of pregnancy. There were no indications of em-bryotoxocity or teratogenicity in the treated groups. Inrabbits treated by intravenous injection with Povidone-K12 from days 6–18 of pregnancy, no adverse effectswere observed. Povidone with an average molecularweight of 11,500 given intra-amniotically to rabbitembryos showed no evidence of embryotoxicity orteratogenicity.

ConclusionThe extensive volume of toxicological data on Povidone supports the inertness and hencethe safety of Povidone. The acute, subchronic and chronic toxicity of orally administered Po- vidone is very low, with the only effect observed being diarrhea at high doses due to the osmotic action of Povidone. Occasional observations of minimal absorption with storage in mesenteric lymph nodes seem to be of no toxicological im-portance. Povidone was found to be neither mutagenic nor developmentally toxic. The curren-tly permitted FAO/WHO Acceptable Daily Intake (ADI) of 0–50mg/kg body weight for food use provides an adequate margin of safety.

page 15 – No. 2, July 1999 BASF ExAct

Product LaunchKollicoatY MAE 100 P – A new redispersable powder for enteric coating.

Regulatory AffairsKollidon VA 64 approved for the US market.

Since more than a year Kollicoat MAE 30 DP ismarketed for enteric film-coating of pharmaceu-tical dosage forms. Kollicoat MAE 30 DP is anaqueous dispersion of a copolymer derived frommethacrylic acid/ethyl acetate (1:1). Kollicoat MAE30 DP complies with the requirements of the Euro-pean Pharmacopoeia monograph “Polyacrylatedispersion 30%”, the USP-NF monograph “Metha-crylic Acid Copolymer Dispersion” and the JPEmonograph “Methacrylic Acid Copolymer LD”.

Transporting and storing aqueous dispersions, e.g.Kollicoat MAE 30 DP, involve certain risks. Exposure toheat causes polymer losses as a result of skin forma-tion on the surface, agglomeration and sometimes

sedimentation. Freezing may induce coagulation.Transporting and storing redispersable powders donot involve these risks and hence are particularlysuitable to be used in countries with hot and coldclimates.

Kollicoat MAE 100 P is a new redispersable powderfor aqueous enteric coating and available since May1999.

Kollicoat MAE 100 P is prepared from the aqueousdispersion Kollicoat MAE 30 DP using an FSD-spraying technology. Kollicoat MAE 100 P can beeasily redispersed without further auxiliaries bypouring it into water while stirring.

Redispersion of the powder into the aqueous dis-persion can be performed just before the sprayingprocess. The physical stability of the redispersion is,however, excellent, so that the latex can also be storedfor some days. The technical relevant properties of theredispersion, e.g. particle size, compatibility withadditives, processibility and film formation, are verysimilar to those of the original latex. Processing occursin the usual manner with plasticizer, pigments andother excipients.

Films of Kollicoat MAE 30 DP and Kollicoat MAE 100P are equal with regard to their gastric resistance anddissolution behaviour above pH 5.5.

During the last 12 month the FDA approved 3different formulations containing Kollidon VA 64.

This includes the oral application of Kollidon VA 64and the functionality as an effective dry binder.

A monograph of “Copovidone” was prepared andpublished in the US Pharmacopeial Forum Vol. 24,No. 4, July/August 98, pp 6456-6459.The monograph will be included in the USP as officialmonograph soon.

New production plant for PVP-Iodine.

The production of PVP-Iodine will be transferredfrom the Ludwigshafen production site to our newand modern production plant in Geismar, US in1999.The production plant in Geismar was designed forPharma production and is manufacturing PVP-Iodinesince 1996.Information material and PVP-Iodine samples forreapproval studies are available.

For more information please contact Dr. FolkerRuchatz, MEM/FP, Fax No. +6216094-616 orvia e-mail folker.ruchatz@basf-ag.de.

Please contact your local BASF company

or one of the following regional centres:

Asia

BASF East Asia Regional

Headquarters Ltd.

Dr. Lutz End, Dr. Danilo Mercado

Tower 1,4th Floor, South Seas Centre

Tsim Sha Tsui

P.O. Box 98427

Kowloon, Hong-Kong

Fax: **852/23122261

Europe

BASF Health & Nutrition A/S

Mr. Clemens Karg

Malmparken 5

DK-2750 Ballerup

Denmark

Fax: **45/44730102

NAFTA

BASF Corporation

Pharma Specialties, Mr. Richard Becker

3000 Continental Drive-North

Mount Olive, NJ 07828-1234

USA

Fax: **1/9734265369

South America

BASF S.A.

Fine Chemicals, Mr. Torsten Meid

Caixa Postal 136

09701-970 São Bernardo do Campo

Brazil

Fax: **55/117512199

Or visit our website:

http://www.basf.de/pharma

contactPreview

page 16 – No. 2, July 1999 BASF ExAct

ME

R 9

918

Sustained release products are gaining more andmore interest due to a long lasting drug actionwith low side effects and a better compliancerelated to immediate release dosage forms.

However, for the manufacturing of coated sustainedrelease dosage forms only few polymers areapplicable.

Each of these polymers has certain disadvantages,e.g. curing effects, necessity of high amounts ofplasticizer, pH-dependent release characteristics,interaction with the active ingredient, high tackiness,

etc. Some of the commercially available productsare marketed at a very high price. In view of thesefacts a strong demand for a new polymer becomesobvious.

Kollicoat SR 30 D, a recently developed product forsustained release coating, represents a break-throughin this application field. Besides other topics, ExActNo. 3 will deal with this innovative coating excipient.

Should you require information in advance, pleasecontact your local BASF company or one of ourregional centres.

Solubilizers/EmulsifiersCremophorY RH 40, CremophorY EL,CremophorY ELP, CremophorY A 6/A 25,CremophorY S 9, SolutolY HS 15

ColorantsSicovitY, soluble dyes, SicovitY,lakes and pigments

PEGs, PoloxamersLutrolY E grades, LutrolY F grades

SolventsPropylene Glycol, SoluphorY P

Active IngredientsCrospovidone M, Tretinoin, Isotretinoin,Retinol 50P, Carotenoids,Active ingredients from Knoll

Fat-soluble VitaminsVitamin A, Vitamin D2, D3,Vitamin E, Vitamin K

Water-soluble VitaminsVitamin C, Vitamin B1 (Thiamin),Vitamin B2 (Riboflavin), Vitamin B3 (Nicotinamid),Vitamin B5 (Calpan), Vitamin B6,Vitamin B12, Vitamin H (Biotin)

BASF Fine Chemicals for the pharmaceutical industry.

Direct Compression AgentsLudipressY, LudipressY LCE

Binders, SolubilizersKollidonY 12 PF/17 PF, KollidonY 25/30/90 F

Disintegrants, Suspension StabilizersKollidonY CL, KollidonY CL-M

(Dry) Binders, Film FormersKollidonY VA 64

DisinfectantsPVP-lodine 30/06, PVP-lodine 30/06 M10

Enteric Film CoatingsKollicoatY MAE 30 DP, KollicoatY MAE 30 D,KollicoatY MAE 100 P

Sustained Release Film CoatingsKollicoatY EMM 30 D, KollicoatY SR 30 D