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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 d’acide ascorbique presentant une aptitude a la compaction accrue en vue de compression

directe ont ete pre pares par procede de cristallisation spherique. Au cours du procede, les cristaux d’acide ascorbique sont tout d’abord

precipites par changement de solvant, puis agglomeres par mecanisme de diffusion de solvant a partir d’une quasi-emulsion ou

d’agglomeration spherique. Nous avons cherche a ameliorer les proprietes micromeritiques comme la coulabilite ou l’aptitude a

l’empilement 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 phenomene. L’amelioration des proprietes de compaction des cristaux agglomeres est due a leur fragmentation et une

deformation plastique se produit de maniere 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 phenomene de decalottage en utilisant une machine monopoincon en

compression mdynaique, alors que la limite d’elasticite des comprimes obtenus diminuait de maniere acceptable lorsqu’on 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

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

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

E-mail address: [email protected] (Y. Kawashima).

www.elsevier.com/locate/powtec

Powder Technology 130 (2003) 283 – 289



toward unmanned operation overnight. To do this, highly

compactible properties of drug particles are required, other-

wise 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 tabletingdue 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 crystal-

lization 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 pref-

erentially 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 com-

pactibility was explained by analysing the static compaction

process. The effect of compression speed on the compact-

ibility of agglomerates was evaluated for dynamic compres-

sion in assuming an industrial trial.

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

flowability and compactibility, respectively. The C97 gran-

ulesR for direct tableting were used as reference powder for

both tests. Potassium chloride crystals were used as refer-

ence 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 crystalliza-

tion 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 crys-

tallization 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

The agglomerated and unagglomerated crystals (150

mg) were compressed in an 8-mm die with an Instron

type press (Autograph AG5000D, Shimadzu) at the com-

pression speed of 10 mm/min and the compression pres-

sure of 50–300 MPaF 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) 283–289284



pression speeds at 200 MPaF 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 dia-

metrical fracture test of tablets

Stress relaxation test of powder compact—150 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 ( Y t ) was

calculated in Eq. (1), after compensating the relaxation

of upper punch tested with unfilled die with powder. The

decreasing rate of Y t with holding time was described in

Eq. (2) [2,3].

Y t ¼ ð P 0 P t Þ=ð P 0Þ ð1Þ

where P 0 is maximum compression pressure, P t is resid-

ual compression pressure at time, t .

t =Y t ¼ 1= As Bs þ t = As ð2Þ

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

is holding time to attain A/2.

Elastic recovery test of powder compact—150 mg of test

powder was compressed in the same manner as described in

Section 2.3. The thickness of compact (tablet) was measuredat 200 MPa ( H c) and at 24 h after releasing the tablet from

the die ( H e). The elastic recovery ratio (ER) was calculated

in Eq. (3) [4].

ER ¼ ½ð H e H cÞ= H c 100 ð3Þ

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 ¼ 1 qa=qt ð4Þ

Diametrical fracture test of compact—The 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 Micro-

scopy (JSM-T330A, Nihon Denshi).

T ¼ 2 F =pdL ð5Þ

where d and L are diameter and thickness of tablet,

respectively, F is crushing strength of tablet.

Fig. 2. Mechanism of spherical crystallization.

Y. Kawashima et al. / Powder Technology 130 (2003) 283–289 285



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 quasi-

emulsion (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 agglom-

erated crystals were produced simultaneously after complet-ing 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 ace-

tate = 4:150), the crystallization occurred in the emulsion

system, followed by the random coalescence of crystals with

aqueous bridging liquid liberated from the system. There-

fore, 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 agglomer-

ation (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 agglomeratedcrystals 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 Kawakita’s [6] and Kuno’s [7]

equations as shown in Table 1. The parameter a in

Kawakita’s equation reduced and the respective parameters

b and k in Kawakita’s and Kuno’s 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]

ln½1=ð1 DÞ ¼ KP þ A ð6Þ

where D is relative density of tablet to true density of

powder, 1/ K is average yield pressure ( P y).

A ¼ ln½1=ð1 D0Þ þ B ð7Þ

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

D A ¼ 1 e A ð8Þ

D B ¼ D A D0 ð9Þ

At lower compression pressure, the data of agglomer-

ated crystals were deviated from the linear relation repre-

sented in Eq. (6), although at higher compression pressure

a linear correlation was found. Whereas, potassium chlor-

ide crystals revealed a linear correlation through all

compression pressures, suggesting plastic deformation

Table 1

Micromeritic properties of original crystals, C97 granulesR and agglom-

erated crystals

Sample Angle of repose (j) aa ba k b

Original 56.1F 2.3 0.508 0.066 0.021

C97 33.7F 1.0 0.079 0.151 0.045

SA 33.8F 2.6 0.224 0.176 0.065

ESD 33.0F 1.6 0.133 0.155 0.063a P a ra m ete r s in K a wa k ita ’s e q ua tion : (n/ C )=(1/ ab )+ (n/ a),

C =(V 0 V n)/ V 0, where n is the tap number and V 0 and V n are the powder

volumes at initial and nth tapped state, respectively. b Parameter in Kuno’s equation: qf qn=(qf q0)exp( kn),

where qf , qn and q0 are the apparent densities at equilibrium, nth

tapped and initial state, respectively.

Table 2

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

Sample Heckel analysis Relaxation Elastic

P y (MPa) D A D0 D B

pressure (MPa) recovery (%)

Original 127.4F 2.9 0.741F0.001 0.561F 0.013 0.180F 0.013 7.0F 0.2 9.3F 0.5

C97 134.8F 4.0* 0.682F0.001*** 0.400F 0.005*** 0.282F 0.006*** 28.4F 0.4*** 5.1F 0.4***

SA 168.8F 3.5*** 0.702F0.002*** 0.330F 0.011*** 0.372F 0.010*** 146.1F 0.4*** 5.0F 0.5***

ESD 142.9F 2.9*** 0.747F0.001*** 0.409F 0.010*** 0.338F 0.011*** 124.9F 0.5*** 4.7F 0.2***

KCl 35.4F 1.6*** 0.551F0.005*** 0.523F 0.017 * 0.028F 0.012 13.5F1.1 ** 8.9F 1.1

The results are expressed as meanFS.D. of four runs.

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




occurred under the compression. The parameters, D A, D B,

D0, are tabulated in Table 2. The D B’s 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 ( P y)

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

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 agglom-

erated crystals or original drug crystals is plotted as afunction of compression pressure in Fig. 4. It was impos-

sible to compact the original drug crystals at higher than

200 MPa compression pressure because capping occurred.

Whereas, the agglomerated crystals were successfully tab-

leted without capping at any pressures applied. It was

found that the tensile strength of tablets with the agglom-

erated 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 D B 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 behav-

iors 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

Table 3

Parameter of stress relaxation process for the four ascorbic acid samples and

potassium chloride crystals

Sample As Bs

Original 0.058F 0.001 0.012F0.001

C97 0.168F 0.002*** 0.013F0.000

SA 0.778F 0.004*** 0.021F0.001***

ESD 0.658F 0.006*** 0.029F0.001***

KCl 0.103F 0.005*** 0.004F0.000***

The results are expressed as meanFS.D. of four runs. Significantly

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

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.

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

meanFS.D. of four runs. Significantly different from the value for C97

granulesR at p < 0.001 (***), p < 0.01 (**) and p < 0.05 (*).




strength of tablets with the original drug crystals and C97

granulesR tended to increase with increasing the compres-

sion 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 compressionspeed for all materials. The tensile strength of tablets with

agglomerated crystals prepared under dynamic compression

was lower than under static compression, where the com-

pression 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 compres-

sion 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 D B values in Table 2. In the tablet

of ESD agglomerates, a part of agglomerate structure still

remained. This finding indicated that the ESD and spheri-

cally agglomerated crystals were consolidated primarily by

their rearrangement and plastic deformation and fragmenta-

tion 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 agglom-

erated 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 crys-

tals were agglomerated by two different mechanisms, i.e.emulsion solvent diffusion (ESD) and spherical agglom-

eration (SA) mechanisms, determining the internal struc-

ture 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 Total densification of powder bed due to die filling

and particle rearrangement

As Constant

a Constant

B Densification of powder bed due to particle

fragmentation Bs Constant

b Constant

C Constant

D Relative density of powder at applied pressure P

D0 Relative density of powder at pressure = 0

d Tablet diameter (m)

ER Elastic recovery ratio (%)

F Crushing strength of tablet (N)

H c Tablet thickness at maximum pressure (m)

H e Tablet thickness at 24 h after ejection (m)

K Slope of straight line of Heckel plot (1/Pa)

k Constant

L Tablet thickness (m)

n Tap number

P Applied pressure (Pa)

P 0 Maximum compression pressure (at time, t = 0)

(Pa)

P t Compression pressure at time t (Pa)

T Tensile strength of tablet (N/m2)

V 0 Volume at initial state (m3)

V n Volume at nth tapped state (m3)

Y t Pressure decaying ratio

e Tablet porosity

q0 Apparent density at initial state (kg/m3)

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

meanFS.D. of four runs.




qa Apparent density (kg/m3)

qf Apparent density at equilibrium state (kg/m3)

qn Apparent density at nth tapped state (kg/m3)

qt True density (kg/m3)

References

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Pharmaceutical Processes, Elsevier, Amsterdam, 1994, p. 493.

[2] M. Peleg, R. Moreyra, Powder Technol. 23 (1979) 277.

[3] K. Danjyo, A. Hiramatsu, A. Otsuka, J. Soc. Powder Technol. Jpn. 35

(1998) 662.

[4] N.A. Armstrong, R.F. Haines-Nutt, Powder Technol. 9 (1974) 287.

[5] J.T. Fell, J.M. Newton, J. Pharm. Sci. 5 (1970) 688.

[6] K. Kawakita, Kagaku 26 (1956) 149.

[7] H. Kuno, in: G. Jimbo, et al. (Ed.), Funtai (Powder Theory and Ap-

plication), Maruzen, Tokyo, 1979, p. 342.

[8] R.W. Heckel, Trans. Metall. Soc. AIME 221 (1961) 671.

[9] R.W. Heckel, Trans. Metall. Soc. AIME 221 (1961) 1001.

[10] E. Doelker, in: D. Chulia, et al. (Ed.), Powder Technology and Phar-

maceutical Processes, Elsevier, Amsterdam, 1994, p. 403.

[11] Y. Kawashima, F. Cui, H. Takeuchi, T. Niwa, T. Hino, K. Kiuchi,

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