Pharmaceutical Development and Technology, 7(1), 79–87 (2002)

RESEARCH ARTICLE
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

Comparative Evaluation of Co-processed

Lactose and Microcrystalline Cellulose
with Their Physical Mixtures in the
Formulation of Folic Acid Tablets
Armand Michoel,* Patrick Rombaut, and Ann Verhoye

Laboratory of Pharmacotechnology and Biopharmacy, Catholic University of

For personal use only.

Leuven, O&N Gasthuisberg, B-3000 Leuven, Belgium

ABSTRACT

In this study, a new co-processed filler –binder ingredient for direct compression,
MicroceLac 100, was compared with three different lactoses mixed with
microcrystalline cellulose. The aim was to improve a folic acid tablet
formulation. Therefore, the influence of drug addition to these mixtures was
studied with regard to flow and binding properties. Another part of the study was
focused on the interaction and segregation behavior of the drug.
MicroceLac 100 showed superior flow and binding properties. Good adhesion of
folic acid to the MicroceLac 100 particles could decrease demixing and segregation.
The improved characteristics of co-processed material are attributed to spray
drying. Sodium stearyl fumarate was chosen as a lubricant, based on ejection force
measurements. The content uniformity of the newly formulated direct compression
tablets met the official requirements.

Key Words: Co-processing; Direct compression; Lactose; MicroceLac; Segre-

gation; Spray-drying

INTRODUCTION tabletting process. Ready-to-use mixtures were supplied

with improved functionality, compared to physical
In recent years, a new generation of filler – binder mixtures (1). Utilizing particle engineering in the
excipients was introduced in the direct compression development of combined ingredients resulted in further

*Corresponding author. Fax: 32 16 345996; E-mail: armand.michoel@farm.kuleuven.ac.be

79
Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com
 ORDER
80
improvement of these co-processed excipients. The
advantages lie in optimized flow and binding properties,
which are important when using high-speed rotary
presses.
One of the newer co-processed filler –binders is
MicroceLac 100. It consists of 75% lactose and 25%
microcrystalline cellulose (MCC), which are spray-dried
together. The purpose of this study was to evaluate this
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13
excipient in comparison with physical mixtures of MCC
and different lactoses. Not only were the flow and
binding properties compared, but also the interaction and
segregation behavior when mixed with folic acid. Added
drug substances can bring about significant changes in
some properties, like flow behavior, of lactose qualities,
especially those with a more open exposure of the drug
particles (2). The aim of this study was, therefore, to
study possibly similar effects of folic acid and improve
existing folic acid tablet formulations. In addition, a
number of lubricants were compared regarding their
influence on flow properties of the mixtures and on the
ejection behavior of the tablets.
For personal use only.
MATERIALS AND METHODS
Materials
Folic acid, Ph. Eur. grade, was obtained from Federa,
Brussels, Belgium. The filler – binder compounds used
were: MicroceLac 100 (Meggle, Wasserburg, Germany);
MCC (Avicel PH 102; FMC, Brussels, Belgium); a-
lactose monohydrate (lactose 100 M ); anhydric b-lactose
(Pharmatose DCL21); spray-dried lactose (Pharmatose
DCL11). All lactose types were obtained from DMV,
Veghel, The Netherlands.
The lubricants used were: magnesium stearate
(Ludeco, Brussels, Belgium), glyceryl behenate (Com-
pritol 888 ATO; Gattefossé, Saint-Priest, France);
hydrogenated vegetable oil (Lubritab; Mendell, Patter-
son, NY); sodium stearyl fumarate (Pruv; Mendell,
Patterson, NY). Other materials used in the formulations
were: talc (Federa, Brussels, Belgium); polyvinylpyrro-
lidone (Povidone K30; Federa, Brussels, Belgium); starch
(Federa, Brussels, Belgium) and croscarmellose sodium
(Ac-Di-Sol; Metsä-Serla, Nijmegen, The Netherlands).
METHODS
Particle Size Determination
The size of the folic acid particles was measured by
the electrical sensing zone method with a Coulter
REPRINTS
Michoel, Rombaut, and Verhoye
Multisizer (Model II; Coulter Corp., Hialeah, FL). A
saturated suspension of folic acid was prepared with
Tween 80 and 0.9% sodium chloride. From the size
distribution, a median diameter was calculated.
Sampling
The powder blends were sampled using a spinning
riffler (type PT; Retsch, Haan, Germany). These samples
were used for determining flow characteristics, demixing
potential (DP), and adhesion tendency.
Storage
All powders, powder mixtures, and tablets were stored
at room temperature and 38% relative humidity for at
least 24 hr before any measurement, using a saturated
sodium iodide suspension (3).
Powder Blends
Physical mixtures [M] of 25% MCC with 75% lactose
(Pharmatose 100 M, DCL11, DCL21) were mixed in a
small laboratory mixer (Type M9; Paul KG, Esslingen-
Zell, Germany) for 15 min. The batch size was always
400 g. The composition of these powder blends is given
in Table 1.
Folic acid (11.4 g) was mixed with MicroceLac 100
and with the physical mixtures (batch size of 400 g) for
15 min [MF].
In a third series of mixtures, 11.4 g folic acid and 2.1 g
magnesium stearate were mixed with MicroceLac 100
and with the physical mixtures (batch size of 400 g) for
15 min and 90 sec, respectively [MFL].
Flow Characteristics
A sample of 100 g was introduced in a dry funnel
without compacting. The dimensions of the funnel were
given by Delacourte-Thibaut et al. (4). After unblocking
the bottom opening of the funnel, the time needed for the
entire sample to flow out of the funnel was measured in
seconds and tenths of seconds, related to 100 g of sample.
The experiment was done in triplicate, and a mean value
was calculated.
Demixing Potential
A 50 g sample was split into different sieve fractions
using a vibrating sieve apparatus (Type EML; Haver and
Boecker, Oelde, Germany). To avoid segregation during
 ORDER REPRINTS

Use of MicroceLac 100 in Folic Acid Tablets 81

Table 1
Composition of Powder Blends

Code Composition Lactose-Type Process

M0 MicroceLac 100 Spray-dried and co-processed

M1 75% Lactose DCL21 and 25% Avicel PH 102 Anhydric b-lactose Granulated
M2 75% Lactose DCL11 and 25% Avicel PH 102 Spray-dried lactose Spray-dried
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

M3 75% Lactose 100 M and 25% Avicel PH 102 a-Lactose monohydrate Crystallized

sieving, only a short period of 2 min and a low- acetone. Force and displacement data were used to
vibrational energy input were used. Each sieve fraction calculate the lower punch work (LPW), used in the
was analyzed in terms of drug content, allowing the compression. The porosity of the tablets under maximum
calculation of DP according to Thiel et al. (5), by the pressure (“in-die” porosity) was also calculated from
following equation: these displacement data. Displacement data were
hX i1=2 corrected to account for deformation of the punches.
DP% ¼ ð100=BÞ f ðx 2 bÞ2 ð1Þ The crushing strength of the tablets obtained was
P P measured using a motorized tablet hardness tester
where b ¼ fx= f ; x is the drug concentration in each (Model 2E/205; Schleuniger, Zurich, Switzerland). The
sieve fraction (mg/g), f the sieve fraction (weight%/100), experiment was done in triplicate, and a mean value was
and B the theoretical drug content in the total powder calculated.
For personal use only.

mixture (mg/g). The tensile strength was calculated according to Fell

et al. (7):
Adhesion Tendency
s ¼ ð2P9:81Þ=ðpDtÞ ð2Þ
To determine the adhesion tendency of the folic acid 2
where s is the tensile strength (N/cm ), P the crushing
mixtures, a 5.0 g sample was sieved for 10 min on a strength (kp), D the diameter (cm), and t the thickness (cm).
50 mm test sieve in an air-jet sieve (Model A-200; Compression behavior was studied by comparing
Alpine, Augsburg, Germany). To promote the separation tensile strength against LPW curves.
of drug particles from their carrier excipient particles,
different negative pressures were used during sieving.
Lubrication Effects
The oversize fraction was analyzed, and the amount of
drug adhering to this oversize fraction was calculated as a
To study lubrication effects, different lubricants were
percent of the initial concentration and expressed as %
mixed with MicroceLac 100 and folic acid. The
adhesion. The experiment was done in triplicate, and a
lubricants were used at their minimal advised concen-
mean value was calculated.
tration (8). So, 0.375 g magnesium stearate (0.25%),
0.75 g sodium stearyl fumarate (0.5%), 0.75 g glyceryl
Compression Characteristics
behenate (0.5%), or 1.5 g hydrogenated vegetable oil
(1.0%), respectively, were mixed with 4.275 g folic acid
Compressions were carried out using an eccentric
and enough MicroceLac 100 to obtain a total amount of
tabletting machine (Type EK-O; Korsch, Berlin,
mixture of 150 g. Mixing was performed in a Turbula
Germany), instrumented as described earlier (6).
mixer (model T2A; WA Bachofen, Basel, Switzerland)
Sufficient material to produce a compact of 1.5 mm
for 5 min. For lubricant evaluation, the ejection force was
thickness at zero theoretical porosity was poured into a
measured.
11.0 mm diameter die and compressed between flat-faced
punches at a constant rate of 6 cycles/min. Tablet mass
was calculated from true density values, as determined Tablet Manufacture
by an air comparison pycnometer (Model 930; Beckman
Instruments, Fullerton, CA). The die was prelubricated A batch of 6000 tablets of 5 mg folic acid was
using a 0.5% (w/v) magnesium stearate suspension in produced using an eccenter tabletting machine (Type 27;
 ORDER
82
Courtoy, Halle, Belgium). A premix, consisting of 30.0 g
of folic acid and 60.0 g of Ac-di-Sol was mixed with
954.6 g MicroceLac 100 for 5 min in a high-shear mixer
(Gral 10; Machines Collette, Wommelgem, Belgium).
Thereafter 5.4 g sodium stearyl fumarate, premixed with
20.0 g of the previous mixture in order to improve color
uniformity, was added and further mixed for 30 sec. The
target tablet weight was 175.0 mg.
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13
Analysis of Folic Acid Tablets
Folic acid tablets were analyzed individually using a
high-performance liquid chromatography (HPLC) sys-
tem equipped with a 515 HPLC pump Model 6000A
solvent delivery system, a Model 440 ultraviolet (UV)
detector set at 254 nm, and a Model UK6 universal
chromatograph injector (all from Waters Associates,
Milford, MA). Ultra violet signals were integrated using
a Model D-2500 Chromato-integrator (Merck Hitachi,
Ltd., Tokyo, Japan). The column used was a LiChro-
spher 60 RP Select B (5 mm) (Merck, Darmstadt,
For personal use only.
Germany). The flow rate was 1 mL/min and the volume
injected was 20 m L. The tablet was dissolved in 1 L
water (pH 9.3). The mobile phase consisted of 2%
acetonitrile and 98% phosphate buffer (pH 7.2;
0.05 M ).
The absorbance was linear in a concentration
range 1– 10 mg/mL ðR 2 . 0:999Þ: The detection limit
was 0.25 mg/mL. The relative standard deviation
(RSD) for replicate injections was 1.6%. The limit
of quantification was 0.5 mg/mL ðn ¼ 6; RSD ¼
9:6%Þ:
Ten tablets were weighed and finely powdered. A
measured amount of 175 mg of the powder was analyzed
using the HPLC system described above. This assay was
repeated three times.
Table 2
Time (sec) for Mass-Flow of 100 g
Code Mixture Mixture + Folic Acid
(M) (MF)
M0 6.3 ^ 0.1 8.6 ^ 0.3
M1 8.6 ^ 0.2 14.9 ^ 1.2a
M2 7.0 ^ 0.2 9.4 ^ 0.1a
M3 7.3 ^ 0.3 12.2 ^ 0.6a
The data are expressed as mean ^ SD of three experiments.
a
Hindered flow.
REPRINTS
Michoel, Rombaut, and Verhoye
RESULTS AND DISCUSSION
Flow Behavior
Due to the high speed of present-day rotary machines,
the flow characteristics of modern filler –binders become
more important in the direct compression process. Even
small amounts of drugs can impede flow (2). Also the
addition of lubricants to the mixtures must be monitored
carefully, because they can have a detrimental influence
not only on flow but also on dissolution and binding
properties. Therefore the drug and lubricant effects on
the flow properties of the filler – binders are studied
separately.
From Table 2 and Fig. 1, it can be observed that a
spray-drying process, which results in spherical particles,
decreases the time necessary for the mass-flow of a given
sample mass, thereby increasing the flow rate. The spray
drying of two components together further improves the
flow rate, as shown by the co-processed MicroceLac 100
data. The sieved crystalline lactose 100 M also shows
free flowing behavior due to its regular shape and its
appropriate size distribution (9). The irregular shape and
broad size distribution are responsible for the slower flow
rate of the granular lactose DCL21 mixtures (1).
The addition of folic acid, even in a small amount
ð, 3%Þ; has a moderate effect on the spray-dried
products. On the other hand, the flow of the other two
mixtures becomes unacceptable ð. 10 secÞ: Due to the
high porosity of the individual spray-dried particles, they
can hold the small folic acid particles (median diameter =
4.6 mm) in their pores, decreasing the amount of free
drug particles.
The further addition of magnesium stearate restores
the small negative influence of folic acid in the case of
spray-dried products. Being primarily a lubricant,
magnesium stearate nevertheless also has some glidant
Mixture + Folic Acid + MgSt
(MFL)
6.5 ^ 0.4
15.0 ^ 0.1a
7.2 ^ 0.3
12.4 ^ 1.2a
 ORDER
Use of MicroceLac 100 in Folic Acid Tablets
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13
Figure 1. Influence of folic acid (MF) and magnesium stearate [MgSt] (MFL) on the flow behavior of direct compression mixtures
(M). Each point represents the mean value of three samples and error bars show standard deviation.
For personal use only.
effects, when mixed under the right conditions. A short
mixing time under low energy conditions avoids the
coating of the excipient particles by the small particles of
the hydrophobic lubricant material. No improvement by
magnesium stearate, however, is observed with the
crystalline and granular lactose mixtures. For any
particular system, there is usually an optimal concen-
tration of glidant. If that level is exceeded, the glidant
may start to have antiglidant effects (10). Therefore it is
not unexpected to see opposite effects of magnesium
stearate on the flow properties of the mixtures, which
consist of different size, shape, and surface roughness.
The surface coverage by the lubricant will indeed
depend on these parameters.
SEGREGATION
One of the main disadvantages of the direct
compression method in producing tablets is the increased
occurrence of segregation, especially in formulations
with a small amount of fine drug particles. Electrical
sensing zone results indeed indicated that folic acid has
fine particles, 90% of the total volume being occupied by
particles , 10 mm with a median diameter of 4.6 mm.
Good mixing quality then depends on some drug
adhesion to occur onto the surface of the larger excipient
carrier particles. Only weak physical forces are
responsible for such surface-dependent adhesion. There-
REPRINTS
83
fore, such interactive mixtures can segregate by two
mechanisms.
On the one hand, adhesion-unit segregation can occur
due to the different concentrations of drug in the different
size fractions of the filler – binder. The larger these
differences in drug concentration, the more chances of
such segregation behavior, which is expressed by DP.
This is the coefficient of variation of the minor
component (drug) in the different sieve fractions of the
carrier material (filler –binder).
On the other hand, constituent segregation occurs
when the weak adhering bonds are broken and the fine
drug particles become dislodged from their carrier and
percolate through the powder bed. Some experiments,
which simulate this behavior, allow comparison of the
adhesion tendency of the different mixtures.
Demixing Potential
In Table 3, the drug concentrations in the different sieve
fractions are given. The examples, given in Fig. 2, clearly
show that the smaller carrier sieve fractions contain a
higher drug amount, because they have a larger surface
area per unit weight. The larger this difference, the greater
the chance that segregation problems can occur if the
carrier particles become segregated themselves according
to their size. The calculated DPs are summarized in
Table 3, together with the mean drug concentration in the
powder mixtures. The granulated lactose-type (DCL21)
 ORDER REPRINTS

84 Michoel, Rombaut, and Verhoye

Table 3 The results shown in Table 4 and Fig. 3 indicate that

the spray-dried products have stronger bonds with the
Demixing Potential, Calculated from Different Sieve Drug
drug particles. The porous surface structure seems to be
Contents (mg/g)
advantageous due to multiple interparticle contacts.
M0 F M1F M2 F M3F These pores also protect adhered particles from
becoming detached by abrasion (11). The particles,
Sieve-size (mm) adhered to the surface of the two other excipients, are
63 – 90 — — 34.0 34.1 more exposed and will roll off from such a surface. The
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

90 – 125 37.3 37.6 27.5 29.9 demixing and adhesion experiments show that segre-
125– 180 34.4 31.6 27.4 28.6 gation problems can be minimized by using the spray-
180– 250 26.0 27.0 22.3 13.4 dried excipients.
250– 355 20.9 9.8 — —

Mean drug content (mg/g) 28.1 27.1 27.8 27.6

Demixing potential (%) 16.9 34.4 11.7 19.3 COMPRESSION

By using tablet masses, calculated from true density

mixture with MCC shows the largest DP. Its largest sieve
fraction (250 –355) contains only a small amount of folic
acid ð, 1%Þ; probably due to lower binding forces, which
will be confirmed in the following adhesion experiments.
This mixture has the lowest mean drug content, which also
For personal use only.
values, constant true volume of material was compared in
our compaction study. Using a constant punch displace-
ment profile, tablets were therefore compressed to a
constant “in-die” porosity. Table 5 shows the tensile
strengths of tablets with a relatively high “in-die”
porosity of 24%.

indicates a higher loss of folic acid during the sieving
operation to obtain the different fractions.
Adhesion
Three rather small negative pressures were used to
simulate possible breaking of the adhesion bond between
drug and excipient carrier.
There is only a slight decrease in tensile strength
by the further addition of folic acid and magnesium
stearate to the mixtures, without any change in the
sequence of the different excipient types. MicroceLac
100 tablets have much greater strength than the other
products. Spray-dried products are well known for their
good deformation properties. Compared to the spray-
dried-MCC mixture (M2), there seems to be an

Figure 2. Folic acid content in different sieve fractions.

 ORDER REPRINTS

Use of MicroceLac 100 in Folic Acid Tablets 85

Table 4
% Adhesion

Pressure (kPa) M0F M1 F M2 F M3 F

2 1.96 46.9 ^ 0.2 24.4 ^ 0.1 46.5 ^ 0.3 33.1 ^ 1.0

2 2.94 43.0 ^ 0.2 22.6 ^ 0.5 41.4 ^ 0.4 24.5 ^ 0.6
2 3.92 40.6 ^ 0.1 20.4 ^ 0.1 40.2 ^ 0.1 22.2 ^ 0.1
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

The data are expressed as mean ^ SD of three experiments.

additional advantage by co-processing lactose and MCC
(M0). The crystalline lactose mixture (M3) was not able
to produce some compacts at this porosity. It shows
little plastic deformation and their crystals do not
deform easily.
In order to evaluate energy utilization in the
production of tablets, the tensile strength of the tablets
was plotted vs. the LPW, as shown in Fig. 4.
For a given LPW, MicroceLac 100 tablets have the
highest tensile strength, showing the efficient use of the
energy, resulting in strong bonds. The sequence
For personal use only.
lactose products was related to the powder surface area
directly (12).
LUBRICATION
The lubrication effect was studied by measuring the
ejection force of the tablets. The sodium stearyl fumarate
mixture showed the lowest ejection force, which is
indicative of efficient lubrication. Lubrication can have a
negative effect on flow and binding properties (13).

between the products remains the same over the
whole LPW-range: higher strength for the mixtures of
MCC with lactose DC21 than for those with lactose
DC11 or 100 M. The high binding strength of the
lactose DCL 21 is probably a result of the presence of
b-lactose and the special texture of the particles. This
roller-dried product has a rather high specific surface
area. It appeared that the binding capacity of crystalline
Table 6 shows however that no such effect is observed,
probably because a small amount of lubricant is used and
also because mixing was performed with a low energy
input. The sodium stearyl fumarate mixture showed the
largest flow rate. Sodium stearyl fumarate was chosen as
a lubricant for the final formulation because of its
performance regarding both flow rate and ejection force
experiments.

Figure 3. Adhesion tendency of folic acid in different direct compression mixtures. Each point represents the mean value of three
samples. Error bars, representing ^standard deviation, are shown if larger than symbol.
 ORDER REPRINTS

86 Michoel, Rombaut, and Verhoye

Table 5 MicroceLac 100 is chosen as the only filler – binder

excipient, together with sodium stearyl fumarate as a
Tablet Strength
lubricant. Ac-di-Sol, already present in our former tablet
Crushing Strength (kp) Tensile Strength (N/cm2) formulation, was maintained as a disintegrant. In order to
improve the color uniformity of the final mix, the
M0 6.7 ^ 0.2 203 ^ 6 lubricant was premixed with a small amount of the drug –
M0FL 5.9 ^ 0.1 182 ^ 4 excipient mixture. This lubricant premix was then mixed
at the end of the process with the other components.
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

M1 4.1 ^ 0.3 126 ^ 9 The assay of tablets resulted in a mean content of

M1FL 3.6 ^ 0.1 112 ^ 3 96.8%. The content uniformity test showed acceptable
results: the content of 10 individual tablets lies between
M2 2.9 ^ 0.1 89 ^ 4
91.1 – 98.7% of the label claim, with an RSD of 2.1%.
M2FL 2.2 ^ 0.2 64 ^ 8

M3 0 0
M3FL 0 0 CONCLUSION
The data are expressed as mean ^ SD of three tablets.
Tablet porosity (in-die) = 24%.
In conclusion, the results of the present study indicate
that co-processing can enhance the functionality of
excipients. The co-processed MicroceLac 100 shows
FINAL FORMULATION excellent flowability. Furthermore, folic acid shows
stronger adherence to the porous surface of this spray-
Based on the results of this study, a final formulation dried excipient than to some other physical mixtures of
For personal use only.

for direct compression of 5 mg folic acid tablets is direct compression excipients, decreasing the possibility
proposed in Table 7. of segregation. In addition, MicroceLac 100 tablets also

Figure 4. Energy utilization plot of tensile strength against LPW. Each point represents the mean value of three samples and error
bars show standard deviation.
 ORDER REPRINTS

Use of MicroceLac 100 in Folic Acid Tablets 87

Table 6
Influence of Lubricant Type on Flow and Binding Characteristics of Mixtures of MicroceLac 100 with Folic Acid

Lubricant Type Lubricant Concentration Ejection Force Time (sec) for Tensile Strength
(%) (N) Mass Flow of 100 g (N/cm2)

Magnesium stearate 0.25 285 ^ 1 6.2 ^ 0.1 417 ^ 3

Sodium stearyl fumarate 0.5 204 ^ 1 5.9 ^ 0.2 420 ^ 2
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

Glyceryl behenate 0.5 303 ^ 1 7.2 ^ 0.1 416 ^ 2

Hydrogenated vegetable oil 1.0 268 ^ 1 7.4 ^ 0.1 425 ^ 4
a
The data are expressed as mean ^ SD of three experiments.

Table 7 3. Nyqvist, H. Saturated Salt Solutions for Maintaining

Specified Relative Humidities. Int. J. Pharm. Technol.
Formulation of Folic Acid Tablets (5 mg) Prod. Manuf. 1983, 4 (2), 47– 78.
4. Delacourte-Thibaut, A.; Denise, B.; Guyot, J.C.; Traisnel,
Ingredient Quantity/Tablet (mg) M. Formulation of Tablets with the Aid of Chain
Extensiometry. II. Methodology of Formulation. J. Pharm.
Folic acid 5.0 Belg. 1974, 29, 489– 522.
MicroceLac 100 159.1 5. Thiel, W.J.; Nguyen, L.T. Fluidized Bed Granulation of
Ac-di-Sol 10.0 an Ordered Powder Mixture. J. Pharm. Pharmacol. 1982,
Sodium stearyl fumarate 0.9
For personal use only.

34, 692– 699.

have the highest tensile strength for a given energy input,
showing its efficient use of energy, resulting in strong
particle bonds. Low dosage folic acid tablets formulated
with MicroceLac 100 further showed acceptable results
in the content uniformity test.
ACKNOWLEDGMENT
The authors are grateful to N. V. Boucquillon, Belgium,
for providing MicroceLac 100 from Meggle, Germany.
REFERENCES
1. Bolhuis, G.; Chowhan, Z. Materials for Direct Com-
pression. In Pharmaceutical Powder Compaction Tech-
nology; Alderborn, G., Nystrom, C., Eds.; Marcel Dekker,
Inc.: New York, 1996; 419– 500.
2. Nyqvist, H.; Nicklasson, M. Flow Properties of
Compressible Lactose Containing Small Quantities of
Drug Substances. Drug Dev. Ind. Pharm. 1985, 11,
745– 759.
6. Michoel, A.; Verlinden, W.; Rombaut, P.; De Smet, P.
Carrier Granulation: A New Procedure for the Production
of Low-Dosage Forms. Pharm. Technol. 1988, 12 (6),
66 –84.
7. Fell, J.T.; Newton, J.M. Determination of Tablet Strength
by the Diametral Compression Test. J. Pharm. Sci. 1970,
59, 688– 691.
8. Kibbe, A.H. Handbook of Pharmaceutical Excipients; 3rd
Ed.; American Pharmaceutical Association and Pharma-
ceutical Press: London, 2000; 229, 305, 505, 578.
9. Bolhuis, G.K.; Lerk, C.F. Comparative Evaluation of
Excipients for Direct Compression. Pharm. Weekbl.
1973, 108, 469– 481.
10. Sadek, H.M.; Olsen, J.L.; Smith, H.L.; Onay, S. A
Systematic Approach to Glidant Selection. Pharm.
Technol. 1982, 6 (2), 42 – 62.
11. Staniforth, J.N. Order Out of Chaos. J. Pharm. Pharmacol.
1987, 39, 329– 334.
12. Vromans, H.; Bolhuis, G.K.; Lerk, C.F.; Kussendrager,
K.D. Studies of Tableting Properties of Lactose. IX. The
Relationship Between Particle Structure and Compact-
ibility of Crystalline Lactose. Int. J. Pharm. 1987, 39,
207–212.
13. Lerk, P.C.; Sucker, H. Interaction of Magnesium Stearate
and Talc upon Tabletting Mixtures, I: Effect on Ejection
Force After Compaction. Acta Pharm. Technol. 1988, 34,
68 –71.

Received November 10, 2000

Accepted June 19, 2001
 Request Permission or Order Reprints Instantly!

Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.

All information and materials found in this article, including but not limited
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Purdue University on 03/26/13

to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.

Get permission to lawfully reproduce and distribute the Materials or order

reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
For personal use only.

(AAP) website for guidelines on Fair Use in the Classroom.

The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.

Order now!

Reprints of this article can also be ordered at

http://www.dekker.com/servlet/product/DOI/101081PDT120002233