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679 HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688 , 136-791 39-1 (2003 12 9 , 2003 12 17 !) Design of Particles using Supercritical Fluids Youn-Woo Lee National Research Lab for Supercritical Fluids, Korea Institute of Science and Technology, 39-1, Haweolkok-dong, Sungbuk-gu, Seoul 136-791, Korea (Received 9 December 2003; accepted 17 December 2003) ! "#$% &’( ) *+ ,- ./ 01. 23( 456 78 9:/ 4;< => ?@( AB, CB, DE, FB 9:/ GA H(I ’J KL M NO PQ( ) ’./ 01. R/(I ’J ,ST PQT RESS(rapid expansion of supercritical solutions), SAS(supercritical anti solvent) 9:/ PGSS(particles from gas saturated solutions) H( ,J UVW X/ <1. Abstract - The environmentally friendly nature of supercritical fluids such as supercritical carbon dioxide and supercritical water has led to the exploration of their use in a range of materials applications. In the last few years, several supercritical flu- ids-based techniques have been proposed for the production of micronic and nanometric particles for potential applications in areas such as pharmaceuticals, cosmetics, inorganics, biomaterials and explosives. Techniques like the rapid expansion of supercritical solutions (RESS), supercritical antisolvent precipitation (SAS), particle generation from gas-saturated solutions (PGSS), and reactive precipitation in supercritical solutions (RPSS) have been critically reviewed. Key words: Supercritical Fluid, Particle 1. ( ) , , , , ! "#$ %& ’( ) *+,. - . # crushing, grinding, ball milling, spray drying, /0 12, 3 4 "+ 5,. 67* 8 9 : ;< =>? +@A B C DE FG#$A 8 H IJ# K (L# > /M N O,. P+* QR " S+* TU# VW XYZ [\# >/Z ]^ _ Na, b 6 c d eF .+ fg IJ# h_i + ’jk 5,[1]. lmn+o( pqr 6s Dt UuA vwx m n Ec- @ 5 IJ# " yz- 4 # { |j +}f@ 5,[2]. Fig. 1 # *~ liquid solvent emulsion precipitation 9_ Z fR 9# Z /V O VW v$ :, /r yz, DDS " # { /+ k 5,. lmn- +/ yz- 120 2_ 7 x;,. 1897 Royal Society of London #$ Hannay b Hogarth lmn FG #o#$ M_™ /c- #$ / _ ¡ £∕¥ƒ I §(snow) yz - ¤ N 5, ',[3]. 1980 lB“ «‹@ lmn- /V, ›/V, › _ $ +/Z yz- { 4+ fikf =fl 5,[4-8]. ›>_ ?°– <²‡+* ·µ¶ + •+ 3 ‚„ j-   »…‰, 6s ¿B_ fg ,. 6s ?°– <²‡ =j`Z M =W ´#$ k ´ # Z B ˆ- ˜f¯˘ u vwx, <²‡ (ˆ( (protease) _B“ f ¥˙¨ ”Qf, É¥˚ + ¸,Ì ˝_ ˛v5,. 67* ˇ =W# z¾+ —_ v É /+,. ˇ_   2ÀÑ M =W : Ò |j fÓÔ yz Õ@* c "# Ös@ × { Ø ˇ ‹@ i›ÙÚ +,. A# cx@}* Yl}- Ûr To whom correspondence should be addressed. E-mail: [email protected]
10

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Page 1: HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688 · 679 HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688 , 136-791 ˘ˇˆ˙ 39-1 (2003˝ 12ˇ 9˛ ˚˜, 2003˝

HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688

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��������, ��� �������136-791 ��� ��� ���� 39-1

(2003� 12� 9� ��, 2003� 12� 17� !)

Design of Particles using Supercritical Fluids

Youn-Woo Lee

National Research Lab for Supercritical Fluids, Korea Institute of Science and Technology, 39-1, Haweolkok-dong, Sungbuk-gu, Seoul 136-791, Korea(Received 9 December 2003; accepted 17 December 2003)

� �

�������� ��� �� ��� �� ����� ��� ����� ���� � ! "#$%� &'( )

� *+� ,-� ./ 01. 23(� ��� �� 45�6 78� 9:/ 4;< => ?@( �AB, �CB, �DE,

FB 9:/ GA H(I �� �'�J KL M� N�O ��� ���� PQ( )� �'./ 01. R/(I� ��

� �� �'�J ����� ���� ,S�T PQT RESS(rapid expansion of supercritical solutions), SAS(supercritical

anti solvent) 9:/ PGSS(particles from gas saturated solutions) H( ,�J UV�W �X�/� <1.

Abstract − The environmentally friendly nature of supercritical fluids such as supercritical carbon dioxide and supercritical

water has led to the exploration of their use in a range of materials applications. In the last few years, several supercritical flu-ids-based techniques have been proposed for the production of micronic and nanometric particles for potential applications in

areas such as pharmaceuticals, cosmetics, inorganics, biomaterials and explosives. Techniques like the rapid expansion of

supercritical solutions (RESS), supercritical antisolvent precipitation (SAS), particle generation from gas-saturated solutions(PGSS), and reactive precipitation in supercritical solutions (RPSS) have been critically reviewed.

Key words: Supercritical Fluid, Particle

1. � �

�� ��(�� �� �� ��) �� � � ���� ��� �

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� �*+,. ��� ��- �.�� ��#� crushing, grinding, ball

milling, spray drying, /0 12, 3�� 4� "+ 5,. 67* �8

9� : ;<�� =�>? ���� ��+@A �B ���� C

DE FG#$A �8 H�� IJ# K� ��� (�L#� >

/M N O,. �P��+* QR� "� S+* TU# VW XY�Z

[\# >/�Z ]^ ��_� `� Na, ����b 6� ��c d

eF �.+ fg� IJ# h_i ��+ 'jk� 5,[1].

lmn+ �o(� pqr 6s� Dt� UuA vwx `� m

n Ec- @� 5� IJ# ��� "� yz��- ���� 4�

# {� |j +}f@� 5,[2]. Fig. 1# *~� ��� ���

liquid solvent emulsion precipitation 9�_ ���Z �fR �9# �

�Z �� /V �� O� � ���� VW �� ������

�v$ �:�, �/r ���� yz�, DDS "� �� ��# {

� �/+ ��k� 5,. lmn��- +/� yz��- ����

��� 120� 2�_ ��7 �x;,. 1897� Royal Society of London

��#$ Hannayb Hogarth� lmn FG� #o�#$ M_�� �

�� /�c- ���� ��#$ �� /�� �/ � ����_ ¡

U¢ £¤¥¦ I §(snow)� �� yz ��- ̈N 5,� �©,[3].

1980�� lBª «�¬@ lmn��- /V, ­/V, �� ­� _

$ +/�Z yz��- ���� {� 4�+ �®kf =¯� ��

5,[4-8].

�­>�_ ?°±� �� <²³+* ´µ¶ �+ ��·+ �� 3

¸¹ j�- º� � � »¼½, �:¾ 6s� ¿B_ 2À�� fg

,. 6s� ?°± �� <²³� =jÁZ M =W Â#$ ��k� Â

# ��Z �B� �Ã- ÄfÅÆ u vwx, <²³ (�Ã(

(protease)_Bª �f ¥ÇÈ� ºQf���, �:¾� É�¥Ê� �

+ Ë,Ì Í�_ Îv5,. 67* Ï� =W#� z�¾+ �Ð_ �

v É� /+�,. Ï_ � � 2À�Ñ� M =W : Ò |j �

�� fÓÔ yz�� �Õ@* �c "# Ös@ ×� {� Ø� Ï

¬@ i­�ÙÚ �� �+,. A�# cx@}* Yl}- Ûr�†To whom correspondence should be addressed.E-mail: [email protected]

679

Page 2: HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688 · 679 HWAHAK KONGHAK Vol. 41, No. 6, December, 2003, pp. 679-688 , 136-791 ˘ˇˆ˙ 39-1 (2003˝ 12ˇ 9˛ ˚˜, 2003˝

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N 5,. <²³� �E, DE# ��$ 0-50oC#$ ,}f� �õ_

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²³� 3̧ ¹ j�- �@M I �_( 6 �Ã- *~�� å nàór

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×�,. ôx$ lmn��Ì ‘mn Ecb �ù +F#$ 5� ��’_

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clustering FG- �.M N 5,. lmn ��#$� �c ü�b /V

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local density augmentation, enhanced local composition)+x� �s�

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time)+x� M N 5,[9, 10]. (Fig. 3) /V� /�ù� /V� �cb

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Fig. 1. Comparison of particle size and distribution of HYAFF 11microspheres produced by (a) SAS; and (b) liquid solvent emulsionprecipitation. Average particle size for (a) is 350 nm. E. Rever-chon, Supercritical antisolvent precipitation of micro- and nano-particles, J. Supercritical Fluids 15 (1999) 1-21.

Table 1. Optimum temperature for drying proteins, mab, and vaccine

Temp (oC)Pressure (mmHg)

Familiar mileposts

120 1,489 Conventional spray dryer inlet gas temp.No acteria survive at 120oC

100 760 Proteins are cooked80 355 Many proteins and vaccines degrade60 149 Maximum temp Mab and proteins40 55 Normal bacteria and proteins fluorish at body temp

(Top temp. for E. Coli culture 47oC)20 17 Room temp0 5 Low limit of drying aqueous solution

−20 0.8 Some proteins denatured by freeze dryingFig. 2. Supercritical fluid region in pressure-temperature diagram (val-

ues are density of H2O).

���� �41� �6� 2003� 12�

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����� �� � �� 681

I J� k� øà:ù# ��$ �f*� wetting J� �� �c �

f*@ ×� " Z7 @ :¼� ºÔ ý,.

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o(- /V_ ñ/�Z Ë¿¹�_Bª 0%?� ���� 4�+,

[13]. lmnFG� + �o(� 0%?� �+ `� ��·� º� �

Cr  ³� # /��@A Ë¿ -� Õn5� Cr� carbohydrates

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N 5,. «� lmn+ �o(- +/� decaffeinated coffee 2 z

n>�_ |; � 100,0003 +F+ 4 k� 5,. �#� Q¤, �

5, z� " �s�� �� u vwx ��6r, ���)6, �­�

� �2�� ��­��� �� 6s� c�, »7, *8�� "� ��

����# Ö9 2­>�_ ��+ ®2�� 5,(Fig. 6).

3. �� ������ ��� ����

3-1. RESS(rapid expansion of supercritical solution)

RESS4�(Fig. 7)� *8��_ AL�- ¹�� /³� lmn��

# /�¥: ; yz� nozzle� É�Z ¡�¢ <=¥Êà lmn��

Ç FG_ k� ��#$ /³+ /�ù� ÄÔ k� >ç ¥;

�# ���kf /�kf 5^ /³+ ?¤k� «F� +/� �+

,. �­>�_ +7� ���FG� 10−5-10−6 l� VW @� ¥;#

Àrý,. RESS4�� 1897� Hannayb Hogarth[3]+ Royal Society

of London��#$ lmn #o�# ����#$ cobalt chloride,

potassium iodide 6s� potassium bromide� /�c- ���� ��

#$ �� /�� �/ � ����_ ¡U¢ £¤¥¦ I §(snow)�

��  ³� Añ� ��_Bª ®2�Z Krukonis 1984� y���

4��#$ 4�> �/� �B�©,[1]. �� 4rk� ��� %

4r� 3�r:� � <n_ *CfR,. � <n� �c� /³� D

c �� ���c# ��Z 3�ý,. �­>? 3�r:+E# ôFà

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�� �� �v@@A ���c `�à 3�r:+ ��kf �

�� ��� Ë@Ô ý,. RESS4��_ �fR ��� eG� <=8

Fig. 3. Spatio-temporal fluctuation of density due to molecular associa-tion in supercritical fluid.

Fig. 4. Solubility of tocopherol as a function of CO2 density.

Fig. 5. Diffusion coefficient of carbon dioxide.

Fig. 6. Technical tree of supercritical fluid.

HWAHAK KONGHAK Vol. 41, No. 6, December, 2003

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682 � � �

,

G, Ec 6s� �ù "# ôx$ Àx@ò je, H�F, I� ½ "

� �� JØ� @K,. RESS4�� �>�_ lmn��A� ñ/

�� IJ# �� ��/V O� � � ��M N 5� :¼+ 5,.

67* /�c �� � � ���� Â�$ �� /V- ñ/��

=W#� �� /Vb ��� L1+ ÕMý,. RESS4�#$ ���

�6 + {� =W H�F c� I� ½�_ 4rý,. lmn/0+

<=N I ���� 0� �� ��_ ?¤k�å H�F� ����

��� 0F�_ ?¤N I �fR,. H�F ���� O=� ��

1-5µm �c ý,. ���6 � lmn/V_� CO2, nitrous oxide,

trifluoromethane, ethylene, pentane� �� �+ ñ/kò /�c- �

�¥Ê� Â�$ N PQú �c� Cr /V- ñ/��c �,.

RESS� ÿRÿ SJ#$� ;<� 4��_ Vù+ 5�* F!>

4 #$� ��� ����- �f�� fÑT u vwx /³� V

W `� /�ù�_ �Z >/M N 5� �� VW ��>+,. @�

¬@ RESS4��_ |j�Z JU# ®øý �6 � Krytoxdiamideof

hexamethylene(KRYTOX), Polycaprolactone, Poly(carbosilane), Poly(2-

ethylhexylacrylate), Poly-l-lactic acid, Poly(heptadecafluorodecylacrylate),

Poly(methylmethacrylate), Poly(phenylsulfone), Polypropylene, Polystyrene,

Poly(vinyl chloride) "� �� ���b AgI, Agtriflate, Al(hfa)3, Anthracene,

Benzoic acid, Cr(hfa)3, Cu(oleate)2, Cu(thd)2, Naphtalene, Pd(tod)2, SiO2, Zr(tfa)4"� �� �� �� p�  6s� Aspirin, Caffeine, Cholesterol, β-estradiol,

Griseofulvin, Ibuprofen, Lecithin, Lidocaine, Mevinolin, Lazaroidcompound

U-74389F, Tropic acid ester, α-tocopherol, Theophyllin, Testosterone

Stigmasterol "� �� ���+ 5,[14-19]. �B�� � +* ��

�6 � RESS4�� É�Z �;� 3�r+ p�e�_ VW� �

�_ *~),. 67* Õ.X Y��? 3�eG� Celecoxib- 50oC,

290��� lmn + �o(#$ Z? ; ����_ <=�©� =

W 4rý ��� [2¢ p�e�_ VW� ��_ �� k',[20].

RESS4�� :¼� �\> ��=�� �� � O=+ N Þ+�

_ N]� ��- VW >FÔ �� N 5,� �+,. ��+ 3��

b ë�4�+ ê¥# �f*� �� �#� /V ���@ ×Ô ý

,. ��- N��� �+ �\> <^�Z Z�b z_4�# `'�

4;c .�ý,. 67* RESS4�� lmn��# /�k�  ³#

A >/+ H�� �B� Õ&�F�  ³� /�c `� IJ#

�� Ø� ��- A¶� å#c {� Ø� lmn�� ('k� <

¼� @� 5,[4].

3-2. SAS(supercritical antisolvent) ��

SAS 4�� ��- ��M /³+ lmn��# �� /�c VW

`� =W#� /³� >.� /V# Z? ; +- antisolvent? lm

n��b a62�_$ /V� /�ù� ¡U¢ D�¥b /0 )� /

³� ?¤¥Ê� ¹s- +/� �3� 4�+,[21]. + �9� +y

��6r+* ��� )6� �� ��#$ cs ñ/kfE �3��

�9(liquid-liquid anti-solvent precipitation)� �*+,. ä 6rý  ³

+* ���� �­>�_ /V# Zv 5� FG_ ���Ô k� å

Z�# antisolvent- dfÛà �� ?¤k� +Yb �,. ôx$ �

�� /V# # Zv� �� antisolvent#� # Z@ ×v��� ��

��+� /Vb antisolventc $_ # Zv��,(Fig. 8). SAS4��

>/ Hr� �v�� Â�$� /³-/V-lmn��� 3Ýe /�

c ðc- 6s� �+ `N>+,. �­ 0F� antisolvent �3��

4�� SAS4��� ¸+¼� SAS#$ ñ/�� lmn��� K�

#$ �eý,. Antisolvent? lmn��b /Vb�  ³2À�c�

�  ³� � �c# �f�� IJ# SAS4�#$� 0F4�# �

�Z VW >ç  ³2À+� IJ# ¡U� ��� d %4r+ +}

fR,. 3�>�_ 0F4�# ��Z VW �� ��- �� N 5,.

�< ��� er+ [�kà �� 3���� gh- S� n��Z

lmn��- Û��à$ �� ÛÂ# Îv5� /V- z_�,. RESS

4�# ��$ `� Ecb �ù#$ �!+ kf SAS4�� S# X

Y� ���+* <²³ "� �� /V O+ yz��� å# VW �

Fig. 7. Acetylsalicylic acid particles by RESS Process.

Fig. 8. The diagram for solvent-solid-antisolvent and SAS process.

���� �41� �6� 2003� 12�

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����� �� � �� 683

s�,. SAS4�� (b i+ Usý FG#$ ��ý,� :¼+

5�ò �­>�_ 99% ¬i Na� ���� Þ,� üN- �(

�M N 5� 4��_ �Ñ� 5,. SAS4�� �� �9# ôx$

GAS, ASES, SEDS "�_ ,¥ � ý,.

GAS(gas antisolvent)4� (Fig. 9)� /³+ Zv 5� /V- ��

3�� �# B�>�_ ji ,k lmn��- ��Z /V- <

=¥Ê� �9�_ /�ù� Y(¥Ê� �� +/� 3�� 4�+,[5].

GAS# �� ��� 1950�� )­¬@ ��7 �x;,. 1954�

Francis� 0�� + �o(- +/� 2l �� 3l ¥ÇÈ#$ +

�o(� ?¤Ã�# ��Z ���� 5,. GAS4�� 1989�

Gallapher "# ��Z �k�_ nitroguanidine P� "� ��  ³�

lmn + �o(- ñ/�Z �3���� �9�_ (�k',[23-

26]. GAS4�#$ 3���c� antisolvent� c��c ä �ù��

c# ��$ �.ý,. �ù���� %4r� 3�r:# m-� y

Y� ���c� ü�b |3ý,. �ù� >FÔ Fn¥Êà >ç �

��- �c�Ô k� 3�� >ç %4r IJ# yz� ��- �Ô

ý,. lmn��� Ã�>? a6� �c�� Â�Z /0� Vo�_

c��,. GAS4�#$� antisolvent? lmn��� ��c ��

��cb Õp+ 5� ôx$ ��� ��- �.�� å VW )'�

,. 3� ?¤� �B� \­ �cc ��� ��# m-� ],. GAS

4�� Û_ ����_ �!� �� IJ# ¥�- :q��, �ù�

�s� ,¥ �s�, ��- �N�� å# Fæ� ¥;+ ('k� 3

¼� @� 5,. + 4�� #á@ {+ L�c �@A �Û �ù

� ür�� IJ# :Y sÔ ÞtN N 5,.

ASES(aerosol solvent extraction system)4� (Fig. 10)� ��� 3�

���B#$ |�>�_ uF� lmn�� ��_ 8G� �Z /

0� � ¥Ê� �9�_ ­|�>? + 4�#$� GAS 4�#$ �

,c � �� ���c- ^;>�_ �� N 5� IJ# 4rý ��

� �� VW �� ����_ �Ô *~�,[27-34]. �� T�¢

�f@à /0� �ñ� )<�� lmn��_ ��- z_�,. ASES

4�#$� � @ vËww+ ��� ��b eG# VW )'� ì

M� �Ô ý,. �� /�kf 5� /0� 8G� É�Z �Ô B

x$ yz� 0>� ALf Ûà /Vb lmn�� ñ+# VW y�

nà+ 4rkf  ³2À# VW Ë,Ì cz+ ý,. �­>�_ y

z� 0>� A¶� 4�# )'� p¸¹ FN� weber number+ò

,k� �+ ¥ÇÈ� {|s� }� h_+ er�� }� �_$ �

��,.

We = (1)

Z�$ do� characteristic length scale(Û_ droplet diameter)+�, V

� lmn��# �� /0� �¤�c, ρ� |�F? lmn���

�c+�, γ� /0� lmn��ñ+� nà:ù ~+,. �­>�_

|�F? lmn��� �c Ë@à nà:ù� ~� �v@� IJ

# weber number� �J� �v@�, ��� Ë@� IJ# weber

number� ¡U�Ô Fn�Ô k� deformation force F�>�_ Ë

@à$ 0>� VW �v³ �+ �Fý,. �� Ø� /V- yz�

0>�_ ALf Ûà /Vb lmn��ñ+� nà� à>+ �f*

� IJ#  ³ 2À� Ã�� ËR,. �� �� 0>+ erý ;#

� 0>�� /V� lmn�� 5� V���_ � � �� lm

n+ �o(� 0> �B_ � �à$ /0# Zv5^ ��� ��

� FG kf ?¤�Ô ý,. ����c >Fà >-N� ���

�� �v@� IJ# lmnFG� �ë� yz��- A¶� å

�s� �:+ ý,. lmn�� �#$�  ³� � �c� �­>

? 0F �#$� � �c�,c � 100£ �c >F� IJ# lm

n��4�� +/�à >ç ��� �c- �cM N 5Ô ý,. �

� superconductor- �F�_ ÿR� 3� 4rý ��� ��� /

0� Dc ��à Ë@� ��_ �� k',[35]. Gadolinium

acetate(GdAc)- dimethyl sulfoxide(DMSO)# Z? ; CO2# �ñ�

ÿR#$ DMSO/V#$ GdAc� Dc 20, 200 6s� 350 mg/ml

� =W 4rý ��� ��� Fig. 11� 12# *~� ��� ËR,.

�­>�_ Dc `� =W#� ��k� ?¤k� �+ 0>+ <

=�� êB# VW �Ô �f�,. +7� =W#� %4r+ ��4

r# Ûc>? ìM� �Ô k� ��= �� VW �� yz��

�f@Ô ý,. /0� Dc Ë@à 0> <=�;� l�# ���

doVργ

------------- deformation forcereformation force----------------------------------------------=

Fig. 9. SAS/GAS process diagram.

Fig. 10. ASES process diagram. Fig. 11. PSD of GdAc powders precipitated from DMSO.

HWAHAK KONGHAK Vol. 41, No. 6, December, 2003

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684 � � �

ione,

?¤+ +}f@Ô k� % 4r�,� ��� r:+ Ûc>? ìM

� �Ô kf ��=+ �� ��= ��c Ò �� �f@Ô ý,.

Z7 @ ,ç Û:� 3� ���@A ��>�_ GAS4��,

� ASES4�+ � yz� ��- �� N 5� ��_ kf5,

[36](Fig. 13).

SEDS(solution enhanced dispersion by supercritical fluids) 4� (Fig.

14)� co-axial 8G� ñ/�� IJ# ASES 4�#$ lmn��

/0� �n>�_ � ¥Ê� �� cbÛ� ìM(spray enhancer)+

Qý,. ��� lmn�� /0� �Ô ��$ yz� 0>� A

Lf Ûà *8 ��- 4r�� å cz+ ý,[37-40]. @�¬@ ®ø

ý �� ���à RDX, HMX, NTO, Nitroguanidineb �� P�,

ALAFF, Dextran, HYAFF-7, HPMA, HYAFF-11, PLA, Polycaprolactone,

Poly(methacrylatedsebacicanhydride), Polystyreneb �� ��� 5�

ò, Barium Chloride, Ammonium Chloride, Buckminster- fullerene,

Bronze Red, Cobaltousnitrate, Hydroquinone, Nickel Chloride, Red Lake

C, Yellow 1, Samariumacetate, Silver nitrate, Yttriumacetate, Zinc acetate

"� �� p�, ���6 + 5�, Acetaminophen, Albumin, 7-

aminocephalosporanicacid, Amoxicillin, Antibody Fabfragment, Antibody

Fvfragment, Ascorbic acid, β-carotene, Catalase, Chloramphenicol, p- HBA,

Hydrocortisoneacetate, Insulin, Lecithin, Lysozyme, Maltose, Mefenamicacid,

Methylprednisolone, Myoglobin, Naproxen, Nicotinic acid, Phospholipids,

PlasmidDNA pSVbwith no protectant, PlasmidDNA pSVbwith protectant,

Prednisoloneacetate, RhDNase, Salbutamol, Salmeterolxinafoate, Sodium

cromoglicate, Sucrose, Tetracycline, Trehalose, Trypsin, Calcitonin+HYAFF,

Chloramphenicoland urea, GMCSF+HYAFF, p-HBA+PLGA, p-HBA+PLA,

Insulin+HYAFF, Insulin-lauricacid conjugate+PLA, Insulin+PLA, Lysozyme

+PLA, Naproxen+PLA, PLA+clonidineHCl, PLA+hyoscine "� ��

� L+ GAS/SAS/ASES/SEDS "� �9�_ ��k',[20].

3-3. PGSS(particles from gas-saturated solutions)

PGSS4�(Fig. 15)� lmn�� 0�* ��# # ZvLf�

�� +/� 4��_ /�0 �� «�/0# lmn��- ZZ$

Ç-��/0/«�0� A� ; 8G� É�Z <=¥Êõ_$ ��/V

O� ��* 0>� A¶� �9+,. ¥ÇÈ# ôx$ Àx@@A

yz�� �� yz 0>+ �fR,. + 4�#$� Ü@�* % ³

+ lmn��# Zv�A �� �� vw@A lmn��� 0F# V

W # Zv� �,. �B ���� + �o(- � 10-40 wt%¬@ �

N�� ���� Z�¼+* �s2+Ec- 10-50oC ¬@ ��¥Ê

õ_ �s�Ô >/M N 5�ò �6� yz��- ���� å#c

�/ý,. PGSS4�� lmn��� ñ/·+ >,� :¼+ 5,. @

�¬@ PGSS �9�_ ��ý ��_� Adhesives, Benzoicacid,

Glucose, Glycerides, Metal oxides, Phosphors(Y2O3: Eu), Plastic additives,

Polyethyleneglycol "� �� p�, ���6 , Albuterolsulfate, Alkaline

phosphatase, Cromolynsodium, DL-alanine, Glucose oxidase, Glutath

Fig. 12. A SEM image of micronized GdAc at 150 bar, 40 C (a) 20 mg/ml DMSO (b) 200 mg/ml DMSO. (c) 350 mg/ml DMSO.

Fig. 13. Examples of the morphology of p-hydroxy benzoic acid (p-HBA) precipitated by (a) solvent evaporation at RTP (scale: 25 m), (b) the GASprocess (scale: 25 m) and, (c) ASES process (scale: 25 m).

Fig. 14. SEDS process diagram.

���� �41� �6� 2003� 12�

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����� �� � �� 685

Horseradish peroxidase, Na2Fe(DTPA), Nifedipine, RhDNase, Tobramycin

�� �  "+ 5,[41-46].

3-5. DELOS(depressurization of expanded liquid organic solution)

Fig. 16#� DELOS 4�� <n� <��� *~�',. DELOS

4�#$� 3�� ¥Ê�� �� /³� ����#$ ��/V# /

�¥Ê� ��� /�# df�,. + �o(- ��/�# c��Z

0�- /� � <=¥: ; <=ý 0� /0� gh- É�Z >F

Ô £¤¥b �ù� ����_ ÷f|sà /0� Ec ¡U¢ `

v@à$ ��� FG >FÔ R�kf yz��- ��,[47, 48].

3-6. RPSS(reactive precipitation in supercritical solution)

�� lmnN- antisolvent_ +/�Z �� � � *8��- �

��� �� =W#� antisolvent#$ ­�� ê¥# 12+ �f�,.

RPSS(Fig. 17)#$� 0F�  # ­� (precursor)+ Zv ­�� �

_ c�k� ­�); 4r + lmnN# Z@ ×� ?¤k�* n

� ­��Z �[ �� � _ k� +�+ antisolvent? lmnN#

$ ?¤kf 3�� +}fR,. N/r ��X�  �#$ S�à

N�­�+ �f* ��N �  [M(OH)x]� 4r�,. ��N � 

� �� Ec#$ �N ­�+ �f* �� � ��L� 4r�,.

Hydrolysis (����) Dehydration (����)M(NO3)2 ��������� M(OH)2 ������� ��� MO2

RPSS )� �B_$ lmnN#$ �� � � ���� 4�� �

� ê���� Adschirib Arai 6�#$ �k �®�Z hydrothermal

synthesis in supercritical water x� �s� 5,[49, 50]. lmnN�

`� +E�s FNuA vwx `� �2FN- @� 5f lmn

FG#$ ��/V* ��# �� �� a6r� �+� �Cr /V

�� �ê�� ­à, `� +E�sFN IJ# p�/V# ��$�

`� /�ù� *~�,. �� � � VW `� /�ù�_ ?�Z

lmnN#$ 4rý �� � � VW �� ���c- �c�Ô k

� VW �� �� 4rý,. lmn��- +/�Z 3�r:� �

� =W#� 0�F#$�, lmn�� F#$� `� ¼c, �� �

r IJ# solid-fluid interface#$ /³+ Ãa>�_ 2Àkf >

ç 3�r:�cb ��f س� micro-structure �� single crystal

��- H� �,(Fig. 18). + 4�#$� ;S�s 4�� �Y@

×� 3�r+ Ø�� ��- 4rM N 5,� :¼� @� 5,.

@�¬@ PGSS �9 )#$ lmn |� NS6r9� É�$ ��

c �r��V�? Barium Hexaferrite(BaFe12O19)b NixZn1-xFe2O3, -

��, gas sensors, varistors, transducers# ñ/k� Zinc Oxide(ZnO),

CMP(Chemical Mechanical Polishing)��_ ñ/k� Cerium Oxide

(CeO2), 2���b ��V��? Titanium Oxide(TiO2) 6s� s�+E2

@� ØC��? Lithium Cobalt oxide(LiCoO2), Lithium Manganese

oxide(LiMn2O4) "� �� �� � � 6r+ |jk',[51](Fig. 19).

�#� lmn�»�#$ �� � � ��- 6r�� 4�+ h

�Ô (�k� 5,. + 4�#$� lmnN �ß# lmn vo�, #

o� "� �� �»�� ñ/�� ��_ ��� �� u vwx eF

"c �.+ H� ��_ ��,.

4. ��� ���� ��

�|� �,� �� Ü£|�x� *8��# w»�+x� � �

»7¥b$ ?�_ :  sÔ 2À�� ¡< ��+,. Ü£|��

�R, ¢, B� "� j�kò ��r�  ³+ |(�� ��#$ ®4

� ��, �[2 |( (CO), ��, N� "� 2��� ��_$ ���

0.1-1µm+ �B�+,.  E w»� +Ð#c ~F, £®r nitrosamines,

£®r aldehyde, hydrogen cyanide "+ �qr �6 + �2kf 5

,. � J�� Ü£|�- Þÿ I w»� 0.1-0.2 mg(� �� æ 2 mg)

+ ?�# �Ný,. Ï_ ��� Ü£|� �� w»�+ ¤# cÀ�

Ñà � 10l �c Ö±,� �,. A�# Ü£- ¿W� ¥� ñ¦#

Fig. 15. PGSS process diagram.

Fig. 16. Different steps in DELOS process (1) A liquid solution of thecompound to be crystallised is added to the autoclave. (2) Addi-tion of CO2 produces a new expanded liquid solution which fillsall the autoclave volume at a given pressure, PW, temperature,TW, giving rise to a solution with a molar fraction of CO2 of XW.(3) Depressurization of the expanded liquid solution through a valveleading to precipitation of monodispersed nano- or micron-sizedparticles.

Fig. 17. RPSS equipment concept.

HWAHAK KONGHAK Vol. 41, No. 6, December, 2003

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ALf$ ���Ô �$ Ï_ 2À�à r� ¹�� ¥;# ���

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j3�- V¹�_ � ¡< � 2À¥ÇÈ(drug delivery system: DDS)

+ �®kf y\#� r�L+ Ûñ- è� �É#$ ºf» ��_

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s� Nektar Therapeuticsñ Ãù�_ �®kf +y 2 zn>�_

2,000· +F� 澿 r�#Ô 5� +F mFÿR(Phase III)+ [�

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�; ���� =W# Ï �O�  F+ 5�* Ï� �Nù� *ÇÔ

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x� �Ésv- Y��� Â� |j ¥�k'�ò 1997�# FDA�

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_ 1998�# �k�_ �®k',. mFÿR 3�#$ TOBI� � {�

Ø� B2�Ô 2ÀM N 5�ò �¹�� ÒNb ¥;� Óf],[52].

+ þ#c �Û� Eiffel Technologiesñ� y�� BattellePharmab Ã

ù�Z lmn����_ ¶�Y��- �®�� 5,.

5. !

lmn��- +/� *8�� ��� � ��# ��k@ ×�

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���, _Õ/ ��QR� *8��, Öx$á/ ��� *8��

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� " �×Â� ��#$ |j �®k� 5,. + þ#c lmnFG�

Fig. 18. Impurity concentration in the solid-liquid(fluid) interface dur-ing crystal growth.

Fig. 19. Metal oxides synthesis in supercritical water.���

�(a) BaO · Fe2O3, (b) ZnO, (c) CeO2, (d) TiO2, (e) LiCoO2, (f) LiMn 2O4, (g) CuO, (h) NixZn1-xFe2O3.

���� �41� �6� 2003� 12�

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/ CeO2, magnetic recording media/ ferrites(BaOØ6Fe2O3), NixZn1-x ·

Fe2O3), 2̧ 2@ ØC ³? LiCoO2, LiMn2O4, �:�/ ZnO, �V/

TiO2, CuO, Co3O4, MLCC/ BaTiO3 "+ 5,. lmn����_ *

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$%&'

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nute Solids,” the AIChE Annual Meeting, San Francisco(1984).

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3. Hanney, J. B. and Hogarht, J., “On the Solubility of Solids in Gases,”

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micrometer-Sized Biodegradable Particles of Poly(L-Lactic Acid)

via the Gas Antisolvent Spray Precipitation Process,” Biotechnol. Prog.,

9, 429-435(1993).

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Transfer and Chemical Reactions,” Chem. Rev., 99(2), 355-389(1999).

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Fluids,” Chem. Rev., 99(2), 391-418(1999).

11. Johannsen, M. and Brunner, G., “Solubilities of Fat-Soluble Vitamins

A, D, E and K in Supercritical Carbon Dioxide,” J. Chem. Eng. Data,

42, 106-111(1997).

12. Chrastil, J., “Solubility of Solids and Liquids in Supercritical Gases,”

J. Phys. Chem., 86, 3016-3021(1982).

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Pronciples and Practice, 2nd Ed. Butterworth-Heinemann, Boston,

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