Ind. Eng. Chem. Res. 1992,31, 2339-2345 Synthetic Polymers; Glass, J. E., Swift, G., Eds.; ACS Syposium Series 433; American Chemical Society: Washington, DC, 1990; pp 65-75. Griffin, G. J. L. Biodegradable fillers in thermoplastic. Adv. Chem. Ser. 1974,134, 156-170. Griffin, G. J. L. Biodegradable synthetic resin sheet material containing starch and a fatty acid material. U.S. Patent 4016 117, 1977a. Griffin, G. J. L. Synthetic resin sheet material. U.S.Patent 4021 388, 1977b. Griffin, G. J. L. Degradable plastics. U.S.Patent 4983 651, 1991. Holmstrom, A,; Sorvik, E. M. Thermooxidative degradation of polyethylene. J. Polym. Sci. 1978, 16, 2555-2586. Iannotti, E.; Fair, N.; Tempesta, M.; Neibling, H.; Hsieh, F. H.; Mueller, R. Studies on the Environmental Degradation of Starch-Based Plastics. In Degradable Materials: Perspectives, Issues and Opportunities; Barenberg, S . A., Brash, J. L., Narayan, R., Redpath, A. E., Eds.; The First International Scientific Consensus Workship; CRC: Boca Raton, FL, 1990. Iring, M.; Tudos, F. Thermal oxidation of polyethylene and polypropylene. Prog. Polym. Sci. 1990, 15, 217-262. Jasse, B. In Food Packaging and Preservation; Mathlouthi, M., Ed.; Elsevier: London, 1986; Chapter 15. Lee, B.; Pometto, A. L.; Fratzke, A. R.; Bailey, T. B. Biodegradation of degradable plastic polyethylene by Phanerochaete and Streptomyces species. Appl. Environ. Microbiol. 1991, 57, 678-685. Maddever, W. J.; Campbell, P. D. Modified Starch Based Environmentally Degradable Plastics. In Degradable Materials: Perpectives, Issues and Opportunities; Barenberg, S . A,, Brash, J. L., Narayan, R., Redpath, A. E., Eds.; The First International Scientific Consensus Workshop; CRC: Boca Raton, FL, 1990.
2339
Nelson, N. A photometric adaptation of the Somogyi method for the determination of glucose. J. Biol. Chem. 1944, 153, 375-380. Otey, F. H.; Westhoff, R. P.; Russell, C. R. Biodegradable films from starch and ethylene-acrylic acid copolymer. Ind. Eng. Chem. Prod. Res. Dev. 1977, 16, 305-308. Otey, F. H.; Westhoff, R. P.; Doane, W. M. Starch-based blown films. Ind. Eng. Chem. Prod. Res. Dev. 1980,19,592-595. Otey, F. H.; Westhoff, R. P.; Doane, W. M. Starch-based blown films. 2. Znd. Eng. Chem. Res. 1987,26, 1659-1663. Peanasky, J. S.;Long, J. M.; Wool, R. P. Percolation effects in degradable polyethylene-starch blends. J. Polym. Sci., Polym. Phys. 1991,29, 565-579. Swanson, C. L.; Westhoff, R. P.; Doane, W. P. Modified starches in plastic films. In Proceedings of the Corn Utilization Conference ZI, Columbus, OH; National Corn Growers Association: St. Louis, MO, 1988. Swinkels, J. J. M. Sources of starch, its chemistry and physics. In Starch Conversion Technology; Van Beynum, G . M. A., Roels, J. A., Eds.; Marcel Dekker: New York, 1985. Wool, R. P.; Cole, M. A. Microbial degradation. In Engineering Materials Handbook; ASM International: Metals Park, OH, 1988; Vol. 2, pp 783-787. Wool, R. P.; Peanasky, J. M.; Long, J. M.; Goheen, S. M. Degradation mechanisms in polyethylene-starch blends. In Degradable Materials: Perspectives, Issues and Opportunities; Barenberg, S . A,, Brash, J. L., Naraym, R., Redpath, A. E., Eds.; The First International Scientific Consensus Workship; CRC Boca Raton, FL, 1990.
Received for review February 25, 1992 Accepted June 1, 1992
Drug Release Profiles in the Shrinking Process of Thermoresponsive Poly(N-isopropylacrylamide-co-alkyl methacrylate) Gels Ryo Yoshida and Kiyotaka Sakai Department of Chemical Engineering, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169, Japan
Teruo Okano* and Yasuhisa Sakurai Institute of Biomedical Engineering, Tokyo Women’s Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162, Japan
Thermoresponsive poly (N-isopropylacrylamide-co-alkyl methacrylate) gels are capable of ”on-off“ regulation of drug release in response to external temperature changes because a gel surface skin formed with increasing temperature stops drug release from the gel interior. In this gel shrinking process, observation of bubble formation on the surface indicates that pressure is induced within the gel. This pressure may result in an outward convection of water. Drug must therefore be released not only by diffusion but also by convective transport. We have created a drug release model for this shrinking process using a tortuous pore model and simulated four decreasing patterns of release rate for different induction patterns of pressure. Experiments using indomethacin could match simulated release patterns by changing the chemical structure of polymer and thermal gradient. These changes induce different pressure fluctuations within gels and affect the release pattern from the gel “on” state to the “off“ state.
Introduction Recently, physiologically active therapeutic peptides have been artificially produced with genetic engineering techniques. These peptides are easily decomposed under physiological conditions and encounter absorption problems due to their high molecular weight. Hence, they cannot be utilized effectively in conventional dosage forms. Control of drug release rates in response to external stimuli would provide optimal therapeutic efficacy for such drugs having short pharmacologicql half-lives. Appropriate amounts of drug would be dosed via stimulus supplied exterior to the body only when drug is required. Such a system may lead to avoidance of drug tolerance by dosing
* To whom correspondence should be addressed.
in pulses, or achievement of an intelligent drug delivery system in which drug itself senses the signal caused from disease, judges the magnitude of signal, and then acta to release drug in direct response. To realize such modulated drug release system, polymer materials which change their structure and function in response to environmental change are attractive. Recently, temporal control of drug release has been attempted using stimuli-responsive polymers in response to specific chemical agents (Ishihara et al., 1984; Heller, 1988; Ito et al., 1989; Kitano et al., 1991), pH changes (Siegel, 1990,Dong and Hoffman, 1991), and electric fields (Sawahata et al., 1990; Kwon et al., 1990).
We have developed cross-linked poly(N-isopropylacrylamide) (PIPAAm)as a material for an intelligent drug delivery system responding to temperature. PIPAAm
0888-5885f 92f 2631-2339$03.00 f 0 0 1992 American Chemical Society
2340 Ind. Eng. Cham. Res., Val. 31, No. 10,1992
demonstrates a lower critical solution temperature (LCST) in aqueous solution and its networks show high swelling thermwnsitivity in water. The thermoaensitivity has been investigated by swelling measurements and characterization using differential scanning calorimetry (DSC) (Bae et al., 1990,1991). PIF'AAm gels shrink in water at higher temperatures and demonstrate a sharp swelling transition in the vicinity of 32 "C. Below this temperature, the gels swell with decreasing temperature. We have prepared mawlinked monolithic gel devices in which indomethacin was uniformly dispersed using copolymers of IPAAm with alkyl methacylates (RMA). Using these devices, we have achieved complete "on-off" regulation of drug release in response to stepwise temperature changes between 20 and 30 OC (Bae et al., 1987; Okano et al., 1990a,b). Release patterns at low temperature (the "onn state) have been analyzed using a two-layer model we have recently created (Yoshida et al., 1991a). The 'on-aff' switching mechanism has been clarified in terms of a dense skin layer formed on the surface of the gel with shrinking upon increasing temperature. This surface skin layer stops drug release from inside the polymer matrix. The surface skin layer has been directly observed by optical and yanning electron microscopy (Okano et al., 199Oa; Yoshida et al., 1992). After polymer skin formation, gel bubbles form on the device surface because the skin layer preventa the subsequent outflow of water and internal pressure to expel water is exerted on the surface from the inside after shrinking (Okano et al., 1990a). It is proposed, therefore, that hydrodynamic pressure is induced within the gel in the process of shrinking. This internal pressure may induce the outward convection of water. In the 'on" state, drug is released through the surface by diffusion through the hydrated gel matrix. However, in the transitional process from the "onn state to the "off" state, upon increasing temperature, drug must be released not only by diffusion but also by convective transport. In this study, we have developed a drug release model for the shrinking process using a tortuous pore model (Sakai et al., 1987) for solute transport a m m a membrane. Four decreasing drug release rate patterns were simulated from the model for different pressure induction patterns. From measurements of swelling-deswelling kinetics and optical transmittance changes of gels in response to stepwise temperature changes, we have suggested that surface skin layer formation process is controlled experimentally hy changing the alkyl side chain length of alkyl methacrylate comonomers (Yoshida et al., 1991b, 1992). Such changes in the dynamic processes of skin formation may affect the induction pattern of pressure within the shrinking gel. To experimentally realize the induction pattern of pressure assumed in our release simulations, we changed both the gel chemical structure and temperature differences. Release rates of indomethacin from the poly(1PAAm-coRMA) gels after increasing temperature were continuody monitored using a flow cell system and compared with simulations. Effecta of the dynamic skin formation processes on decreasing drug release rate patterns have been rationalized in terms of changing the copolymer alkyl side chain lengths and the temperature difference between the gel "on" and the "off" state. Theory The shrinking process of PJPAAm gel in water from the swollen state has been investigated in detail (Sato Matauo and Tanaka, 1988; Okano et al., 1990a). When temperature is increased from the swelling temperature to the shrinking temperature, the outermost surface of the gel exposed to warmer water immediately shrinks to form a
(1) Swollen stale
Polymer matrix
Solvent
!Hi1 irpl
-
Solute flux, Jsr (only dinusion)
Distance into polymer (2) Shrinking process
High I" pressure
-
(diffusion + convection) ?X
(3) Shrunken state (Skin formation)
H2rpt-
--.
Surface skin layer
Figure 1. Drug release model in the process of polymeric gel skin formation.
denser surface layer than bulk matrix. This layer on the surface of PIF'AAm gel is often dense enough to retard the following outflow of water from the inside, preventing the gel from further shrinking, and stopping the shrinking proceaa for a certain time period. After thisperiod, bubbles are formed on the surface due to irregular shrinking, breaking the continuity of the skin layer. Water is then released through these bubbles, and the gel subsequently shrinks very slowly. In the case of gel disks (15-mm diameter, 0.5-mmthickness) 2 or 3 months are required to reach equilibrium states at 30 OC from an equilibrium swollen state at 20 O C . Drug release from the gel is stopped by the dense skin layer formed on the surface immediately after increasing temperature. This mechanism results in quick 'on-off" response, although more than 1month is needed to reach the equilibrium shrunken state. Since drug is not released from the gel after skin formation, structural changes inside the gel after skin formation would not affect the release pattern. Consequently, only shrinking processes prior to skin formation affect the release pattern in the switching process from the *on" state to the "off" state. Shrinking processes prior to skin formation may be approximated as shown in Figure 1. The dense skin layer (AX thickness) is finally formed on the gel surface. An imaginarJr layer having the m e thicknes is considered on the surface in a swollen state. Thii layer decreases its water content (pore radius) as the gel shrinks. Actually, the water content in the surface layer must change continuously because gel shrinks successively with distance from the surface. However, if the layer is considered as a composite membrane consisting of several layers in series having different water contents (permeabilities), it would be mathematically reasonable to consider the layer as a homogeneous membrane having one average water content (and permeability). Thus, the water content in the surface layer is considered to be uniform in this model. Drug is assumed to be released from inside the polymer matrix through this surface membrane. In a swollen state, drug is released only by diffusion. In the shrinking process, however, the internal pressure induced by shrinking results in outward convection of water
Ind. Eng. Chem. Res., Vol. 31, No. 10, 1992 2341 through the membrane and then drug is released by diffusive and convective transport. After skin formation, the convective transport stops because the volume of gel remains temporarily constant. The balance between diffusive and convective transport must affect the drug release pattern in the switching process from the "on" state to the "off" state. According to a tortuous pore model (Sakai et al., 1987) developed from the pore model (Verniory et al., 1973), solute flux through a membrane (drug release rate in this case) is as follows:
Perlstaltlcpump
uv
detector
Flow cell (cell volume : 2.4 ml ) Dru loaded pol mer ( Reyeafa devlcsr
Recorder Thermostated
H
Graduated cyllnder
Flow rate : 1.O ml / mln
Figure 2. Schematic of the monitoring system for direct release rate measurements.
where
SD = (1- q ) 2 S* = 2(1 - q ) 2 - (1 - q ) 4 f(q) =
1 - 2.lq
+ 2.1q3 - 1.7q5+ 0.73q6 1 - 0.76q5
Q = rs/r, J, = L , ( P - UAT)
(2)
ulated against dimensionless time, t/r, for various changes
(3)
in A€?
(4)
(6) (7)
In this model, osmotic pressure, AT, is omitted because of high hydrophobicity of drug. From the Hagen-Poiseuille law, pure water permeability can be expressed as
It is both theoretically and experimentally shown that the gel size decreases exponentially under shrinking until skin formation is attained (Tanaka and Fillmore, 1979; Sato Matsuo and Tanaka, 1988). Therefore, decreases in water content are approximated by H-H2 = ex.( - i) HI - H2 7 Actually, our experimental data in initial stage of deswelling process was explained by eq 9. Water content, H, can be expressed by H = n?rrprp2 (10) In both swollen and shrunken states, drug is released only by diffusion because no volume changes (no water convection) are observed. Release rates at these states are expressed only by the diffusive term in eq 1:
where rpl and rp2express pore radius within the surface layer at a swollen state and shrunken state, respectively. The time course of normalized release rate, (J, - J u 2 ) / ( J , 1 - Js2),with shrinking can be calculated from eq 1 to 12. Dimensionless transmembrane pressure hp (=r,224Pr/ (8pD)) was arbitrarily changed as a function of time. - Js2),were simNormalized release rates, (J, - Ju2)/(Js1
Experimental Section Synthesis of Cross-Linked Poly(1PAAm-co-RMA). Cross-linked random copolymers of N-isopropylacrylamide (IPAAm) (Eastman Kodak Co., Rochester, NY)with alkyl methacrylate (RMA) (5 w t % in feed composition) were synthesized using ethylene glycol dimethacrylate (EGDMA) (Nakarai Chemicals Ltd., Kyoto) as a crosslinker (1mol %), tert-butylperoctanoate (BPO) (Nippon Oil and Fats Co., Ltd., Tsukuba, Japan) as an initiator, and distilled l,li-dioxane (KantoChemical Co., Inc., Tokyo) as a diluent. Butyl methacrylate (BMA), hexyl methacrylate (HMA), and lauryl methacrylate (LMA) were used as RMA monomers (Tokyo Kasei Kogyo Co., Ltd., Tokyo). Monomer solution was bubbled with dried nitrogen for 15 min and injected between two Mylar sheets separated by a Teflon gasket (0.5 mm) and backed by glass plates. The solution was polymerized at 80 O C for 18 h. After cooling to room temperature, the membrane was separated from the Mylar sheets and immersed in 100% methanol for 1 week to remove all unreacted water-insoluble compounds. The methanol was changed every other day. The membranes were then soaked in 75/25, 50150, and 25/75 vol/vol 70 methanol/distilled water mixtures for 1 day each. The fiial washing was in pure distilled water for 1 day. Swollen membranes were cut into disks (15-mm diameter) using a cork borer and dried ambiently for 1day and under vacuum for 3 days at room temperature. Drug Loading. Dried disks were equilibrated for 3 days in solutions of indomethacin (Sigma Chemical Co., St. Louis) in ethanol-water mixture (80:20, vol %/vol %). The swollen disks were dried under vacuum for 1day at -20 "C and for 3 days at room temperature to prevent drug migration to the surface with evaporation of the solvent. Usually the loaded drug is liable to move to the surface side in the process of drying. This migration of drug, however, was prevented by reducing temperature under -20 "C in the process of vacuum. Release Experiments. Figure 2 shows the monitoring system for direct measurement of drug release rate using a flow cell. Phosphate buffered saline (PBS, pH 7.4) was supplied with a peristaltic pump (1.0 mL/min) to the flow cell (volume 2.4 mL) in which the release device was fixed. The effluent was introduced to the single path UV detector (266 nm, Model 875-UV, Japan Spectroscopic Co., Ltd., Tokyo). Release rate of indomethacin from copolymer gel was continuously monitored in response to stepwise temperature changes. The lag time of this system was 2 min with this flow rate.
2342 Ind. Eng. Chem. Res., Vol. 31, No. 10, 1992
-
I
I
OFF
ON
I 0
1
2
Time, t l r
3
4
5
0
2
1
[-I
3
Time, t I T
Figure 3. Simulation of drug release rate during the transition state from the 'onn state to the "off" state for AP = 0 (ql = 0.1,q2 = 0.5). 2.0
5
Figure 6. Simulation of drug release rate during the transition state from the "on" state to the 'off" state for linear and pulsatile induction of AP ( Q =~ 0.1,Q~ = 0.5).
'5 . .
I
4
[-I
a
2 [
l
.
al I
z
\
20°C
I
25°C
Poly(lPAAm-co-HMA)
Y)
x 9
l -
E
u.u
0
1
2
3
4
5 I
Time, t / 7 [-]
0
Figure 4. Simulation of drug release rate during the transition state from the "on" state to the "off" state for linear increase in AP (ql = 0.1,42 = 0.5).
- , .L
tG z .
1.5
I j OFF
1.0
h
I 7 h
z
0
2
0.5
I
0
d
0.0 0
1
2
3
4
5
Time, t / T [-]
Figure 5. Simulation of drug release rate during the transition state from the "on* atate to the "off" state for pulsatile induction of AP (ql = 0.1,q2 = 0.5).
Results and Discussion Induction patterns of hydrostatic pressure with shrinking may affect the balance between diffusive and convective transport. The effect has been theoretically investigated by the model. Figures 3-6 show the decreasing pattern of drug release rate simulated from the tortuous pore model for various induction patterns of transmembrane pressure, AP. Figure 3 demonstrates the release pattern in the case that AP is assumed to be zero throughout the shrinking process. AP = 0 means that convective transport does not occur. The release rate then decreases monotonically from the "on" state (release rate = 1) to the "off" state (release rate = 0). When AP is
5
10
15
20
Time [min.]
Figure 7. Release rate of indomethacin from poly(IPAAm-co-HMA) gel during the transition state from the 'on" state (20 "C)to the 'off" state (25 "C).
assumed to increase linearly after switching from the "on" state to the "off" state (Figure 41, the release rate increases, demonstrating a sharp peak immediately after the switching because convective transport largely serves to increase the release rate. After showing a sharp peak,the release rate decreases to the "off" state. In the case of pulsatile induction of bp after a certain period,the release rate decreases at first and then shows a sharp peak with a lag time (Figure 5 ) . By adding a linear increase of AP immediately after the switching to the pulsatile induction, the release pattern resulta show two sharp peaks as in Figure 6. These four decreasing patterns of release rate were simulated from calculations using the model equations for various induction patterns of transmembrane pressure during the shrinking process. To realize these induction patterns for AP experimentally in our devices, the chemical structures of the polymer gels and applied temperature difference were changed. Figure 7 shows the decreasing patterns of indomethacin release from poly(1PAAm-co-HMA)gel after stepwise increase in temperature from 20 to 25 "C. From swellingdeswelling kinetics and turbidity measurements for gels having different chemical structures, we have suggested that copolymers with HMA or LMA quickly formed thinner and denser skin layers on the surface with shrinking compared to copolymers with BMA (Yoehida et al., 1991b, 1992; Okano et al., 1991). Rapid formation of thin, dense skin layers leads to small volume changes. Figure 8 shows volume changes of the gels with shrinking after increasingtemperature. Poly(IPAAm-co-HMA) gel shrunk about 5 % in response to temperature changea from
Ind. Eng. Chem. Res., Vol. 31, No. 10, 1992 2343 I
2 ,
Poly(lPAAm-cc-BMA) 20%
j
25%
I
..e
x
u
-s 0 1 0
B
I
io
0
30
20
0
60
Time [min.]
0
0 :POly(lPAAmcoBMA) ;20% --C 25°C A :Poly(1PAAmcoHMA) ;20% --C 25% A :Pog(lPAAm-mLMA) ;10°C --C30°C 0 :Poly(lPAAm-M-BMA) ;10°C --c30%
15
20
Figure 10. Release rate of indomethacin from poly(IPAAm-coBMA) gel during the tramition state from the "on" state (20 'C) to the "off state (25 "C).
Volume changes of poly(PAAm-co-RMA) gels &r increase in temperature.
Figure 8.
step*
io
5
Time [min.]
Volume change
Accumulallon
3 T
._
E . . 0 2 0
1O'Cj
30°C
Poly(lPAAm.co.BMA)
.
I
0 r
Release by dlffuslon
x
s e
1
1. Squeezing lmm
2. Rapid release wlth
water cO""ectl0" (second peak)
i
-e
QN
! I
QE
0 60 0
5
10
15
20
25
30
e I Hlgh
LOW
Time [min.]
-
Figure 9. Rslaese rate of indomethacin from poly(IF'Mm-co-BMA) gel during the transition state from the "on" state (10'C) to the "OF state (30 "C).
20 to 25 OC. Such a small volume change results in suppression of convectivetransport with shrinking. Consequently the release rate decreased monotonically as shown in Figure 3, simulated from the model for AP = 0 (no convection). Release pattern from poly(IPAAm-co-BMA) showed a sharp peak immediatsly after increasing temperature from 10 to 30 "C (Figure 9). Large temperature changes and thick skin formation of gel led to large volume changes with shrinking as shown in Figure 8. This large volume change must have induced a transmembrane pressure gradient (or convection) immediitely after increasingtemperature and resulted in the same pattern as Figure 4, simulated for a hem increase in AP. For the m e poly(IPAAm-eo-BMA) gel, however, release patterns showed a sharp peak with a lag time similar to Figure 5 when temperature was increased from 20 to 25 O C (Figure 10). In this case, skin layers formed on the surface must be thinner and weaker because the volume change is smaller as shown in Figure 8. After a skin layer grows to a critical density, the layer acta to prevent the outflow of water. This results in accumulation of pressure within the gel which increases with t i e . In this case of a weaker skin layer, bursts of water convection must occur to cause rapid drug release when the skin layer cannot further withstand the accumulated pressure (Figure 11). Such induction of rapid convection after a certain period gave the same release pattern as
m e
Figure 11. Mechanism of gel shrinking to yield a sharp pssk with a lag time hy accumulation of internally hydmatatic pressure. 2 1
0 1
0
i
I
'
I
60 0
5
10
15
20
25
30
35
40
Time [min.] Figure 12.
Release rate of indomethacin from poly(PAAm-co-
LMA) gel during the transition state from the "on" state (IO 'C) to the 'off state (30 "C).
shown in Figure 5, simulated for puleatile induction of AF' after a certain period. Figure 12 shows the release pattern from poly(PAAmCO-LMA)gel after a temperature change from 10 to 30 OC. Two peaks were observed during the decreasing process
2344 Ind. Eng. Chem. Res., Vol. 31, No. 10,1992 1
I
3 $
E
1
0 1
0
2
3
4
5
Time, t I T [-I Figure 13. Simulation of drug release rate during the transition state from the 'on" state to the 'off" state for induction of AP in several pulses (ql = 0.1,q2 = 0.5).
'S
1.0 . .
Poly(lPAAm-co-BMA)
01 01
0.5
Nomenclature Ak = surface porosity C, = solute concentration, kg/m3 D = diffusivity in free water, m2f s f(q) = wall correction factor for diffusion g(q) = wall correction factor for filtration H = water content HI= water content at swollen state Hz= water content at shrunken state J, = solute flux through a membrane, kg/(m2*e) J, = filtrate flux,m3/(m2.s) L, = pure water permeability, m3/(m2-s.Pa) n = number of pores per unit surface area, m-2 A P = transmembrane pressure, Pa AP = dimensionless transmembrane pressure 4 = rafrp 41 = raIrp1 42 = ralrpz
a 0.0
diffusive and convective transport were developed using the tortuous pore model. Four theoretical release patterns were simulated for various induction patterns of internal hydrodynamic pressure. These induction patterns were obtained experimentally by changing the chemical structures of the polymer gel and the applied temperature differences during transition. The same release patterns as these generated by simulations were observed. Shrinking and release stopping mechanisms for poly(IPAAm-co-RMA) gels were clarified.
1
0
I 60
0
5
10
15
20
25
30
Time [min.] Figure 14. Release rate of indomethacin from poly(1PAAm-coBMA) gel during the transition state from the "onwstate (20 "C) to the 'off" state (22"C).
of release rate similar to Figure 6. Large volume changes as shown in Figure 8 and thinner skin layers than that of poly(IPAAm-co-BMA) resulted in the first and the second peak, respectively. If pressure accumulations within the gel and subsequent burst convection are repeated during the shrinking process, the release rate would decrease in a pulsatile manner as shown in Figure 13, simulated from the model for hp induction in several pulses. The release pattern having three peaks was actually observed when temperature was changed from 20 to 22 OC for poly(IPAAm-co-BMA) gel (Figure 14). Rslease patterns showing more peaks would be poadble by increasing gel volume by using sphericalgels. This phenomenon would be availablefor syatems releasing drug in pulses automatically under constant temperature. Consequently,induction patterns of pressure arbitrarily assumed in the simulation can be achieved experimentally by changing the length of alkyl side chains of polymer conatituenta as well as the temperature difference between the 'on" state and the 'off" state. Such changes affect the generating mechanism of convective transport to yield sharp peaks in the release patterns during the switching process from the 'on" state to the "off" state.
Conclusions In "on-off" regulation of drug release using thermoresponsive poly(1PAAm-co-RMA) gels, pressure is induced within the gel during the shrinking process, causing outward water convection. This convection changes the decreasing pattern of drug release. Release models based on
rp = pore radius, m rpl = pore radius of surface skin layer at swollen state, m rp2 = pore radius of surface skin layer at shrunken state, m r, = Stokes radius of solute, m SD = steric hindrance factor for diffusion SF= steric hindrance factor for filtration AX = skin layer thickness, m
Greek Symbols = viscosity, Pa s AT = osmotic pressure, Pa u = reflection coefficient T, = tortuosity T = time constant of shrinking, s
p
Registry NO.Poly(PAAm-co-EGDMA-BMA), 111984-73-7; poly(IPAAm-co-EGDMA-HMA), 137197-34-3; pOly(IPAAm-CO-
EGDMA-LMA), 137197-35-4;indomethacin, 53-86-1.
Literature Cited Bae, Y. H.; Okano,T.; Hsu, R.; Kim, S. W. Thermo-Sensitive Polymers as On-Off Switches for Drug Release. Makromol. Chem., Rapid Commun.1987,8,481-485. Bae, Y. H.; Okano, T.; Kim, S. W. Temperature Dependence of Swelling of Croselinked Poly(N,N'-alkyl subtituted acrylamidea) in Water. J. Polym. Sei. B, Polym. Phys. 1990, 28, 923-936. Bae, Y.H.; Okano,T.; Kim, S. W. ' O n - W Thermocontrol of Solute Transport. I. Temperature Dependence of Swelling of N-Isopropylacrylamide Networks Modified with Hydrophobic Components in Water. Pharm. Res. 1991,8,531-537. Dong, L. C.; Hoffman, A. S. A Novel Approach for Preparation of pH-sensitive Hydrogels for Enteric Drug Delivery. J. Controlled Release 1991,15,141-152. Heller, J. Chemically Self-Regulated Drug Delivery Systems. J. Controlled Release 1988,8,111-125. Ishihara, K.; Muramoto, N.; Shinohara, I. Controlled Release of Organic Substances using Polymer Membranes with Responsive Function for Amino Compounds. J. Appl. Polym. Sei. 19M,29, 211-217. Ito, Y.;Casolaro, M.; Kono, K.; Imanishi, Y. An Insulin-Release System That Is Responsive to Glucose. J. Controlled Release 1989,IO, 195-203. Kitano, S.; Kataoka, K.; Koyama, Y.;Okano, T.; Sakurai, Y.Glucose-responsive Complex Formation Between Poly(viny1alcohol) and Poly(N-vinyl-2-pyrrolidone)with Pendant Phenylboronic
Ind. Eng. Chem. Res. 1992,31,2345-2362 Acid Moieties. Makromol. Chem., Rapid Commun. 1991, 12, 227-233. Kwon, I. C.; Bae, Y. H.; Okano, T.; Berner, B.; Kim, S. W. Stimuli Sensitive Polymers for Drug Delivery Systems. Makromol. Chem., Macromol. Symp. 1990,33,265-277. Okano, T.; Bae, Y. H.; Jacobs, H.; Kim, S. W. Thermally On-Off Switching Polymers for Drug Permeation and Release. J. Controlled Release 1990a,11, 255-265. Okano, T.; Bae, Y. H.; Kim, S. W. Temperature Responsive Controlled Drug Delivery. In Pulsed and Self-Regulated Drug Delivery; Kost, J., Ed.; CRC Press: Boca Raton, FL, 1990b;Chapter 2. Okano, T.; Yoshida, R.; Sakai, K.; Sakurai, Y. Thermo-Responsive Polymeric Hydrogels and Their Application to Pulsatile Drug Release. In Polymer Gelq DeRossi, D., Ed.; Plenum Press: New York, 1991;pp 299-308. Sakai, K.; Ozawa, K.; Mimura, R.; Ohashi, H. Comparison of Methods for Characterizing Microporous Membranes for Plasma Separation. J. Membr. Sci. 1987,32,3-17. Sato Matsuo, E.; Tanaka, T. Kinetics of Discontinuous VolumePhase Transition of Gels. J. Chem. Phys. 1988,89,1695-1703. Sawahata, K.; Hara, M.; Yasunaga, H.; Osada, Y. Electrically Controlled Drug Delivery System Using Polyelectrolyte Gels. J. Controlled Release 1990,14, 253-262.
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Siegel, R. A. pH-sensitive Gels: Swelling Equilibria, Kinetics, and Application for Drug Delivery. In Pulsed and Self-Regulated Drug Delivery; Kost, J., Ed.; CRC Press: Boca Raton, FL, 1990; Chapter 8. Tanaka, T.; Fillmore, D. J. Kinetics of Swelling of Gels. J. Chem. P h p . 1979, 70, 1214-1218. Verniory, A.; Du Bois, R.; Decoodt, P.; Gassee, J. P.; Lambert, P. P. Measurement of the Permeability of Biological Membranes. J. Gen. Physiol. 1973,62,489-507. Yoshida, R.; Sakai, K.; Okano, T.; Sakurai, Y. A New Model for Zero-Order Drug Release I. Hydrophobic Drug Release from Hydrophilic Polymeric Matrices. Polym. J. 1991a,23,1111-1121. Yoshida, R.; Sakai, K.; Okano, T.; Sakurai, Y.; Bae, Y. H.; Kim, S. W. Surface-Modulated Skin Layers of Thermal Responsive Hydrogels as "On-Off" Switches: I. Drug Release. J. Biomuter. Sci. Polymer Ed. 1991b,3,155-162. Yoshida, R.; Sakai, K.; Okaao, T.; Sakurai, Y. Surface-Modulated Skin Layers of Thermal Responsive Hydrogels as "On-Off" Switches: 11. Drug Permeation. J. Biomater. Sci. Polymer Ed. 1992,3,243-252. Received for review December 23, 1991 Revised manuscript received April 20, 1992 Accepted July 21, 1992
SEPARATIONS The Product Composition Regions of Single-Feed Azeotropic Distillation Columns 0. M. Wahnschafft,*it J. W. Koehler,' E. Blass,' and A. W. Westerberg? Engineering Design Research Center and Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213,a n d Lehrstuhl A f u r Verfahrenstechnik, Technical university of Munich, Arcisstrasse 21, 8000 Munich 2, Germany
This paper shows how the limiting operating conditions, total reflux and thermodynamicallyoptimum operation, can be used to determine the feasibility of a desired separation by continuous distillation. *To assess feasibility, so-called pinch point trajectories are established as the limits of separations achievable in each column section. These trajectories may be determined graphically using residue curve maps. The feasibility criterion is generalized to result in a method to establish the ranges of top and bottom product compositions achievable by a single-feed distillation column for a given ternary feed. One particularly interesting application is to reveal where and to what extent distillation boundaries for azeotropic mixtures, derived for total reflux, can be surpassed in columns operated at finite reflux ratios. We present a criterion to estimate the maximum reflux for such separations and illustrate process schemes that exploit the possibility of crossing of total reflux boundaries to separate azeotrope-forming mixtures. Finally, we demonstrate how intermediate heat exchangers can be used to improve separations of azeotropic mixtures across total reflux boundaries.
Introduction Due to the well-known advantages of continuous distillation processes, azeotropic and extractive distillation continue to be among the most frequently used methods for the separation of azeotropic and nonideal close boiling mixtures, a task quite common in industrial practice (e.g., Malesinski, 1965;Horsley, 1973). Although it is possible to separate certain azeotrope-forming mixtures of three or more componente in a simple sequence of distillation
* To whom correspondence should be addressed. t Engineering Design Research Center, Carnegie Mellon
University. Technical University of Munich.
*
columns without introducing another species into the system and without change of operating pressures, separation by distillation in general requires the addition of an entrainer species and a more complex process scheme with recycle(s). The role of the mass separating agent is normally to facilitate separation either through the introduction of a new, extreme b o i i g azeotrope, or through the change of volatilities of the original components in presence of the entrainer (solvent). Depending on the physical property behavior of the original mixture and the way in which the mass separating agent is to enhance the separation, the entrainer stream can be mixed with the primary feed or has to be supplied separately to an azeotropic column. While heterogeneous azeotropic distillation
0888-5885/92/2631-2345$03.00~0 0 1992 American Chemical Society
