BASF Fine Chemicals No.

2, July 1999

Excipients & Actives for Pharma

Calendar 60th Anniversary of

Povidone
2nd to 4th November, 1999 Dear reader,
CPhl, Pharmaceutical Ingredients Worldwide In 1939 Professor Reppe did the invention of Povidone
Frankfurt* as part of the acetylene chemistry, well-known under
the expression Reppe Chemistry". Professor Reppe
14th to 19th November, 1999 together with chemists like Dr. Fikentscher, Dr. Herrle,
Dr. Sanner and Mr. Denzinger and generations of
AAPS (American Association of young chemists in polymer research continued to
Pharmaceutical Scientists) Annual Meeting develop types of PVP-based polymers or at least
New Orleans* improved the existing ones up to now.
Quality
18th to 19th November, 1999 Parallel to the research chemistry, production of
Supply safety
Povidone underwent also an evolution process
Asian Conference and Exhibition resulting in GMP-like production sites in Ludwigs-
Global commitment.
on Controlled Release hafen and Geismar. BASF Your
partner for the
Hong Kong
Names, which supported these efforts have been future.
th th
7 to 10 December, 1999 Dr. Penning, Dr. Dall, Dr. Gellrich, Dr. Schrder and
on the quality control side Dr. Schmtzer, Mr. Miersch,
PharmaIndustria 99 (Exhibition on raw Dr. Lamprecht and Dr. Filges support the Povidone line
60th Anniversary
materials, semi-finished drugs and medicines with new analytical methods or introduced new lab of Povidone page 1
in bulk to the Russian market) standards.

Moscow Last but not least two groups responsible for marke-
Calendar page 1
ting and technical support were part of the success
3rd to 6th April, 2000 of Povidone. Mr. Zllner, Mr. Lffler, Mr. Grgens, Great 60 Years
3rd World Meeting on Pharmaceutics, Mr. Jenke, Mr. Lappas in marketing and on the
technical side Dr. Rutz, Dr. Seelert, Dr. Schwarz,
of Polyvinyl-
Biopharmaceutics and Pharmaceutical
Dr. Bhler, Mr. Reich and Dr. Lang were part of the pyrrolidone page 24
Technology positive development of this product line.
Berlin*
At the beginning there was this brilliant idea called
KollidonY
* BASF will be represented. Reppe chemistry", but to develop all the different A Review on
aspects of this idea, it took all the skills of chemists, its Use in
salesmen, pharmacists over a long period of time to
imprint reach the status of Povidone nowadays.
Granulation page 513

Publisher:
BASF Aktiengesellschaft
Team work and dedication for a production line were Toxicology
responsible for the success and will also help Povi-
Editorial staff: done to be a winner in the decades coming up.
of Polyvinyl-
Dr. Volker Bhler, Dr. Hubertus Folttmann,
pyrrolidone page 14
Yours sincerely,
Dr. Karl Kolter, Dr. Siegfried Lang,
Birgit Wesche BASF Aktiengesellschaft
News page 15
Marketing Pharma
Concept/Layout:
MLW KommunikationsForm
Ingredients Preview page 16

GmbH Werbeagentur, Mannheim

Print:
Contact page 16

Frotscher Druck, Darmstadt

Dr. Lang
BASF ExAct page 2 No. 2, July 1999

Great 60 Years of Polyvinylpyrrolidone

Chemistry and physicochemical properties of Povidone.
H. Witteler, M. Gotsche

Introduction

As a water-soluble polymer Polyvinylpyrrolidone,

also named Povidone or PVP, has a large number
of commercial uses. The polymer derives its Prof. Walter Reppe,
success from its low toxicity, biocompatibility, film father of acetylene
forming and adhesive characteristics, complexing chemistry, explains the
ability to proton donors, and a low osmotic synthesis of polyvinyl-
pressure. Due to this exceptional combination of pyrrolidone. Kollidon
properties, PVP finds diverse applications in was already used as a
pharmaceutical and cosmetic products, food, trademark for pharma
adhesives and textile auxiliaries. quality.

Looking back, PVP is one of the numerous products

of Reppe's acetylene chemistry. By reaction of acety-
lene with formaldehyde 1,4-butine diol is formed. After
hydrogenation to 1,4-butane diol, -butyrolactone is
Pharmaceutical Quality Average Molecular obtained by oxidative cyclization. The conversion with
PVP Grades Weight, Mw/g mol-1 ammonia to pyrrolidone is finally followed by addition
of acetylene generating N-vinylpyrrolidone (NVP)
(Figure 1). The first polymerization product of N-
Kollidon 12 PF )1 20003000 vinylpyrrolidone was patented in 1939. On its 60th
Pharmaceutical Quality
Povidone Grades. Kollidon 17 PF )1 700011000 anniversary, PVP is still under investigation and the
(Table 1) number of applications is still growing. Moreover, PVP
Kollidon 25 2800034000
is a perfect example of Verbund (integrated manu-
Kollidon 30 4400054000 facturing) in the chemical industry. Verbund of pro-
duction facilities for basic chemicals, intermediates
Kollidon 90F 10000001500000
and polymerization technology has made PVP a great
)1 PF = pyrogen-free success for both BASF and our customers.

Synthesis and Properties of PVP

Substance Complex formation N-Vinylpyrrolidone is usually polymerized by radical
constant in L/mol polymerization. Cationic polymerization with BF3 leads
only to oligomers. The polymerization can be con-
ducted in solution or in bulk.
Acetaminophen 1.5
The radical polymerization of NVP in organic solvents
Acetylsalicylic acid 0.7 leads to low or medium molecular weight products,
due to the fact, that the solvent may act as a chain
Benzoic acid 0.9
Complex formation transfer agent. The higher molecular weight polymers
constants of a number Chloramphenicol 0.4 can be produced by solution polymerization in water
of drugs and other using hydrogen peroxide as initiator. The polymeriza-
Methotrimeprazine 3.2
substances with soluble tion is usually conducted at pH 7 to prevent a hydro-
Kollidon grades Methylparaben 1.8 lysis of the monomer. The molecular weight is regu-
(D. Horn, W. Ditter, Phenol 0.8 lated by the concentration of hydrogen peroxide.
J. Pharm. Sci. 71, 1021- Under these conditions the polymers contain hydroxyl
26 (1982)). Resorcinol 2.4 end groups from the starting hydroxy radicals. In most
(Table 2) Salicylamid 1.3 cases an aldehyde function is found as the second
end group, which is formed during chain termination,
Salicylic acid 1.5
followed by the elimination of pyrrolidone (Figure 2).
Sorbic acid 0.5
PVP typically is characterized by its K-Value. The K-
Sulfamoxole 0.3
Value is related to the weight average of the molecular
Sulfathiazole 0.4 weight and is obtained from viscosimetric measure-
Trimethoprim 0.2 ments. Since the K-Value plays a dominant role in the
properties of PVP, it is usually part of the name of PVP
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. O O
15 percent of PVP K 90 in aqueous solution boosts the CH + HC CH + HC HOCH2C CCH2OH
viscosity of water from 1 mPa s to more than 5000 mPa s H H
and consequently, this type of PVP may be used as a
thickener in various types of formulations (Table 1). Synthesis of +2 H2 2 H2 O O
The most frequently used Povidone grades are Kolli- N-vinylpyrrolidone. HOCH2 CH2CH2CH2OH
don 12 PF, 17 PF, 25 and 30. The qualitative identifica- (Figure 1)
tion is provided by the infrared spectrum. At the same H H2C CH
N O N O
time the infrared spectrum allows the study of com- + NH3 HC CH
plex formation of PVP with organic and inorganic
molecules (see below). Quantitative determination of H2 0
soluble PVP grades may be carried out by photometry
of the PVP-iodine complex. This also points into the
H
direction of an important application. HOCH2CCH2C
PVP is a hygroscopic substance. When used as a N O N O + HO
binder, the hygroscopic character of PVP is of great n
importance and plays a role in the binding properties.
Besides intrinsic physical properties, the particle size
distribution has a marked effect on application proper- Formation of alde-
ties. Pharma quality means that all Kollidon grades hyde end groups in HOCH2CCH2CHOH
N O O
fulfill the requirements of the important pharmaco- NVP-polymerization in N
poeias like USP, Ph. Eur. and JPE. water.
(Figure 2) n
Complex Formation with soluble PVP
Due to their chemical structure, namely the amide O
bond, PVP forms a variety of complexes with other HOCH2CCH2C
H O
N O
chemical compounds including pharmacological
H + N
actives. For these compounds, complexation results in
either enhanced solubility, improved bioavailability or n
increased stability. Complexation is a technique to
obtain formulations that dissolve quickly in water from
actives 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- O
N N N
fectant iodine in water is poor and for this reason in Structure of the
the past the increased solubility of the potassium PVP-HI3 complex.
triiodide was used to overcome this hurdle. But, tinc- (Figure 3) O O
ture of iodine a mixture of potassium iodide and
H
iodine in water and ethanol contains considerable
amounts of free iodine. Free iodine leads to unwanted I3
side effects like strong staining and itching when used
in wound disinfection. PVP provides the tool to dis-
solve iodine in water while maintaining an extremely
low level of free iodine. Here, very small doses of No complexation occurs between PVP and hydrogen copolymer of 60 wt. % N-vinylpyrrolidone and 40 wt.
iodine as low as 1 ppm in a solution that contains peroxide in aqueous solutions. Still, in dried, an- % vinyl acetate. Like PVP, it is soluble in a variety of
1 % of iodine are supplied from a complex of PVP hydrous form complex formation is proven by IR- solvents ranging from water to 1-butanol, but unlike
with HI3 (Figure 3). spectroscopy. Powders of PVP-H2O2 offer a versatile PVP it is much less hygroscopic. For film-coating of
vehicle for the application of H2O2 in many appli- tablets, moisture uptake is of disadvantage, and here
Typical complexes of organic molecules with PVP are cations due to their stability and the ease in handling a less hygroscopic copolymer of N-vinylpyrrolidone is
much weaker than the PVP-iodine complex. Com- as compared to aqueous solutions of H2O2. Possible of advantage. Applications of PVP/VA range from
plexation is effective at a high concentration of PVP applications cover disinfectants, topical formulations, galenic (coatings, binders, polymer/excipient extru-
that is typical of the formulated drug. At typical gastro- and many others. sion) to cosmetics (film former in hair spray formula-
intestinal concentration, complexation can be neglec- tions). Copovidone is listed in the European Pharma-
ted. Still, formulation with PVP is a versatile tool to im- Copolymerization copoeia and Japanese Pharmaceutical Excipients. A
prove solubility or dissolution rate of both liquid and Solution polymerization in water is also used for the USA-NF draft monograph was published in 1998
solid dosage forms. This effect is based on the ability copolymerization of NVP with different monomers to (Figure 4).
to form solid solutions with a solute, e. g. an active alter or to improve the properties of the PVP. Copoly-
ingredient and thus prevent it from crystallizing. The mers with vinyl acetate (VA) are usually prepared in Crosslinked Polymers
absence of crystallinity leads to improved dissolution. water leading to more hydrophobic polymers than There are different ways used for the preparation of
(Y. Nozawa et al., Pharm. Acta Helv. 60, 175 (1985); PVP. In order to obtain a homogenous copolymer crosslinked PVP. Slightly crosslinked PVP is obtained
M.M. Devilliers et al., Int. J. Pharm. 163, 219 (1998)) composition, vinyl acetate is added gradually to the by treatment of linear PVP with hydrazine or hydro-
(Table 2). reaction mixture. Kollidon VA 64 (Copovidone) is a gene peroxide or by -irradiation of the linear polymer.
BASF ExAct page 4 No. 2, July 1999

More densely crosslinked PVP is prepared by copoly-

Property Dimension Kollidon Kollidon Crospo-
merization of N-vinylpyrrolidone with bifunctional mo- CL CL-M vidone M
nomers. Because of the combination of high water
uptake and insolubility, swelling is observed with
crosslinked PVP when exposed to water while soluble
PVP simply dissolves. Particle Size < 15 m > 90 %
(air jet screen, < 50 m < 60 % > 90 %
The popcorn polymerization bulk polymerization of 5 min, 20 mbar) < 250 m > 96 %
N-vinylpyrrolidone either in presence of alkali metal Properties of insoluble
hydroxide above 100C or in presence of small PVP grades. Bulk density g cm-3 0.300.40 0.150.25 0.310.41
amounts of bifunctional monomers at 100C leads (Table 3) Specific surface m2 g-1 app. 1 36 app. 2
to highly crosslinked PVP particles with a specific sur- area (det.
according Ph.
face area of a few square meters per gram. This pop- Eur. 2, V 5.5.3)
corn PVP, Crospovidone, finds important use as tablet
disintegrant, as an agent for clarifying beverages and Swelling pressure kPa app. 55 app. 30
of lightly com-
as active ingredient for stomach and gastrointestinal pacted PVP in
diseases. In contrast to soluble PVP, complexes of water
crosslinked PVP with high complexation constants en-
able the extraction of the complexed molecule. The balanced aqueous solubility properties, Kollidon Miscellaneous Applications
usefulness of crosslinked PVP for gastrointestinal dis- grades have been found to provide a comprehensive Further pharmaceutical, biomedical and biochemical
eases is based on the following properties: and universal base for various types of drugs. After applications cover protein isolation and protein stabi-
melt extrusion, the active drug can be present in the lization (J. F. Carpenter et al., ACS Symp. Ser. 567, 134-
formation of a protective layer on the mucous extrudate in one or two forms: as a crystal suspended 47 (1994)), gene therapy (K. Anwer et al., Human Gene
membranes in the hardened Kollidon matrix, or as a molecule Therapy 9, 659 (1998)), cancer therapy (R. Katoh et al.,
adsorption of gas dissolved in the polymer during the melting phase Oncology Reports 5, 103 (1998)), and reproduction
adsorption of water, swellability and remaining dissolved in the finished product a biology (J. L. Titterington, J. Robinson, Human Repro-
complexation of toxins of microbial origin solid solution". Melt extrusion technology paves the duction 11, 2697 (1996)). Besides pharmaceutical
way for benefits in therapy (Figure 5): uses, technical grades of PVP are used throughout the
Complex formation of crosslinked PVP with tannin is industry. Applications cover cosmetics and toileteries,
of interest both in pharmacology and in beverage specifically designed controlled-release for- beverage filtration, photographic products, dyeing
technology (K. J. Siebert, P. Y. Lynn, J. Am. Soc. Brew. mulations (both instant and sustained release) applications and inks, detergents, dispersions, sus-
Chem. 56, 24 (1998); D. Horn, W. Ditter, J. Pharm. Sci. formulation with improved bioavailability for pensions and emulsions, adhesives, paints and
71, 1021 (1982)). Tannin is a biopolymer with poly- compounds with low aqueous solubility. coatings, and paper manufacturing.
phenol structures. The complexation constant of
tannin with Kollidon CL is >1000 L mol-1 (in 0.1 N
60
hydrochloric acid).
Kollidon 25, 30, 90 F
Particle size distribution plays a more crucial role for
Water absorption, [%]

the application properties of crosslinked PVP as com- 40

pared to soluble grades. The properties of Kollidon
grades as a disintegrant for tablets vary with particle Hygroscopicity of
size (Table 3) (V. Bhler, Polyvinylpyrrolidone for the Kollidon VA 64 and
pharmaceutical industry, BASF, Ludwigshafen 1996). Kollidon 25, 30 or 90 F 20
In tablets obtained from Kollidon by compression the for comparison, after Kollidon VA 64
disintegration time decreases with the particle size of 7 days at 25 C.
the PVP used for the formulation. Like soluble PVP, (Figure 4)
Kollidon CL-M is capable of stabilizing suspensions, 0

such as antibiotics, antacids, vitamin preparations and 0 20 40 60 80

Rel. humidity [%]
topical formulations.
Lately, it has been demonstrated, that pH-controlled
drug release is possible from PVP/Polyacrylic acid
interpenetrating networks (J. F. Yaung, T. K. Kwei, J. Polymer, Excipient, Drug
Appl. Polym. Sci. 69, 921 (1998)). Radiation cured (Feeder system)
Monitoring
hydrogels of PVP, polyethylene glycol, and agar have (in-process sensors)
many desirable properties for using as wound Conveying, Mixing, Melting
dressings (A. B. Lugao et al., Radiat. Phys. Chem. 52, (Extruder)
319 (1998)). Polymer/Drug Melt
Extrusion. Product is Shaping
Polymer/Drug Melt Extrusion either tablet, granulate, (Calender,
As a result of close collaboration over the past ten pellet, sheet ... Cutting system)
years, Knoll AG and its parent company BASF have (Figure 5)
developed a patent-protected novel pharmaceutical
manufacturing technology: drug is incorporated by
melt extrusion in a matrix consisting of a pharma-
ceutical polymer. Due to its thermoplasticity and
page 5 No. 2, July 1999
KollidonY (Polyvinylpyrrolidone)
A Review on its Use in Granulation
Prof. Dr. Peter C. Schmidt, Dept. of Pharmaceutical Technology, Eberhard-Karls-Universitt Tbingen
Historical Background
Polyvinylpyrrolidone (Povidone), which is one
of the products resulting from Reppe's studies
of acetylene chemistry, was patented in 1939.
Originally it was introduced as a blood plasma
expander and was widely used during the second
world war. This application was cancelled later
on due to the fact that medium molecular weight
Povidone (K-25 - K-30) is not able to pass the
kidney barrier completely. But nevertheless the
unique properties of Povidone like high solubility
in solvents of differing polarity, solubilizing and
film forming ability, suspension and emulsion
stabilizing effects and last but not least its binding
properties make it one of the most important
excipients in phamaceutical technology.
Besides the parenteral application early reviews
(Lesser 1954, Greenfield 1956, Ferraris 1959) deal with
uses like complexation, sustained release action,
emulsion and foam stabilizer, applications in cosmetic
(Greenfield 1957) and printing industry as well as a
water removable adhesive. Although a hint on tablet
binding properties is given by Lesser (Lesser 1954),
the first paper about the use in tablet formulations was
published by Lehrman (Lehrman 1958) who found that
aqueous Povidone solutions in a concentration range
from 5 to 25 % were in comparison to acacia muci-
lage, starch paste and syrup an acceptable" binding
agent. The amount of binder used was described as
quantum satis" to reach granular consistency, no
absolute figures were presented. Next a German
pharmacist described the use of Povidone to prepare
charcoal tablets (Khler 1961), lozenges (Khler
1962 a) and its application in sugar coating of tablets
(Khler 1962). Later on the use of Povidone as a con-
stituent for pills (Klmn 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 in
tableting and has replaced natural materials like gum
acacia, gelatin, traganth and others as well as many of
the semisynthetic cellulose derivatives. It is available in
different grades making an optimum choice possible.
For further details of Povidone properties see the ex-
tensive review of Bhler (Bhler 1993).
Basic considerations
Granulation is done for a number of purposes: to
enhance compressibility and compactability, to in-
crease flowability of the bulk and to reduce dust in the
tableting mixture. According to Rumpf (Rumpf 1974)
the following forces of increasing order can be in-
volved in the binding between particles: van der Waals
forces, electrostatic forces, liquid bridges, binder con-
taining bridges, salt and solid bridges. Van der Waals
and electrostatic forces as well as solid bridges act
The formation of a binder bridge between two
particles depends on: the particle's surface, its
porosity and wettability, the solubility of the ingre-
dients being granulated in the solvent or binder
solution and on the dissolution rate of the binder.
(Figure 1)
Solids (actives and
excipients) 100 %
Working area
Solvent Roller compaction/
granulation direct compression
Solvent 20 % Solution Dry binder
100 % of a binder 100 %
Phase triangle showing the relations between the
solids, the solvent and the binder in a conventional
granulation process. As an example working point
representing 60 % solids, 32 % solvent and 8 %
binder is given.
(Figure 2)
BASF ExAct
mainly in dry powder compaction while liquid bridges
with or without a polymer as a binder are the domina-
ting mechanisms in conventional and fluidized bed
granulation. The parameters influencing the formation
of a bridge between two particles are presented in
figure 1.
In the first step the solvent or the binder containing
solution has to wet the surface of the solids to be
granulated. The wetting depends on the surface ten-
sion of the solid and the liquid and on the interfacial
tension between solid and liquid. The amount of liquid
necessary 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 the
binder solution will influence the formation of liquid
bridges. When the binder, in most cases an organic
polymer, is mixed together with the other ingredients
as a powder and moistened afterwards by the solvent,
the dissolution rate of the binder in the solvent during
the granulation process will also influence the proper-
ties of the resulting granules. In these cases the type
of equipment used for granulation will become very
important.
The correlations between the solid , the solvent and
the binder can be visualized as a triangular phase
diagram as shown in figure 2.
The corners of the triangle represent the solids, the
solvent and the binder respectively. Along the line
solids/dry binder, where the solvent content is zero,
roller compaction and direct compression are located.
A solvent granulation without using a binder takes
place along the line solids/solvent. At any place within
the triangle a ternary system comprising of solids,
solvent and binder is existing. The working area for
practical purposes is marked in the upper region of
the triangle. The aim of a granulation process is to
granulate the material with a minimum of binder. In a
conventional granulation process the amount of sol-
vent is limited by the solubility of both the binder and
the solids, because an over-moistening effect leading
to a suspension has to be avoided. In fluidized bed
granulation, 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 bed
granulator an unlimited solvent supply is possible and
therefore 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
BASF ExAct page 6 No. 2, July 1999

beads one part of the resulting granules was dried for

Conventional Granulation Fluidized Bed Granulation 3 h at 60C, the other one was compressed into molds
Differences between a and the molds were dried for 12 h at 60C. The
Binder Solvent Binder Solvent
conventional and a strength of the agglomerates and the molds, measu-
solution solution
fluidized bed granu- red using a special equipment, is shown in figure 4.
Solids plus dry Solids plus dry lation process. In both
Solids Solids cases the binder con- For agglomerates and for molds Povidone K-90
binder binder
tent in the final granules showed the highest strength values followed by
High shear mixer Fluidized bed granulator can easily kept constant Povidone K-30, the cellulose derivatives and lactose
when granulating with indicating the high binding efficiency of Povidone.
the pure solvent. When When silicon treated glass beads were used the
Moist granules using binder solutions strength values were in general lower but of the same
Continuous
the binder content order showing the importance of wetting as a first step
solvent
varies depending on in granulation. These findings are supported by Danjo
evaporation
Drying unit the amount of fluid and (Danjo 1993) who found a similar ranking when using
is nearly unlimited in lactose as an excipient and preparing granules by
the case of fluidized extrusion, fluidized bed and conventional granulation.
Dry granules Dry granules bed granulation. Jger and Bauer (Jger and Bauer 1984) found
(Figure 3) coarser granules with high molecular Povidone. The
authors recommend polymer blends to adapt the
particle size distribution to a desired value.
Agglomerate strength [kg/cm2]

Povidone 40 30
K-30
Strength of molds [kg/cm2]

Agglomerate strength
Povidone 30
Mode of incorporation of Povidone in granules
K-90 and strength of molds
20 The binder can be incorporated into granules by three
HPC-EFP as a function of binder
20 different methods:
HPC-LFP solution added (ml/g
10 powder). Concentration
HPMC
TC-5E 10 by dry granulation using a roller compactor
of binder solution: 10%
HPMC
by mixing the binder with the actives and
(w/w) for polymers,
TC-5S 0 0 excipients and subsequent moistening with a
saturated solution for
Na-CMC 0,00 0,05 0,10 0,15 0,20 0,25 0,00 0,05 0,10 0,15 0,20 0,25 solvent preferably water
lactose. Sample: un-
Lactose by granulating the powder mass using a binder
Proportion of binding solution added [ml/g] treated glass beads.
solution
(Figure 4)
liquid depending on the properties of the solids could and to compare Povidone with other binders used in Dry granulation does not require any solvent and is
be added before over-moistening takes place. Bin- granulation. Cutt et al. (Cutt et al. 1986) investigated advantageous whenever stability problems arise with
ders forming high viscous solutions, e. g. tragacanth or the binding effiency of Povidone, Methocel E 15 , a a drug in contact with water or other solvents. No
sodium alginate, can therefore be incorporated only in hydroxypropyl methylcellulose (HPMC) and Byco C drying operation is necessary, therefore the product is
an amount of up to 3 to 5 % based on the solid content gelatin, a hydrolized gelatin, in a model system com- not stressed by higher temperatures. It is a simple
of the granulate. prising of glass beads of a mean diameter of 26 and process of high capacity. Nevertheless it is not fre-
Soluble Povidone is available in five different grades 40 m respectively. They found a uniform binder dis- quently used in pharmacy for several reasons. The
as shown in table 1 (Bhler 1993, p.36). tribution throughout all granulations. Povidone show- granules produced by a compaction process are
ed the lowest granule friability, formed stronger gra- irregular in shape, show a high friability and contain
The molecular weight MV which is taken from viscosity nules compared to HPMC but not as strong as Byco often quite a high amount of fines. Povidone, although
measurements shows for all types a range according gelatin. The granule strength was slightly lower when recommended as a dry binder has in the dry state less
to the European Pharmacopoeia. The low molecular the glass beads were coated with a hydrophobic layer binding properties compared to e. g. Kollidon VA 64,
weight types are designed for parenteral use due to of dimethylsilane. Horisawa et al. (Horisawa et al. 1993) a copolymer of vinyl pyrrolidone and vinyl acetate
the fact, that they pass the kidney barrier. In earlier granulated glass beads of 152 m in a kneader using (Bhler 1993, pp. 129-222). In wet granulation the
times the main product in granulation was Kollidon 25, Povidone K-30, Povidone K-90, two types of hydroxy- powders are normally granulated using a binder
but is now replaced by Kollidon 30 and Kollidon 90 F. propyl cellulose, two different hydroxypropyl methyl- solution. This process involves a lot of parameters,
Several attempts were made to differentiate between celluloses, one sodium carboxymethylcellulose and the most important are:
the binding behaviour of different types of Povidone lactose for comparison. After granulating the glass
properties of the powder mass like wetting
behaviour, solubility and tendency to rapid
Mv calculated from Mv calculated from the K-
the nominal K-Value value range given in Ph. Eur. over-moistening".
Table 1: Viscosity- amount of binder solution
average values of the concentration of binder in the solution
Kollidon 12 PF 3900 26005500 molecular weight, Mv mode of application of the binder solution
for the soluble Kollidon like pouring or spraying
Kollidon 17 PF 9300 710011000 grades, calculated type of granulating equipment
Kollidon 25 25700 1930031100 from the K-value. time of kneading the moistened powder mass
in conventional granulation processes
Kollidon 30 42500 3170051400

Kollidon 90 F 1100000 7900001350000 The advantage of this type of process is that the binder
is used in solution and the polymer is present in a
page 7 No. 2, July 1999
molecular distribution developing highest binding
efficiency. On the other hand, a solution has to be
prepared in advance and the amount of binder will
vary within certain limits due to the fact that quite often
the amount of liquid required reach the end point of
the granulation has to be adapted.
The third possibility is to mix the binder in the dry state
with the powder mass to be granulated and to moisten
the mixture using a solvent, which is preferably water.
This method has the advantage that the amount of
binder is constant and independent from the amount
of liquid required for granulation. But the process has
some 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 treated
according to this method. It is soluble to a high degree
in 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 methods
of binder addition.
D'Alonzo et al. (D'Alonzo et al. 1990) used a model
system consisting of microcrystalline cellulose and
Povidone as binder to study the effect of binder con-
centration and the method of addition on granule
growth in a high shear mixer. The concentration range
of Povidone was 1 to 5 % which is recommended for
tablet formulations, the amount of water to moisten
1 kg of microcrystalline cellulose was 1 litre. The gra-
nulation time was kept constant for all experiments
and the process was followed by a resistance
measurement at the impeller blade of the mixer, which
was also used for end point detection. The mean
particle diameter of the resulting granules for both
methods is shown in figure 5.
The granules prepared by the dry method indicate a
more consistent behaviour in dependence of the
amount of Povidone. Furthermore the authors state
that the percentage of fines was reduced. The resis-
tance at the impeller blade was lower for the binder
solution compared to water indicating a lubrication
effect of the aqueous binder solution. In a second
paper (Alkan and Ulusoy 1983) granulations of lac-
tose, starch and Povidone are described. Again the
dry addition method was compared to a binder solu-
tion. The composition of the mixture was 80 % lactose,
12 % starch and 8 % Povidone. Granulation was done
in a fluidized bed dryer. To granulate 400 g of powder
200 ml of ethanol were used leading to a Povidone
concentration of 16 % when used as a binder solution.
The particle size distribution of the resulting granules
was log-normal, the mean particle diameter for the dry
method was 680 m and for the granules prepared
using a binder solution 330 m. Flowability was
Wet Addition Method
Dry Addition Method
650
Mean Granule Size, d [m] 600
550
500
450
400
350
0 1 2 3 4 5
Povidone Concentration [% w/w]
similar for both granulations, friability was lower for the
granules prepared with Povidon in solution. A more
uniform distribution of Povidon in the granules was
found for the binder added in solution. The authors
come to the conclusion that it is advantageous to add
the binder in solution.
Comparing the two papers the results seem not to be
in agreement. For the system microcrystalline cellu-
lose/Povidone/water the dry method was recommen-
ded while for lactose plus starch/Povidone/ethanol
the solution method was superior. But two aspects
were not considered in both papers: the properties of
the excipients and the equipment. Microcrystalline
cellulose absorbs high amounts of water before
agglomeration 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 methods
used were not directly comparable. The mechanical
stress in a kneader is high compared to a fluidized
bed 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 and
a better distribution of the liquid.
Voigt and Richter (Voigt and Richter 1988) and Richter
et al. (Richter et al. 1989) compared the dry and the
solution 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 bed
granulator. The mean particle diameter of the granules
was smaller in all cases, when the dry method was
used and was nearly concentration independent,
while with the solution method an increase of the
mean particle diameter with increasing amount of
binder was observed. Gelatin and PVA gave harder
tablets after solution granulation while Povidone
showed no differences. This was explained by the
high dissolution rate of Povidone during granulation.
Again Povidone was recommended for the method
of dry binder addition and subsequent moistening.
Wan and Lim (Wan and Lim 1989) used the dry and
the solution method to granulate lactose and starch
respectively using 25 g of Povidone per 400 g of
material in a fluidized bed dryer. They found larger
BASF ExAct
Influence of the
Povidone concentration
after addition of the
binder as a dry powder
or a binder solution
respectivily on the
mean granule size.
(D'Alonzo et al. 1990)
(Figure 5)
6 7 8 9 10 11 12
particle diameters for the dry method for lactose and
no significant differences for starch. The higher water
absorption of starch should again be responsible for
the differences between both substances.
To summarize these findings: Povidone is a valuable
binder when incorporated in a powder mixture as a
dry substance being granulated by the addition of
water or an organic solvent. Due to its high dissolution
rate it is superior to other polymers like gelatin. The
experimental conditions depend on the type of ma-
terial to be granulated and on the equipment used.
Povidone as a binder in model systems
Basic investigations of the granulation process are
quite often carried out using model formulations.
Frequently used excipients in this field are lactose,
starch, mixtures thereof, microcrystalline cellulose and
dicalcium phosphate. Most of the work published in
the past was done with lactose or mixtures thereof with
starch. The following tables summarize work which
was done with Povidone alone or in comparison to
other binders. Investigations dealing with lactose are
summarized in tables 2 and 3, those with mixtures of
lactose and starch are presented in table 4.
The results from fluidized bed granulation of lactose
can 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/Povidone
system granulated in high shear mixers of different
types.
Due to the limited amount of liquid being used in this
type of granulation the binder concentration in the
solution is in general much higher compared to
fluidized bed granulation. Concentrations ranging
from 10 to 45 % are usual. The amount of liquid should
BASF ExAct page 8 No. 2, July 1999

Lactose Povidone-solution Parameters Results Literature be chosen as large as possible because all experi-
investigated
ments cited in table 3 indicate that there is a strong
type type influence of the amount of liquid added on the pro-
particle size (m) amount
amount (g) concentration (w/v) perties of the granules and later on on the tablets.
lactose BP K-25 amount of lactose high influence of Povidone binder Wan and Lim Besides this the intensity and time of kneading should
84,73,84 200600 concentration of concentration on size of granules 1988 have some substance dependent influence. The
200500 110 % Povidone solution low Povidone concentration, slow
volume of spray rate, small volume of Povidone particle size of the powder and the type of solvent
Povidone solution solution and a large lactose feed lead
spraying rate to small monosized granules (water, ethanol or mixtures thereof) have less influ-
lactose powder (Pharma- K 90 type of Povidone particle size of granules is increased Wan et al. ence.
tose 200, DMV. Veghel, 150300 concentration and with K 120 1995
The Netherlands) 13 % volume of binder granule size is increased with
K 120 solution increasing concentration, spray rate The situation using mixtures of lactose and starch is
400 150300 spraying rate and volume of binder solution
13 % summarized in table 4.
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. Wan and Lim (Wan and Lim 1991) investigated mix-
70150 150250 10 % size and tensile strength of the tablets 1983
1000 and in a decrease of granule friability tures of lactose and starch of different ratios in a
fluidized bed apparatus using Povidone K-25 as a
Model granulations of lactose/Povidone using a fluidized bed granulator binder. The binder was applied in different concen-
(Aeromatic-Strea 1, Aeromatic-Fielder, Bubendorf, Switzerland). (Table 2) trations and at different spray rates. The results indi-
Lactose Povidone Apparatus Parameters Results Literature cate best granule properties when a ratio of lac-
-solution investigated tose : starch of 3 :1 was used, while a ratio of 1: 3 was
Solution difficult to granulate due to the small particle size of the
type type
particle size (m) amount starch. In general the granulation of small particles in
amount concentration
a fluidized bed apparatus is a problem because the
lactose Ph. Eur. VA-64 high speed mixer method of liquid granule growth is Holm et al. particles are partially exhausted by the air into the filter
X50 = 52 up to 750 g Fielder-PMAT 25 VG addition controlled by the 1983
7.5 kg 10 % liquid flow rate amount of binder and sometimes do not take part in the granulation
impeller speed added and the
chopper speed impeller speed process. A 2 :1 mixture of lactose and maize starch
lactose Ph. Eur. VA-64 high speed mixer kneading time after no influence of Holm et al.
was granulated by Crimella et al. (Crimella et al. 1984)
X50 = 52 up to 750 g Fielder-PMAT 25 VG liquid addition kneading time on 1984 using five different types of equipment. They found
7.5 kg 10 % impeller speed granule growth (in
chopper speed contrast to calcium differences in the granule and tablet properties and
phosphate)
recommended a combination of a high shear mixer
lactose 100 mesh K-25 planetary mixer mixtures of the two no correlation bet- Tapper and for granulation and a fluidized bed dryer for drying to
X50 = 103 38133 ml Kenwood 707 A lactose types ween surface area Lindberg
1000 g 18.444.0 % (w/w) concentration of of lactose and 1986 obtain tablets within the desired specifications. In
corresp. to 30 g binder solution volume of
granulation fluid contrast Held et al. (Held et al. 1993) found similar
lactose 350 mesh Povidone
tablet properties when comparing a formulation con-
X50 = 32 taining lactose, starch and 2.5 % of nitrazepam using
1000 g
combinations of a planetary mixer, a high shear mixer,
-lactose- K-25 planetary mixer solvent type tablet strength Wikberg and
monohydrate 90300 ml Kenwood A 71 C (water/EtOH/water: increased with Alderborn a tray dryer and a fluidized bed dryer in a factorial
EtOH 0 50 : 50) increasing amount 1990 design experiment. They concluded that through a
1000 g 1645 % amount of liquid of liquid in
granulation careful validation process identical products can be
obtained even with differing equipment.
Model granulations of lactose/Povidone using conventional mixing equipment. (Table 3)

Lactose Starch Ratio Povidone Granulation Parameters Results Litera- In a series of papers Vojnovic et al. (Vojnovic et al.
-type -type lactose: -type -amount equipment investigated ture
-particle size -particle size starch/feed -concentration 1992, 1993 and 1995) optimized the operating con-
lactose BP maize starch BP 1 : 1/400 g K-25 Aeromatic Strea 1 ratio of lactose/ ratio 3:1>1:1> Wan and
ditions of two high shear mixers Roto J and Roto P
84.73.84 m 16.31.43 m 3 : 1/400 g 500 ml (solution) starch 1:3 with respect to Lim 1991 from Zanchetta, Italy. They used a powder mix con-
1 : 3/400 g 7 or 15 ml/min binder conc. in larger granule
solution size and better taining 68.2 % of lactose and 31.8 % of corn starch
spray rate flow properties
which was granulated with a Povidone solution. First
lactose maize starch 2 :1 K-25 1,5 % A: Glatt-WSG 5 granule pro- tablets com- Crimella a central composite design using a Roto J granulator
(tablet) B: planetary perties (humidity, pressed from et al.
mixer (Viani)/ apparent granules pre- 1984 was carried out leading to the following optimum
tray dryer density, porosity, pared by method
C: high shear angle of repose) D were superior conditions for the granulation process:
mixer (Diosna P tablet properties
50)/ Glatt WSG 15 (hardness,
D: high shear friability, dis- moisture level: 17.45 %
mixer (Diosna P integration)
50)/ Glatt WSG 15 impeller speed: 426.5 rpm
E: Viani mixer/
Glatt WSG 15 granulation time: 8.01 min.
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 1993 Their second paper deals with the simultaneous
Pharma- Pharma- high shear mixer properties with
copoeia copoeia (Diosna P 50) different equip- optimization of several response variables. Using the
tray dryer fluid- ment after same formulation the optimum zone of the 10-litre
ized bed dryer validation
machine was determined and scaled up to a 50-litre
lactose, 200 corn starch 2.1 : 1 K-25 2 % (tablet) high shear mixers surface high effect of Vojnovic
mesh (DMV) X50=15m Zanchetta Roto J response design moisture level, et al. high shear mixer. In the third paper the central com-
X50=39m and Roto P tray simultaneous optimum con- 1992
dryer optimization ditions used 1993 posite design was optimized by an a priori" approach.
method for up scaling, 1995
experimental comparison of
design with predicted with Model granulations of lactose and starch with
a priori criterias results obtained
Povidone as a binder. (Table 4)
page 9 No. 2, July 1999 BASF ExAct

Besides lactose and mixtures of lactose and starch starch glycolate respectively tablets were obtained and co- Fluid bed granulation.
some papers deal with other excipients like dicalcium fulfilling all requirements of the USP. The same group workers
phosphate and microcrystalline cellulose as model (Chen et al. 1995) later on published a paper where (Ebube et al.
substances in granulation. Ritala et al. (Ritala et al. they recommended the additional use of a surfactant 1996) com-
1986 and 1988) used a high shear mixer (Fielder like sodium lauryl sulfate or Pluronic F-68 in combi- pared the
PMAT 25 VG) in basic investigations with dicalcium nation with Povidone in granulation to enhance the influence of
phosphate and the binders Povidone K-25, Povidone dissolution rate and the hardness of the resulting acetaminophen
K-90, two hydroxypropyl methylcelluloses Methocel tablets. as an example
E5 and E15, a hydrolized gelatin (Byco C or Protein S) Becker et al. (Becker et al. 1997) compared a place- of a sparingly
and a poly(vinylpyrrolidone-vinylacetate) copolymer. bo granulation and an acetaminophen containing one soluble drug and
Povidone K-90 and Protein S facilitated the granule using a combination of a high shear mixer Diosna P pseudoephe-
growth leading to coarser granules. Avicel was used 10 (Dierks & Shne, Osnabrck, Germany) and a drine sulfate
to study the interactions of this microcrystalline cellu- fludized bed dryer Strea 1 (Aeromatic-Fielder, Buben- showing a high
lose with aqueous solutions of Povidone K-25 and dorf, Switzerland). They compared Povidone K-30, a water solubility on
hydroxypropyl methylcellulose (Pharmacoat 603) hydroxypropyl methylcellulose (Cellulose HP-M 603), tablet properties using
using a laboratory-scale, instrumented mixer torque a pregelatinized starch (Lycatab PGS), a maltodextrin a hydroxypropyl methyl-
rheometer. The authors found differences between the (Lycatab DSH) and a low substituted hydroxypropyl- cellulose and Povidone K-
two binders which were explained by theories relating cellulose (L-HPC, type 11). The binders were added as 30 as binders. The drugs were
binder surface tension to granule properties. powders and granulation was done with water. used alone and in combination in a matrix of the
two binders of differing ratios. The total polymer
Povidone in the granulation of active ingredients Although they were able to detect differences between content was between 3.5 and 19.2 % in the final matrix.
In model systems containing lactose, starch, mixtures the binders there was no formulation found leading to The presence of the water soluble pseudoephedrine
thereof, microcrystalline cellulose or dicalcium phos- a tablet with sufficient properties. Here the question is significantly influenced the properties of an aceta-
phate as excipients, the influence of different binders whether or not the mode of incorporation of the bin- minophen granulation by reducing the particle size
on the granule properties could be studied relatively ders into the granules plays an important role. Ebube distribution of the granules and the friability of the
easily. Except lactose these excipients are water in-
soluble, the bonding between them and the binder Active ingredient Povidone-type Main purpose of the investigation Literature
and concentration
depends on their wetting behaviour, water uptake,
swelling, and later on during compression of the Acetaminophen K-30; 2/5/10 % in Development of acetaminophen for direct compression Liu et al. 1994
granul.
tablets on their compression and compaction proper- 5/7.5/10 % in soln.
ties. When adding an active ingredient the situation Acetaminophen K-30; 2 and 5 % Development of acetaminophen for direct compression Chen et al. 1995
becomes more difficult. Wetting and solubility as well Acetaminophen K-30; 0/2/6/10 % Comparison of Povidone with other binders Becker et al. 1997
as its compressional behaviour will depending on
Acetaminophen/ K-29-32, blended with Effect of drug, formulation and process variables on granulation Ebube et al. 1996
the dosage more less strongly influence the proper- Pseudoephedrine HPMC; 3.4 to 19.2 % and compaction characteristics
ties of the resulting granules and tablets. Table 5 Aminophylline not specified; 1/3/5 % Comparison of Povidone with corn starch and HPC Anjo et al. 1988
summarizes those articles from literature which deal Aspirin K-90, 6 % Influence of solvent type (water/ethanol on granules and tablets) Wells and Walker
with Povidone as a binder. The examples chosen 1983
cover a range of pharmaceutical actives. It was not the Caffeine anhydrous K-30; 2/3/4/5 % Investigation of the granulation process using artificial Kesavan and
neural networks Peck 1996
intention to collect all papers published.
Caffeine K-12/K-17/K-25/ Application of polymer blends in granulation Jger und Bauer
K-90; 3 % 1984
Acetaminophen is a high dosed drug which is
Herbal drugs K-30/K-90; 5 % Effect of binder solution on physical properties of granules Seko et al. 1993
sparingly soluble in water and poorly compressible.
Therefore it is a good example to test the capability of Hydrochlorothiazide K-30; 5 % Comparative evaluation of two pharmaceutical binders Symecko et al.1993

binders in granulation. Liu et al. (Liu et al. 1994) used Metronidazole Povidone; M, 44000 Comparison of Povidone, gelatin and methylcellulose as binders Itiola and Pilpel
for metronidazole 1987
Povidone K-30 to develop a direct compressible
Naproxen K-25; 5 % Comparison of wet granulation and direct compression Tarimci and Satiro-
acetaminophen. In preliminary trials Povidone was glu-Tezcan 1995
applied at the three levels 2, 5, and 10 % in the gra-
Naproxen K-29-32; 5 % Action of superdisintegrants in Povidone based granulations Gordon et al. 1991
nules via 5, 7.5 and 10 % solutions using a Glatt
Phenytoin Povidone, M, 10000; Influence of mode of incorporation on dissolution rate Gabr et al. 1991
GPCG-1 (Glatt Air Techniques Inc., Binzen, Germany) 3.78/7.78/10/15 %
fluidized bed granulator. It was found that in minimum Piracetam Povidone; 3 % Influence of piracetam solubility on granule properties Fbregas and
5 % of Povidone are required to give a free flowing Cucala 1987
granulate. In an additional factorial experiment 5 % of Propranolol K-25/K-29-32/K-90/ Effect of Povidone solutions containing dissolved drug Wan et al. 1996
hydrochloride K-120; 2/3/4/5/6/7 % on characteristics of granules
Povidone were used in two spray concentrations of 5
and 7.5 % in solution. The other factors were spray rate, Ranitidine K-30; 5 % Influence of moisture and different binders on the properties Uzunarslan and
hydrochloride of granules prepared from ranitidine Akbuga 1991
spray pressure and inlet air temperature. The batch
Salicylic acid/ K-29-32; 5 % Influence of wettability of insouble active ingredients on Jaijeoba and
size was 500 g. The validity of the model was proven Sulfanilamide Kaolin granule properties Spring 1980
by three replicates of one of the experiments. It was Sulfadiazine K-90; 5/10/15 % Comparison of Povidone, acacia and gelatin as binders Nouh 1986
concluded that the inlet air temperature was not a for sulfadiazine
significant factor. Through the elimination of this factor, Sulfamethoxazole not spezified; 3 % Effect of type of binder on the properties of Agrawal and
sulfamethoxazole tablets Prakasam 1988
the system becomes a 23 factorial design with two
replicates. Calculation of this model led to a granu- Sulfathiazole not spezified; 5 % Influence of solvent type and drying method on granule Mandal 1995
properties
lation with 5 % Povidone K-30 in the granules applied
as 7.5 % solution. After the addition of 0.5 % magne- Granulation of active ingredients using Povidone as a binder and special purposes
sium stearate and 1 or 3 % of crospovidone or sodium of the investigations. (Table 5)
BASF ExAct page 10 No. 2, July 1999

tablets, while the tablet hardness was increased. This

behaviour was explained by a change in the hydration
characteristics of the polymers by the addition of a
highly water soluble drug.
Aminophylline was granulated using Povidone, corn
starch and hydroxypropyl cellulose by Anjo and co-
workers (Anjo et al. 1988). Povidone showed the best
dissolution rate and the lowest disintegration time at
sufficient hardness values of the tablets. The influence
of binder vehicle upon granule and tablet properties
has been studied by Wells and Walker (Wells and
Walker 1983) in a model system containing aspirin
and Povidone. Water and ethanol were chosen as sol-
vents changing the solubility of aspirin from 4.66 mg
per ml in pure water gradually to 133.6 mg per ml in
pure ethanol. Using mixtures containing 25, 50 and
75 % ethanol besides the two pure solvents it was
possible to study the influence of a change in drug
solubility on the granule and tablet properties. Greater
solubility of the drug increases the granule size distri-
bution and decreases the friability of the granules. The
disintegration time was prolonged when using a sol-
vent with a higher drug solubility.
Caffeine as a model drug was used by Kesavan and
Peck (Kesavan and Peck 1996) to optimize a formula
by artificial neural networks. Their basic formulation is
shown in table 6.
Besides the variation of the type of binder four con-
centrations of Povidone ranging from 2 to 5 %, the
mode of addition of binder in the dry state and as a
solution and a high shear mixer as well as a fluidized
bed dryer were used. The granules were compressed
into tablets and hardness, friability, thickness, disinte-
gration time and average tablet weight were deter-
mined. A good correlation between predicted and
observed values was found for all granule and tablet
parameters. In a second paper dealing with caffeine
Jger and Bauer (Jger 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 in
the 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 superior
properties compared to the single Povidone types.
Seko et al. (Seko et al. 1993) published a paper on the
granulation of crude drug powders comparing hydro-
xypropyl cellulose, sodium carboxymethylcellulose
and the Povidone types K-30 and K-90. The following
powdered drugs were used: Glycyrrhiza, Senna leaf,
Rhubarb, Magnolia bark, Peony root and Cenidium
rhizome. The granulation was done by two methods:
fluidized bed granulation using a Glatt CPCG-1 granu-
lator and by agitation granulation using a Multiplex
granulator FM-MP-10. Different concentrations of
binder solutions were applied.
The results were analyzed by multiple linear regres-
sion yielding a regression equation for each response
parameter and both granulators. The physical pro-
perties of the products of both, agitation and fluidized
Composition % (w/w); range
Formulation composi-
tion of caffeine Tablets
Caffeine anhydrous USP 40.0
according to Kesavan
and Peck (Kesavan and Lactose or dicalcium phosphate 47.544.5
Peck 1996). Povidone K-30 2.05.0
(Table 6)
Corn starch 10.0
Magnesium stearate 0.5
Hydrochlorothiazide: 0.2 kg
Binder: 0.1 kg
Anhydrous lactose: 1.69 kg
Instrumented double planetary mixer
1. 10 min dry mixing
2. granulation with water 60 ml
in 1 min; stop for 30 s
and so on
Preparation scheme for
hydrochlorothiazide 3. end point detection by power
consumption measurement
tablets using the binder
in the dry state and 8-Mesh screen
granulating with water
(Symecko et al. 1993).
Drying oven
(Figure 6) 40 C [down to 0.1 % loss on drying]
0.01 kg
Magnesium Turbula mixer 5 min
stearate
Stokes B-2 instrumented rotary
tablet press 3/8 flat face punches
Tablet weight: 315 mg
Hardness: 68 kg
bed granulation, are closely related to the amount and inflammatory agent, was compared in direct com-
the viscosity of the binder solution. Hydrochlorothia- pression and granulation formulations by Tarimci and
zide was granulated comparing Lycatab DSH, a mal- Satiroglu-Tezcan (Tarimci and Satiroglu-Tezcan 1995)
todextrin, and Povidone K-30 (Symecko et al. 1993). using 5 % Povidone K-25 as a binder. Although the
The binder was added in the dry state and granulation mechanical tablet properties were almost the same for
was carried out following the scheme shown in both preparation methods the authors detected
figure 6. significant differences between direct compression
and granulation. All granulated formulations liberate
This is a typical scheme to prepare granules using the the active ingredient completely within 10 minutes
binder in the dry state and moistening the powder mix while some of the direct compression formulations
during the granulation with water. In these cases the showed a prolonged drug dissolution. Gordon et al.
binder has to have a good water solubility combined (Gordon et al. 1993) investigated the influence of three
with a high dissolution rate. The results obtained in this so called super disintegrants" on the dissolution of
investigation are summarized in table 7. naproxen from granulated tablets on storage under
different conditions and found that crospovidone and
The granule and tablet properties for both binders are sodium starch glycolate were superior compared to
similar. The dissolution of hydrochlorothiazide is a little croscarmellose sodium. The way of incorporation of
bit faster for Povidone. The compression/hardness- the disintegrants did not influence the drug dissolu-
profile of the two formulations is presented in figure 7, tion. The binder used for granulation was Povidone K
indicating a higher binding capacity for Povidone. 29-32 in an amount of 5 % in the final tablet dissolved
Naproxen, a poorly water soluble nonsteroidal anti- in water.
page 11 No. 2, July 1999 BASF ExAct

Phenytoin was used as a model substance to investi- came to the following ranking of the binders: starch > peroral medicines. The binding properties of Povidone
gate differences in the mode of drug incorporation into ethyl cellulose > Povidone> acacia. In an investigation increase with increasing molecular weight. Therefore
a tablet by coprecipitation during granulation, copreci- on the influence of microwave drying on granule and strongest bonds between particles in granulation are
pitation alone, solvent deposition and granulation tablet properties Mandal (Mandal 1995) used Povi- formed by the high molecular weight type K-90. On
using a Povidone solution. Povidone, Mr 10000, in an done in a concentration of 5 % in water, 50 % water the other hand this type shows the highest viscosity
ethanolic solution in different concentrations was used and 50 % ethanol and ethanol respectively to granu- which could be a limiting factor. The formation of
as a binder. The disintegration times of all tablet formu- late mixtures comprising of 45 % starch, 45 % lactose granules is mainly influenced by the factors:
lations were within the USP specifications although and 10 % sulfthiazole. There was no significant differ-
there was an increase with increasing Povidone con- ence between the microwave and the conventional type of Povidone
centration. On the other hand the dissolution of phe- drying method, but water based granules showed a concentration of Povidone in the granulation fluid
nytoin was increased with increasing Povidone con- higher granule strength compared to 50 % water/50 % concentration of Povidone in the final tablet
centration in general. Differences were found for the ethanol and pure ethanol. the mode of addition of the binder
way of incorporation. Best results were obtained when the equipment used in granulation
the drug was dissolved together with Povidone in Summary the properties of the active ingredients being
ethanol and coprecipitation occured during granu- Linear, soluble polyvinyl pyrrolidone (Povidone) was granulated.
lation. The slowest dissolution rates were observed synthetized in 1939 by Reppe. Its main application was
when a simple granulation with a Povidone solution first as blood plasma expander. After the second world The type of Povidone determines the granule strength
was done. war other applications came up and in the field of together with the concentration. Higher molecular
The influence of the solvent used in granulation on the pharmaceutical technology one of the main pur- weight Povidone leads to a higher granule strength.
disintegration time of tablets during storage was in- poses is up to now the use as a binder in granulation. Therefore Povidone K-90 quite often is preferred. On
vestigated with piracetam as an example for a highly At present five types K-12, K-17, K-25, K-30 and K-90, the other hand the use of high viscous solutions could
water soluble drug (Fbregas and Cucala 1987). The differing in their molecular weight, are available. The be a limitation when only a certain amount of liquid
authors came to the conclusion that whenever a part low molecular weight types K-12 and K-17 are used in can be used. The concentration of Povidone in the
of the drug is dissolved during granulation the dis- parenterals while the higher ones are prefered in granulation fluid therefore varies between 10 and 40 %
integration time of the tablets is prolonged on storage
especially under humid conditions. A similar influence Binder
of drug was found for propranolol hydrochloride when
Granules Lycatab DSH Kollidon 30
it was dissolved together with Povidone prior to granu-
lation (Wan et al. 1996). Besides the drug influence the
authors found an increase in crushing strength of the
Flow rate (g/sec) 4.39 4.51
tablets with increasing volume and concentration of
binder used. High molecular Povidone resulted in Granule friability 3.87 4.37
(%)
stronger tablets.
Mean particle 201.7 143.9 Granule and tablet
The effect of wetting ternary powder mixtures in gra- size (m) properties of hydro-
nulation was investigated by Jaiyeoba and Spring Tablets chlorothiazide tablets
(Jaiyeoba and Spring 1980). As a basic mixture they (adapted from
Weight (mg) 315.5 313.1 Symecko et al. 1993).
used a combination of lactose and boric acid in
different proportions and an aqueous 5 % Povidone K Friability (%) 0.38 0.51 (Table 7)
29-32 solution as a binder. The third component of the
Disintegration 13.42 13.71
ternary mixture was either kaolin, sulfanilamide or time (min)
salicylic acid added in an amount of 10 %. The addi-
Hardness (kg) 7.63 7.45
tion of kaolin, which is very readily wetted by water,
resulted in stronger granules. Sulfanilamide did not Dissolution 40 % 60 %
change the granule strength due to its medium wetta- profile: 20 min
bility which lies between lactose and boric acid, while 30 min 100 % 100 %
salicylic acid, which is not wetted by water, reduces
the granule strength significantly.

Sulfadiazine was granulated by the fluidized bed as Kollidon 30

Lycatab DSH
well as by a conventional method comparing gelatin, Comparison of tablet
acacia and Povidone K-90 in concentrations of 5, 10 12 hardness against
and 15 % based on the binder content in the final maximum compression
10
tablet (Nouh 1986). It was found that in all cases force for the two
fluidized bed granulation was superior compared to 8 binders Lycatab DSH,
Hardness [kg]

the traditional method and that Povidone gave better a maltodextrin, and
6
disintegration times at the same hardness level com- Povidone K-30, both
pared to gelatin and acacia. The effect of starch, ethyl 4 added as powders in
cellulose, Povidone (type not specified) and acacia in a concentration of 5 %
2
an amount of 3 % based on the dry basis on tablet (Symecko et al. 1993).
properties of sulfamethoxazole tablets was investi- 0 (Figure 7)
gated by Agrawal and Prakasam (Agrawal and Praka- 0 5 10 15 20 25 30

sam 1988). Although they obtained best flow proper- Max. Compression Force [kN]

ties and lowest angle of repose with Povidone they

BASF ExAct
in conventional granulation while in fluidized bed
granulation the concentration normally is in a range
of 5 to 10 %. In the final tablet the concentration of
Povidone as a binder is between 3 to 5 and 10 %.
The binder could be added either as a dry powder
followed by the addition of a solvent or as a binder
solution. The first method has the advantage that there
is always a constant amount of binder in the formu-
lation, the disadvantage is that the binder in many
cases is not completely dissolved and that therefore
the type of the equipment used and the processing
time become very important for the result of the gra-
nulation process. In addition only could water soluble
binders can be used in this process.
The use of a binder solution has the advantage that
there is a molecular distribution of the binder leading
to the formation of the maximum number of bonds
between particles. The disadvantage is that there
could be a variation in the amount of binder added
due to the fact that the amount of fluid necessary for
granulation varies between different batches of
powder. Therefore when using this method the raw
materials have to be standardized with respect to
particle 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 process
where mixing of the powders moistening of the mate-
rial, granulation and drying are carried out in the same
apparatus. The method has no restrictions with res-
pect to the amount of binder added and yields highly
compressible granules due to its loose structure. Dis-
advantages are the limited batch size and the time
consuming process. The high shear technology offers
a rapid method for mixing the powder, moistening and
granulation within a few minutes leading to a denser
material compared to the fluidized bed technology.
There is equipment ranging from small scale (below
100 grams) to high capacity apparatus of several hun-
dred kilograms available. The disadvantages are: the
amount of binder added as a binder solution is limited
due to the solubility and viscosity of the polymer used
for granulation and drying is normally carried out in a
second unit quite often a fluidized bed dryer.
The presence of active ingredients can tremendously
alter the properties of the granulation mixture. In gra-
nulation the first step is the wetting of the material by
the granulating fluid. This can be facilitated by wetting
agents. The solubility of the actives and excipients in
the granulation liquid will also influence the process
and is quite often the determining factor when highly
water soluble drugs have to be granulated. In addition
a recrystallization during drying can occur leading to
a change in hardness, disintegration and dissolution
of the tablets prepared from these granules. These
physical changes occur during storage over a prolon-
ged period of time. Nevertheless today Povidone is
besides many other applications the most widely used
binder in granulation.
Acknowledgements
The author acknowledges the help of BASF in
the literature search and thanks Dr. Volker Bhler
and Dr. Siegfried Lang, BASF, Ludwigshafen, for
helpful discussions. Thanks should also be given
to Mrs. Renate Beer, University of Tbingen, for
typing and revising the manuscript.
Literature
Agrawal, Y. K., Prakasam, K., Effect of binders on
sulfamethoxazole tablets. J. Pharm. Sci. 77, 885-888
(1988)
Alkan, H., Ulusoy, A., Granulation in a fluidized
bed. I. Effect of addition of the binder in solution or
in dry form. DOGA TU J. Med. and Pharm. 11, (1)
1-7 (1987)
Anjo, S., Suzuki, Y., Kondo, Y., Experimental
aminophylline tablets Effect of various additives on
hardness, disintegration time and dissolution. Byoin
Yakugacu 14, 312-316 (1988)
Becker, D., Rigassi, T., Bauer-Brandl, A.,
Effectiveness of binders in wet granulation: A
comparison using model formulations of different
tabletability. Drug Dev. Ind. Pharm. 23, 791-808
(1997)
Bhler, V., Kollidon-Polyvinylpyrrolidone for the
pharmaceutical 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 granulazione
ad umido sulle caratteristiche tecnologiche dei
granulati 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 of
addition on granule growth in a high intensity mixer.
Drug Dev. Ind. Pharm. 16, 1931-1944 (1990)
Danjo, K., The relationship between tablet
compressibility 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 granulation
and compaction characteristics of heterogeneous
matrices: Part II. HPMC and PVP systems. Drug Dev.
Ind. Pharm. 22, 561-567 (1996)
Fbregas, J. L., Cucala, J., New approach to
aqueous granulation of highly hydrosoluble drugs.
Drug Dev. Ind. Pharm. 13, 1217-1227 (1987)
Ferraris, E., Il polivinilpirrolidone. Mater. plast.
page 12 No. 2, July 1999
(Milan) 25, 208-215 (1959)
Gabr, K. E., El-Shaboury, M. H., Abd El-Gawad H.
A., Hashem, F. M., Combining coprecipitation and
solvent deposition in formulation tablet. Alexandria
J. Pharm. Sci. 5, 119-124 (1991)
Georgakopoulos, P. P., Malamataris, S.,
Dolamidis, G., The effects of using different grades
of PVP and gelatin as binders in the fluidized bed
granulation 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 the
dissolution of wet granulated tablets containing
super 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 of
polyvinylpyrrolidone. Ind. Chem. 32, 11-14 (1956)
Held, K., Kopp, U., Kilchmann-Bohli, I., Sucker, H.,
Einflu unterschiedlicher Herstellungsmethoden auf
die 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 of
agglomerates prepared by the wet method. Chem.
Pharm. Bull. 41, 1428-1433 (1993)
Itiola, O. A., Pilpel, N., Fundamental properties of
metronidazole formulations in relation to tableting. J.
Pharm. Pharmacol. 39, 644-647 (1987)
Jger, K.-F., Bauer, K. H., Verwendung von Poly-
merblends aus Polyvinylpyrrolidonen zur Optimie-
rung der Eigenschaften von Aufbaugranulaten und
Tabletten. Acta Pharm. Technol. 30, 85-92 (1984)
Jaiyeoba, K. T., Spring, M. S., The granulation of
ternary mixtures: the effect of the wettability of the
powders. J. Pharm. Pharmacol. 32, 386-388 (1980)
Klmn, K., A polivinilpirrolidon mint pulula-
ktanyag. Acta Pharm. Hung. 33, 271-274 (1963)
Kesavan, J. G., Peck, G. E., Pharmaceutical
granulation and tablet formulation using neural
networks. Pharm. Dev. Technol. 1, 391-404 (1996)
Khler, H. Rudolf, R., Versuche zur Herstellung
von Kohle-Tabletten. Dtsch. Apoth. Ztg. 101, 324-326
(1961)
Khler, H., Oesterreich, J., Quark, B.,
Pigmentfarben in Tablettenberzgen. Dtsch. Apoth.
Ztg. 102, 1-8 (1962b)
Khler, H., Versuche zur Herstellung von Mund-
und Halstabletten. Dtsch. Apoth. Ztg. 102, 507-510
(1962a)
Lehrman, G. P., Skauen, D. M., A comparative
study of polyvinylpyrrolidone and other binding
agents in tablet formulations. Drug Stand. 26, 170-
175 (1958)
Lesser, M. A., Povidone. Drug & Cosmet. Ind. 75,
page 13 No. 2, July 1999 BASF ExAct

32-33, 126-131 (1954) Vojnovic, D., Moneghini, M., Rubessa, F., polyvinylpyrrolidone as a binder on fluidized bed
Liu, C.-H., Chen, S.-C., Lee, Y.-C., Sokoloski, T. D., Experimental design for a granulation process with granulation of lactose and starch granules. S. T. P.
Sheu, M.-T., Directly compressible acetaminophen a priori criterias. Drug Dev. Ind. Pharm. 21, 823-831 Pharma 5, 244-250 (1989)
compositions prepared by fluidized-bed granulation. (1995) Wan, L. S. C., Lim, K. S., The effect of incorpora-
Drug Dev. Ind. Pharm. 20, 1911-1922 (1994) Vojnovic, D., Moneghini, M., Rubessa, F., ting polyvinylpyrrollidone as a binder on fluidised
Mandal, T. K., Evaluation of microwave drying for Zanchetta, A., Simultaneaus optimization of several bed granulations of lactose. S. T. P. Pharma 4, 560-
pharmaceutical granulations. Drug Dev. Ind. Pharm. response variables in a granulation process. Drug 571 (1988)
21, 1683-1688 (1995) Dev. Ind. Pharm. 19, 1479-1496 (1993) Wells, J. I., Walker, C. V., The influence of granu-
Nouh, A. T. I., The effect of variations in concen- Vojnovic, D., Selenati, P., Rubessa, F., Moneghini, lating fluids upon granule and tablet properties: the
tration and type of binder on the physical character- M., Zanchetta, A., Wet granulation in a small scale role of secondary binding. Int. J. Pharm. 15, 97-111
istics of sulfadiazine tablets and granulations pre- high shear mixer. Drug Dev. Ind. Pharm. 18, 961-972 (1983)
pared by wet and fluidised-bed granulation (1992) Wikberg, M., Alderborn, G., Compression cha-
method.Pharm. Ind. 48, 670-673 (1986) Wan, L. S. C., Heng, P. W. S., Ling, B. L., Effect of racteristics of granulated materials. III. The relation-
Parker, M. D., York, P., Rowe, R. C., Binder- polyvinylpyrrolidone solutions containing dissolved ship between air permaeability and chemical
substrate interactions in wet granulation. 1: The drug on characteristics of lactose fluidized bed strength of tablets of some lactose granulations. Int.
effect of binder characteristics. Int. J. Pharm. 64, granules. Int. J. Pharm. 141, 161-170 (1996) J. Pharm. 63, 23-27 (1990).
207-216 (1990) Wan, L. S. C., Heng, P. W. S., Ling, B. L., Fluidized
Prescott, F., PVP for tablet making. Drug & bed granulation with PVP K90 and
Cosmet. Ind. 97, 497, 621-622 (1965) PVP K120. Drug Dev. Ind. Pharm.
Richter, M., Rahn, H.-W., Voigt, R., Zum Einflu der 21, 857-862 (1995)
Einarbeitungstechnik von wasserlslichen makro- Wan, L. S. C., Lim, K. S.,
molekularen Bindemitteln auf die Eigenschaften von Granulation of mixtures of
Wirbelschichtgranulaten und der daraus herge- lactose and starch by a
stellten Komprimate. Pharmazie 44, 43-46 (1989) fluidized bed technique. S. T.
Ritala, M., Holm, P., Schaefer, T., Kristensen, P. Pharma Sci. 1, 285-293
H. G., Influence of liquid bonding strength on power (1991)
consumption during granulation in a high shear Wan, L. S. C., Lim, K.
mixer. Drug Dev. Ind. Pharm. 14, 1041-1060 (1988) S., Mode of action of
Ritala, M., Jungersen, O., Holm, P., Schaefer, T.,
Kristensen, H. G., A comparison between binders in
the 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 the
physical properties of the binder solution on the
characteristics of the granule from the mixed
powders. Chem. Pharm. Bull. 41, 937-941 (1993)
Symecko, C. W., Romero, A. J., Rhodes, C. T.,
Comparative evaluation of two pharmaceutical
binders in the wet granulation of hydrochloro-
thiazide Lycatab DSH versus Kollidon 30. Drug
Dev. Ind. Pharm. 19, 1131-1141 (1993)
Tapper, G.-I., Llindberg, N.-O., The granulation of
some lactose qualities with different particle size
distributions in a domestic-type mixer. Acta Pharm.
Suec. 23, 47-56 (1986)
Tarimci, N., Satiroglu-Tezcan, N., Design and
evaluation of naproxen tablet formulations
prepared by wet granulation and direct
compression methods. FABAD J. Pharm.
Sci., 20, 1-6 (1995)
Uzunarslan, K., Akbuga, J., The effect of mois-
ture on the physical characteristics of ranitidine
hydrochloride tablets prepared by different
binders and techniques. Drug Dev. Ind. Pharm.
17, 1067-1081 (1991)
Voigt, R., Richter, M., Zum Einflu wasser-
lslicher makromolekularer Bindemittel auf
die Eigenschaften von Wirbelschichtgranulaten und
der daraus hergestellten Komprimate. Pharmazie
43, 191-194 (1988)
BASF ExAct
Toxicology of Polyvinylpyrrolidone
A comprehensive summary of the toxicological properties of Povidone.
St. Schulte
General
Polyvinylpyrrolidone (Povidone) is a linear homo-
polymer of 1-vinyl-2-pyrrolidone monomer used in
a wide range of applications in the pharmaceuti-
cal, food and cosmetic industry. Povidone grades
are available in different molecular weight ranges.
The letter K and an appropriate number related to
the molecular weight are used to designate the
different Povidones. Numerous toxicological and
kinetic studies with Povidones have been per-
formed indicating the biological inertness of the
compound.
Absorption, Metabolism, Distribution, Excretion
The absorption of Povidone from the gastrointestinal
tract is very limited and proceeds primarily by fluid-
phase pinocytosis. After injection, Povidone may be
stored at the injection site or at distant sites (cutaneous
storage syndrome). The disappearance of Povidone
from the bloodstream is inversely related to the mole-
cular weight and involves an initial rapid removal of
low molecular weight materials by the kidney and a
prolonged slower removal of higher molecular weight
material into lymph and tissues, primarily the reticulo-
endothelial system tissues, including liver, spleen,
bone marrow, bone and kidney. Tissue storage
disease in humans occurs only following parenteral
administration of large amounts of the higher mole-
cular weight Povidones. Orally administered Povidone
is eleminated almost totally in the faeces; very little is
found in the bile or urine. Povidone is not metabolized
in the body.
Acute toxicity studies
Studies in rodents, dogs and primates have shown
that Povidone is a substance with a very low acute
toxicity. It is essentially impossible to kill animals by
administration of Povidone except by gross osmotic
imbalance. Thus the LD50 of Povidone orally is repor-
ted to exceed 100 g/kg and to be around 10g/kg or
more intravenously or intraperitoneally. The only
evidence of toxicity following oral administration is
production of diarrhea with doses exceeding 0.5 g/kg
due to the non-absorbed osmotic load in the gut
lumen.
Subchronic toxicity studies
Repeat-dose oral studies in rodents and dogs have
shown that apart from diarrhea at high doses related
to the bulk purgative actions of Povidone there is no
evidence 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
page 14 No. 2, July 1999
reduced food intake and diarrhea. There is some marrow of Chinese hamsters gave no indication of a
evidence of minimal absorption as judged by the genotoxic or clastogenic activity from Povidone K30.
appearance of cell inclusions in the mesenteric lymph
nodes in one dog study, but this is probably not of any Developmental toxicity studies
toxicological significance. The no-adverse-effect level Four studies have been performed, two in the rat and
in subchronic studies in rodents and dogs is around two in the rabbit, using Povidone with four different
5 g/kg/day. molecular weight distributions. Povidone K30 and
Povidone K90 were given in the diet during the first 20
Chronic toxicity/carcinogenicity studies days of pregnancy. There were no indications of em-
In two well conducted chronic studies using Povidone bryotoxocity or teratogenicity in the treated groups. In
K25 and K90 at dose levels in the diet up to 10 % and rabbits treated by intravenous injection with Povidone
5 %, respectively, over a 2 year period, there was no -K12 from days 618 of pregnancy, no adverse effects
evidence of any substance-related toxicity in clinical were observed. Povidone with an average molecular
chemistry, hematology, urine analysis or histopatho- weight of 11,500 given intra-amniotically to rabbit
logy. There was no evidence of an carcinogenic effect embryos showed no evidence of embryotoxicity or
or evidence of Povidone storage in any organ. In less teratogenicity.
well reported chronic oral dog studies in which
Povidone K30 was administered in the diet for 12
years, there was no evidence of treatment-related Conclusion
effects other than some evidence of Povidone storage The extensive volume of toxicological data on
in the regional lymph nodes. There was no evidence Povidone supports the inertness and hence
of any cumulative damage over the 2 years. the safety of Povidone. The acute, subchronic
and chronic toxicity of orally administered Po-
Parenteral toxicity studies vidone is very low, with the only effect observed
After parenteral administration, Povidone is well tolera- being diarrhea at high doses due to the osmotic
ted, with little evidence of local damage after single or action of Povidone. Occasional observations of
5 injections. However, parenteral administration of minimal absorption with storage in mesenteric
large amounts has been reported to cause histamine lymph nodes seem to be of no toxicological im-
release in the dog and Charolais cow, and other car- portance. Povidone was found to be neither
diovascular phenomena secondary to osmotic imba- mutagenic nor developmentally toxic. The curren-
lance. Histamine release is well-known for the canine tly permitted FAO/WHO Acceptable Daily Intake
family. Numerous studies on the chronic effects of (ADI) of 050 mg/kg body weight for food use
injection of Povidone in rats have given conflicting provides an adequate margin of safety.
results, virtually all due to poorly designed and con-
ducted studies. When well conducted studies have
been carried out, there is no evidence of a carcino-
genic effect from repeated parenteral administration.
Repeated injection of Povidones, especially the larger
molecular weight materials, e. g. K-30 and over, can
result in acculmulation of Povidone in the tissues. This
is particularly so if the Povidone is injected into poorly
perfused sites. This has been demonstrated in ani-
mals to lead to development of foreign body type
sarcomas at the site of injection but with no meta-
stases.
Mutagenicity studies
Several investigations of the mutagenic potential of
Povidone have been carried out, all of which indicate
that Povidone is without mutagenic activity. In the
Ames test, Povidone K30 has given negative results
with and without activation. Povidone K30 was also
found to be non-mutagenic in the mouse lymphoma
assay with and without metabolic activation. In vivo,
the dominant lethal test and a cytogenetic in the bone
page 15 No. 2, July 1999 BASF ExAct

Product Launch
KollicoatY MAE 100 P A new redispersable powder for enteric coating.

Since more than a year Kollicoat MAE 30 DP is
marketed for enteric film-coating of pharmaceu-
tical dosage forms. Kollicoat MAE 30 DP is an
aqueous dispersion of a copolymer derived from
methacrylic acid/ethyl acetate (1:1). Kollicoat MAE
30 DP complies with the requirements of the Euro-
pean Pharmacopoeia monograph Polyacrylate
dispersion 30 %, the USP-NF monograph Metha-
crylic Acid Copolymer Dispersion and the JPE
monograph Methacrylic Acid Copolymer LD.
Transporting and storing aqueous dispersions, e. g.
Kollicoat MAE 30 DP, involve certain risks. Exposure to
heat 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 do
not involve these risks and hence are particularly
suitable to be used in countries with hot and cold
climates.
Kollicoat MAE 100 P is a new redispersable powder
for aqueous enteric coating and available since May
1999.
Kollicoat MAE 100 P is prepared from the aqueous
dispersion Kollicoat MAE 30 DP using an FSD-
spraying technology. Kollicoat MAE 100 P can be
easily redispersed without further auxiliaries by
pouring it into water while stirring.
Redispersion of the powder into the aqueous dis-
persion can be performed just before the spraying
process. The physical stability of the redispersion is,
however, excellent, so that the latex can also be stored
for some days. The technical relevant properties of the
redispersion, e. g. particle size, compatibility with
additives, processibility and film formation, are very
similar to those of the original latex. Processing occurs
in the usual manner with plasticizer, pigments and
other excipients.
Films of Kollicoat MAE 30 DP and Kollicoat MAE 100
P are equal with regard to their gastric resistance and
dissolution behaviour above pH 5.5.

Regulatory Affairs
Kollidon VA 64 approved for the US market.

During the last 12 month the FDA approved 3
different formulations containing Kollidon VA 64.
This includes the oral application of Kollidon VA 64
and the functionality as an effective dry binder.
A monograph of Copovidone was prepared and
published in the US Pharmacopeial Forum Vol. 24,
No. 4, July/August 98, pp 6456-6459.
The monograph will be included in the USP as official
monograph soon.

New production plant for PVP-Iodine.

The production of PVP-Iodine will be transferred

from the Ludwigshafen production site to our new
and modern production plant in Geismar, US in
1999.
The production plant in Geismar was designed for
Pharma production and is manufacturing PVP-Iodine
since 1996.
Information material and PVP-Iodine samples for
reapproval studies are available.

For more information please contact Dr. Folker

Ruchatz, MEM/FP, Fax No. +621 60 94-616 or
via e-mail folker.ruchatz@basf-ag.de.
page 16 No. 2, July 1999 BASF ExAct

Preview
Sustained release products are gaining more and
more interest due to a long lasting drug action
with low side effects and a better compliance
related to immediate release dosage forms.
contact
etc. Some of the commercially available products Please contact your local BASF company
are marketed at a very high price. In view of these or one of the following regional centres:
facts a strong demand for a new polymer becomes
obvious. Asia

However, for the manufacturing of coated sustained
release dosage forms only few polymers are
applicable.
Each of these polymers has certain disadvantages,
e. g. curing effects, necessity of high amounts of
plasticizer, pH-dependent release characteristics,
interaction with the active ingredient, high tackiness,
Kollicoat SR 30 D, a recently developed product for BASF East Asia Regional
sustained release coating, represents a break-through
in this application field. Besides other topics, ExAct Headquarters Ltd.
No. 3 will deal with this innovative coating excipient. Dr. Lutz End, Dr. Danilo Mercado
Tower 1,4th Floor, South Seas Centre
Should you require information in advance, please
contact your local BASF company or one of our Tsim Sha Tsui
regional centres. P.O. Box 98427
Kowloon, Hong-Kong
Fax: **852/2312 22 61

BASF Fine Chemicals for the pharmaceutical industry. Europe

Direct Compression Agents Solubilizers/Emulsifiers BASF Health & Nutrition A/S

LudipressY, LudipressY LCE CremophorY RH 40, CremophorY EL, Mr. Clemens Karg
CremophorY ELP, CremophorY A 6/A 25,
Binders, Solubilizers CremophorY S 9, SolutolY HS 15 Malmparken 5
KollidonY 12 PF/17 PF, KollidonY 25/30/90 F DK-2750 Ballerup
Colorants Denmark
Disintegrants, Suspension Stabilizers SicovitY, soluble dyes, SicovitY,
KollidonY CL, KollidonY CL-M lakes and pigments Fax: **45/44 73 01 02

(Dry) Binders, Film Formers PEGs, Poloxamers NAFTA

KollidonY VA 64 LutrolY E grades, LutrolY F grades
BASF Corporation
Disinfectants Solvents
PVP-lodine 30/06, PVP-lodine 30/06 M10 Propylene Glycol, SoluphorY P Pharma Specialties, Mr. Richard Becker
3000 Continental Drive-North
Enteric Film Coatings Active Ingredients Mount Olive, NJ 07828-1234
KollicoatY MAE 30 DP, KollicoatY MAE 30 D, Crospovidone M, Tretinoin, Isotretinoin,
KollicoatY MAE 100 P Retinol 50P, Carotenoids, USA
Active ingredients from Knoll Fax: **1/97 34 26 53 69
Sustained Release Film Coatings
KollicoatY EMM 30 D, KollicoatY SR 30 D Fat-soluble Vitamins
Vitamin A, Vitamin D2, D3, South America
Vitamin E, Vitamin K
BASF S.A.
Water-soluble Vitamins Fine Chemicals, Mr. Torsten Meid
Vitamin C, Vitamin B1 (Thiamin), Caixa Postal 136
Vitamin B2 (Riboflavin), Vitamin B3 (Nicotinamid),
Vitamin B5 (Calpan), Vitamin B6, 09701-970 So Bernardo do Campo
Vitamin B12, Vitamin H (Biotin) Brazil
Fax: **55/117 5121 99

Or visit our website:

MER 9918

http://www.basf.de/pharma