Powder Technology 130 (2003) 283 289

www.elsevier.com/locate/powtec

Improved flowability and compactibility of spherically agglomerated

crystals of ascorbic acid for direct tableting designed by spherical
crystallization process
Y. Kawashima *, M. Imai, H. Takeuchi, H. Yamamoto, K. Kamiya, T. Hino
Department of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan

Abstract
Spherically agglomerated crystals of ascorbic acid with improved compactibility for direct tableting were successfully engineered by the
spherical crystallization technique. In this process, ascorbic acid crystals were precipitated by a solvent change method, followed by their
agglomerations with the emulsion solvent diffusion (ESD) or spherical agglomeration (SA) mechanism. The micromeritic properties, such as
flowability and packability of the spherically agglomerated crystals were preferably improved for direct tableting. Under static compression,
the acceptable compact (tablet) with a sufficient strength was produced successfully without capping, although the capping occurred with the
original unagglomerated crystals. The improved compaction properties of the agglomerated crystals were due to their fragmentation and
plastic deformation occurred significantly during compression. This mechanism was supported by higher stress relaxation and less elastic
recovery of the compact of agglomerated crystals. It was also found that the spherically agglomerated crystals were tableted directly without
capping using a single punch machine under dynamic compression, although the tensile strength of resultant tablet decreased in tolerable
degree with increasing punch velocity.
D 2002 Elsevier Science B.V. All rights reserved.
Resume
Des agglomerats spheriques de cristaux dacide ascorbique presentant une aptitude a` la compaction accrue en vue de compression
directe ont ete prepares par procede de cristallisation spherique. Au cours du procede, les cristaux dacide ascorbique sont tout dabord
precipites par changement de solvant, puis agglomeres par mecanisme de diffusion de solvant a` partir dune quasi-emulsion ou
dagglomeration spherique. Nous avons cherche a` ameliorer les proprietes micromeritiques comme la coulabilite ou laptitude a`
lempilement des agglomerats spheriques de cristaux, en vue de compression directe. Sous compression statique, un compact (comprime)
acceptable presentant une resistance suffisante a` la rupture a ete obtenu sans decalottage, alors que les cristaux non traites donnaient
naissance a` ce phenome`ne. Lamelioration des proprietes de compaction des cristaux agglomeres est due a` leur fragmentation et une
deformation plastique se produit de manie`re significative pendant la compression. Ce mecanisme est renforce par une relaxation des
contraintes plus importante et un moindre comportement elastique du compact forme a` partir des agglomerats. Il a ete egalement montre
que les cristaux agglomeres etaient compactes directement sans phenome`ne de decalottage en utilisant une machine monopoinc on en
compression mdynaique, alors que la limite delasticite des comprimes obtenus diminuait de manie`re acceptable lorsquon augmentait la
vitesse du poincon.
D 2002 Elsevier Science B.V. All rights reserved.
Keywords: Spherical crystallization; Direct tableting; Ascorbic acid; Plastic deformation; Stress relaxation; Fragmentation

1. Introduction

Corresponding author. Tel.: +81-58-237-8574; fax: +81-58-237-6524.

E-mail address: yoshiaki@gifu-pu.ac.jp (Y. Kawashima).

Direct tableting has been renewed as a preferable process

by simply mixing and compressing powder to save time and
cost in comparison with granule tableting. Further, this
process is more easily process-validated and automated

0032-5910/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 3 2 - 5 9 1 0 ( 0 2 ) 0 0 2 0 6 - 1

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Y. Kawashima et al. / Powder Technology 130 (2003) 283289

toward unmanned operation overnight. To do this, highly

compactible properties of drug particles are required, otherwise a lot of powder binder such as microcrystalline
cellulose, dicalcium phosphate dihydrate and others are
necessary to be mixed in the formulation, resulting in bigger
sized tablets.
Ascorbic acid crystals are unsuitable for direct tableting
due to their poorly compactible properties, although
strongly demanded in commercial production by direct
tableting. To accomplish this, agglomerated crystals with
a small amount of binder such as less than 3% have been
developed in commercial scale, e.g. C97 granulesR for
direct tableting. In this paper, directly compactible ascorbic
acid crystals were designed by using the spherical crystallization process [1] newly developed by us without using
any binder. In this process, the precipitated crystals were
agglomerated simultaneously with a suitable amount of
second solvent, termed bridging liquid, introduced to the
crystallization system under stirring. The bridging liquid
was immiscible with the crystallization medium and preferentially wetted the suspended crystals to form spherical
agglomerates. It was found that the micromeritic properties
of spherically agglomerated crystals such as flowability,
packability and compactibility required for direct tableting
were greatly improved. The mechanism of improved compactibility was explained by analysing the static compaction
process. The effect of compression speed on the compactibility of agglomerates was evaluated for dynamic compression in assuming an industrial trial.

flowability and compactibility, respectively. The C97 granulesR for direct tableting were used as reference powder for
both tests. Potassium chloride crystals were used as reference of plastically deformable powder.
2.2. Preparation of spherically agglomerated crystals of
ascorbic acid for direct tableting
Ascorbic acid was dissolved in purified water (good
solvent) at 50 jC to make saturated solution (0.4 g/ml). A
required amount of the resultant solution was poured into
300-ml ethyl acetate (poor solvent), thermally controlled at
5 jC under agitation with a propeller type agitator with four
blades rotated at 300 or 800 rpm for 20 min. The apparatus
for spherical crystallization system is shown in Fig. 1.
Depending on the volume ratio of aqueous drug solution
to ethyl acetate being 1:100 or 4:150, the spherically
agglomerated crystals were produced in different processes.
At volume ratio = 1:100, the agglomeration and crystallization of drug occurred in the quasi-emulsion (without)
droplets formed even in the miscible solvent system. At
volume ratio = 4:150, both solvents were immiscible and
formed the emulsion droplets after mixing, in which crystallization occurred, followed by further agglomeration of
the precipitated crystals with liberated water phase. The
agglomerated crystals were filtrated, washed with a small
amount of methanol and dried in vacuum. The dried
agglomerated crystals were fractionated into 125 500-Am
range consisting of C97 granulesR.
2.3. Preparation of tablets with ascorbic acid crystals

2. Experimental
2.1. Materials
Raw ascorbic acid crystals sieved at 100 mesh (average
diameter, 18.8 Am) and granular crystals (average diameter,
425 Am) were used as referred crystals for evaluating

The agglomerated and unagglomerated crystals (150

mg) were compressed in an 8-mm die with an Instron
type press (Autograph AG5000D, Shimadzu) at the compression speed of 10 mm/min and the compression pressure of 50 300 MPa F 5%. The lubricated crystals with
magnesium stearate were compressed with various com-

Fig. 1. Apparatus for spherical crystallization: (a) vessel (500 ml), (b) motor, (c) propeller-type agitator, (d) baffle, (e) water bath, (f ) thermoregulator. Vessel,
agitator and baffle are coated with Teflon.

Y. Kawashima et al. / Powder Technology 130 (2003) 283289

285

Fig. 2. Mechanism of spherical crystallization.

pression speeds at 200 MPa F 5% with the Autograph or a

single punch tableting machine (TabAll, Okada Seiko)
assuming a practical manufacture of tablets.
2.4. Compaction test of ascorbic acid crystals and diametrical fracture test of tablets
Stress relaxation test of powder compact150 mg of
test powder was compressed in the lubricated die with
magnesium stearate with the Autograph at 10 mm/min
until reaching 200 MPa, followed by holding the upper
punch at the required position. The force applied at the
upper punch was monitored during the holding for 20
min. The stress relaxation ratio of compact ( Yt) was
calculated in Eq. (1), after compensating the relaxation
of upper punch tested with unfilled die with powder. The
decreasing rate of Yt with holding time was described in
Eq. (2) [2,3].

Elastic recovery test of powder compact150 mg of test

powder was compressed in the same manner as described in
Section 2.3. The thickness of compact (tablet) was measured
at 200 MPa (Hc) and at 24 h after releasing the tablet from
the die (He). The elastic recovery ratio (ER) was calculated
in Eq. (3) [4].
ER He  Hc =Hc   100

The apparent density (qa) and true density (qt) of tablet

were measured after stored in a desiccator for 24 h. The
porosity of tablet (e) was calculated in Eq. (4).
e 1  qa =qt

where P0 is maximum compression pressure, Pt is residual compression pressure at time, t.

Diametrical fracture test of compactThe tablet stored

in the desiccator for 24 h was diametrically fractured using a
hardness tester (Grano, Okada Seiko). The tensile strength
of tablet (T) was calculated in Eq. (5) [5]. The fractured
plane of tablets was observed by Scanning Electron Microscopy (JSM-T330A, Nihon Denshi).

t=Yt 1=As Bs t=As

T 2F=pdL

Yt P0  Pt =P0

where As is equilibrium stress relaxation ratio (t = l), Bs

is holding time to attain A/2.

where d and L are diameter and thickness of tablet,

respectively, F is crushing strength of tablet.

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Y. Kawashima et al. / Powder Technology 130 (2003) 283289

Table 1
Micromeritic properties of original crystals, C97 granulesR and agglomerated crystals
Sample

Angle of repose (j)

aa

ba

kb

Original
C97
SA
ESD

56.1 F 2.3
33.7 F 1.0
33.8 F 2.6
33.0 F 1.6

0.508
0.079
0.224
0.133

0.066
0.151
0.176
0.155

0.021
0.045
0.065
0.063

a
Parameters in Kawakitas equation: (n/C)=(1/ab)+(n/a),
C=(V0  Vn)/V0, where n is the tap number and V0 and Vn are the powder
volumes at initial and nth tapped state, respectively.
b
Parameter in Kunos equation: qf  qn =(qf  q0 )exp(  kn),
where qf, qn and q0 are the apparent densities at equilibrium, nth
tapped and initial state, respectively.

3. Results and discussion

3.1. Spherical crystallization mechanism and micromeritic
properties of agglomerated crystals
It was found that the spherical crystallization process was
performed in different mechanism depending on the volume
ratio of aqueous drug solution, i.e. water phase (good
solvent) to ethyl acetate (poor solvent) in the system. When
both solvents were miscible at lower volume ratio (e.g.
aqueous drug solution to ethyl acetate = 1:100), the quasiemulsion (without) droplets of drug solution were produced
initially. Successively, the crystallization of drug occurred at
the outer surface of the droplet due to the decreasing in
solubility of drug with decreasing the temperature of the
system and the counter diffusions of both solvents through
the interface of emulsion droplet. The spherically agglomerated crystals were produced simultaneously after completing the crystallization. This agglomeration mechanism was
termed emulsion solvent diffusion (ESD) process. Whereas,
the water phase was immiscible with ethyl acetate at higher
volume ratio (e.g. aqueous drug solution to ethyl acetate = 4:150), the crystallization occurred in the emulsion
system, followed by the random coalescence of crystals with
aqueous bridging liquid liberated from the system. Therefore, water played a role of bridging liquid as well as good
solvent in this process. Under shear force with agitation, the
agglomerates were spheronized and compacted. This
agglomeration mechanism was termed spherical agglomeration (SA) process. Both ESD and SA mechanisms are

illustrated in Fig. 2. It was found by an SEM observation

that in the ESD agglomerate, the primary crystals were
radially arrayed, whereas in the spherical agglomerate the
primary crystals were randomly coalesced as suggested in
Fig. 2.
The micromeritic properties of agglomerated crystals are
shown in Table 1. The angle of repose for agglomerated
crystals reduced significantly to that of C97 granulesR in
comparison with the original drug crystals. Packing process
of the agglomerated crystals in a measuring cylinder by
tapping was described by Kawakitas [6] and Kunos [7]
equations as shown in Table 1. The parameter a in
Kawakitas equation reduced and the respective parameters
b and k in Kawakitas and Kunos equations increased
compared with those of original drug crystals. Those
findings proved that the flowability and packability of
agglomerated crystals were preferably improved for direct
tableting.
3.2. Compaction behavior of agglomerated crystals
The compaction behavior of agglomerated crystals was
analyzed by applying Heckel equation [8,9]
ln1=1  D KP A

where D is relative density of tablet to true density of

powder, 1/K is average yield pressure ( Py).
A ln1=1  D0  B

where D0 is relative density of powder bed at P = 0.

DA 1  eA

DB DA  D0

At lower compression pressure, the data of agglomerated crystals were deviated from the linear relation represented in Eq. (6), although at higher compression pressure
a linear correlation was found. Whereas, potassium chloride crystals revealed a linear correlation through all
compression pressures, suggesting plastic deformation

Table 2
Heckel parameters, relaxation pressure and elastic recovery for the four ascorbic acid samples and potassium chloride crystals
Sample

Original
C97
SA
ESD
KCl

Heckel analysis
Py (MPa)

DA

D0

DB

127.4 F 2.9
134.8 F 4.0*
168.8 F 3.5***
142.9 F 2.9***
35.4 F 1.6***

0.741 F 0.001
0.682 F 0.001***
0.702 F 0.002***
0.747 F 0.001***
0.551 F 0.005***

0.561 F 0.013
0.400 F 0.005***
0.330 F 0.011***
0.409 F 0.010***
0.523 F 0.017 *

0.180 F 0.013
0.282 F 0.006***
0.372 F 0.010***
0.338 F 0.011***
0.028 F 0.012

The results are expressed as mean F S.D. of four runs.

Significantly different from the value for original drug crystals at p < 0.001 (***), p < 0.01 (**) and p < 0.05 (*).

Relaxation
pressure (MPa)

Elastic
recovery (%)

7.0 F 0.2
28.4 F 0.4***
146.1 F 0.4***
124.9 F 0.5***
13.5 F 1.1 **

9.3 F 0.5
5.1 F 0.4***
5.0 F 0.5***
4.7 F 0.2***
8.9 F 1.1

Y. Kawashima et al. / Powder Technology 130 (2003) 283289

Fig. 3. Normalized relaxation curves of the four ascorbic acid and

potassium chloride crystals. (E) Original drug crystals, (x) C97 granulesR,
(.) spherically agglomerated crystals, (n) ESD agglomerated crystals and
(1) KCl crystals.

occurred under the compression. The parameters, DA, DB,

D0, are tabulated in Table 2. The DBs for SA and ESD
were higher than those of C97 granulesR, original drug
crystals and potassium chloride crystals, indicating that the
agglomerates were highly fractured during compression
[10]. The rank order of average yield pressure ( Py)
calculated from the slope of Heckel plots was as spherical
agglomerates > ESD agglomerates > C97 granulesR > origi> original drug crystals, the values of which were higher
than that of potassium chloride crystals. The elastic
recoveries of agglomerated crystals were smaller than that
of original drug crystals. Those findings suggested that the
agglomerated crystals were easily fractured, and the new
surface of crystals produced might contribute to promote
plastic deformation under compression. The increased
plasticity of agglomerated crystals was proved by the
stress relaxation test as shown in Table 2. It was found
that the stress relaxation process was described in Eq. (2)
as shown in Fig. 3.
The higher values of As, Bs for the agglomerated crystals
in Table 3 indicated that their stress relaxation ratio at
equilibrium and velocity of stress relaxation were higher

Table 3
Parameter of stress relaxation process for the four ascorbic acid samples and
potassium chloride crystals
Sample

As

Bs

Original
C97
SA
ESD
KCl

0.058 F 0.001
0.168 F 0.002***
0.778 F 0.004***
0.658 F 0.006***
0.103 F 0.005***

0.012 F 0.001
0.013 F 0.000
0.021 F 0.001***
0.029 F 0.001***
0.004 F 0.000***

The results are expressed as mean F S.D. of four runs. Significantly

different from the value for original drug crystals at p < 0.001 (***).

287

Fig. 4. Relationship between tensile strength of ascorbic acid tablets and

compaction pressure. (E) Original drug crystals, (x) C97 granulesR, (.)
spherically agglomerated crystals and (n) ESD agglomerated crystals. (y)
Some tablets are capped during compaction. The results are expressed as
mean F S.D. of four runs. Significantly different from the value for C97
granulesR at p < 0.001 (***), p < 0.01 (**) and p < 0.05 (*).

than those of C97 granulesR and original drug crystals as

suggested in Table 2.
3.3. Improved compactibility of spherically agglomerated
crystals
The tensile strength of tablets prepared with agglomerated crystals or original drug crystals is plotted as a
function of compression pressure in Fig. 4. It was impossible to compact the original drug crystals at higher than
200 MPa compression pressure because capping occurred.
Whereas, the agglomerated crystals were successfully tableted without capping at any pressures applied. It was
found that the tensile strength of tablets with the agglomerated crystals was dramatically increased, even more than
that of C97 granulesR. This improvement in compactibility
of the agglomerated crystals might be due to their
enhanced fragmentation during compression resulting in
increased DB in Table 2, increasing the contact points to
bind particles. Further, an increased plasticity of the
agglomerated crystals as shown in Fig. 3 and Table 2
increased the contact point area to produce a strong bond
between particles.
3.4. Effect of compression speed on the compaction
behavior of agglomerated crystals
The effect of compression speed on compaction behaviors of agglomerated crystals and reference particles was
investigated using the Autograph (static compression) and
the single punch tableting machine (dynamic compression)
as shown in Fig. 5. Under static compression, the tensile

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Y. Kawashima et al. / Powder Technology 130 (2003) 283289

strength of tablets with the original drug crystals and C97

granulesR tended to increase with increasing the compression speed, whereas those of the agglomerated crystals
decreased because of insufficient stress relaxation of the
agglomerated crystals at higher compression speed. Under
dynamic compression, the tensile strength of resultant
tablets was almost unchanged irrespective of compression
speed for all materials. The tensile strength of tablets with
agglomerated crystals prepared under dynamic compression
was lower than under static compression, where the compression speed was constant during compression. Whereas,
under dynamic compression, the compression speed was
decreased with punch displacement in compression, leading
to insufficient plastic deformation [11]. This was proved by
higher porosity of tablets prepared under dynamic compression than under static compression. On the fractured plane
of tablet prepared under static compression, a solid bridge
between crystals was found by SEM observation, although
there was no solid bridge formed between crystals in the
tablet prepared under dynamic compression. It was found
that in the tablet of spherically agglomerated crystals, the
agglomerates were fragmented into primary crystals as
indicated by their high DB values in Table 2. In the tablet
of ESD agglomerates, a part of agglomerate structure still
remained. This finding indicated that the ESD and spherically agglomerated crystals were consolidated primarily by
their rearrangement and plastic deformation and fragmentation in the die, respectively. The spherically agglomerated
crystals might be preferably chosen for practical direct
tableting using a continuous high-speed machine due to
their brittle characteristics compared with the ESD agglomerated crystals.

4. Conclusions
The spherically agglomerated crystals of ascorbic acid
were successfully prepared for direct tableting by the
spherical crystallization technique. Depending on the
solvent combination for crystallization, the primary crystals were agglomerated by two different mechanisms, i.e.
emulsion solvent diffusion (ESD) and spherical agglomeration (SA) mechanisms, determining the internal structure of agglomerate. The micromeritic properties of
agglomerated crystals, such as flowability, packability
and compactibility were dramatically improved, resulting
in successful direct tableting without capping under a
practical compression speed. Remarkable fragmentation,
increased plastic deformation and lowered elastic recovery
of the agglomerated crystals during tableting process were
responsible for improving the compactibility. Even at
higher compression speed with a single punch tableting
machine, the agglomerated crystals were tableted directly,
although the mechanical strength of resultant tablet
tended to decrease, which was within tolerable difference
compared with that of the tablet with C97 granulesR.

Nomenclature
A
As
a
B
Bs
b
C
D
D0
d
ER
F
Hc
He
K
k
L
n
P
P0

Fig. 5. Relationship between tensile strength of ascorbic acid tablets and

compression speed. (E, D) Original drug crystals, (x, w) C97 granulesR,
(., o) spherically agglomerated crystals, (n, 5) ESD agglomerated
crystals and (1, B) KCl crystals. Tablets were prepared using Instron-type
hydraulic press (closed symbols) or single punch machine (open symbols)
at compaction pressure of 200 MPa. The results are expressed as
mean F S.D. of four runs.

Pt
T
V0
Vn
Yt
e
q0

Total densification of powder bed due to die filling

and particle rearrangement
Constant
Constant
Densification of powder bed due to particle
fragmentation
Constant
Constant
Constant
Relative density of powder at applied pressure P
Relative density of powder at pressure = 0
Tablet diameter (m)
Elastic recovery ratio (%)
Crushing strength of tablet (N)
Tablet thickness at maximum pressure (m)
Tablet thickness at 24 h after ejection (m)
Slope of straight line of Heckel plot (1/Pa)
Constant
Tablet thickness (m)
Tap number
Applied pressure (Pa)
Maximum compression pressure (at time, t = 0)
(Pa)
Compression pressure at time t (Pa)
Tensile strength of tablet (N/m2)
Volume at initial state (m3)
Volume at nth tapped state (m3)
Pressure decaying ratio
Tablet porosity
Apparent density at initial state (kg/m3)

Y. Kawashima et al. / Powder Technology 130 (2003) 283289

qa
qf
qn
qt

Apparent density (kg/m3)

Apparent density at equilibrium state (kg/m3)
Apparent density at nth tapped state (kg/m3)
True density (kg/m3)

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