European Polymer Journal 40 (2004) 873881 www.elsevier.

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Synthesis and characterization of thermosensitive copolymers for oral controlled drug delivery
Frederic Eeckman, Andr J. Mos, Karim Amighi e e
*
Laboratoire de Pharmacie Galnique et de Biopharmacie, Universit libre de Bruxelles, Campus Plaine, e e CP-207, Boulevard du Triomphe, 1050 Brussels, Belgium Received 19 December 2002; received in revised form 19 December 2002; accepted 14 November 2003

Abstract Poly(N-isopropylacrylamide) (PNIPAAm) copolymers were synthesized in order to obtain co-polymers with a phase transition temperature slightly higher than the physiological temperature, as required by a new drug delivery concept described in a previous paper. Six hydrophilic comonomers bringing about a rise of the phase transition temperature were evaluated. The synthesized copolymers were characterized and the inuence of the type and of the amount of the used comonomer on the phase transition temperature was discussed. Among the comonomers, Acrylamide (AAm), Nmethyl-N-vinylacetamide (MVA), N-vinylacetamide (NVA), and N-vinyl-2-pyrrolidinone (VPL) were found to be capable to raise the phase transition temperature to a value slightly higher than 37 C and to have adequate phase transition behavior. The selected four copolymers were subjected to an additional purication step that should make them t to use as a controlling agent in drug delivery systems. 2003 Elsevier Ltd. All rights reserved.
Keywords: Thermosensitive polymers; Poly(N-isopropylacrylamide); Phase transition temperature; Controlled drug delivery

1. Introduction Thermosensitive polymers have met with an increasing interest during the two past decades [17], particularly in the eld of controlled drug release [811], where, because of their peculiar behavior, they were nicknamed intelligent or smart polymers [1012]. Aqueous solutions of thermosensitive polymers show an inverse dissolution behavior, their isobaric phase diagrams presenting a lower critical solution temperature (LCST) [1 4]. The solutions are homogenous at low temperature and a phase separation appears when the temperature exceeds a denite value. This particular phenomenon is totally reversible and, in some cases, is quite sharp. The LCST is the minimum of the phase diagram of the system

Corresponding author. Tel.: +32-2-650-52-52; fax: +32-2650-52-69. E-mail address: kamighi@ulb.ac.be (K. Amighi).

[5], and in the practical cases to be treated in the following, the phase separation temperatures at which the phase transition occurs, also called demixtion, will be denoted Td . It has however to be kept in mind that LCST and Td are generally very close on account of the atness of the minimum of the phase diagram [5,13]. N-alkyl-substituted polyacrylamides are typical examples of polymer having a LCST in aqueous solution [6,7]. Among them, poly(N-isopropylacrylamide) (PNIPAAm) has been widely studied [1315], mainly because of the sharpness of its phase transition, of the closeness of its LCSTabout 32 Cto the physiological temperature, and of the easiness to vary its Td by copolymerization [1618], addition of salts [19,20] or addition of surfactants [20,21] to the polymer solution. In our laboratory, we have developed a new drug delivery concept making thermosensitive polymers suitable for an eective application in vivo [22]. That might be a new approach to site-specic drug targeting into the GI tract, mainly for colonic drug delivery, which seems quite dicult to be achieved by classical means.

0014-3057/$ - see front matter 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.eurpolymj.2003.11.010

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In summary, that concept consists in controlling the dissolution delay of compression-coated tablets, whose coating is mainly composed of a thermosensitive polymer, by the incorporation of salts in the dosage form. The salt lowers the Td of the polymer (this phenomenon being known as the salting out eect) [19,20], making it insoluble and, as explained in detail in a previous paper [22], bringing about a controllable delay of the drug release. The object aimed at requires that the Td of the thermosensitive polymer be slightly higher than the ambient temperature. If one considers drug delivery at physiological temperature (37 C), the use of PNIPAAmhomopolymer, with its phase transition temperature of 32 C, has however to be discarded and recourse is to be had to PNIPAAm-copolymers, synthesized with hydrophilic comonomers. So, the object of the present paper is a description of the synthesis of PNIPAAm-copolymers with various hydrophilic comonomers, the determination of their

main characteristics and the selection of the most suitable ones to be used in the control of drug release at physiological temperature. Acrylamide (AAm), Methacrylamide (MAAm), N-methyl-N-vinylacetamide (MVA), N-vinylacetamide (NVA), N-vinyl-2-pyrrolidinone (VPL) and 4-acryloylmorpholine (ACMP) were used as potential hydrophilic comonomers in order to increase the Td of PNIPAAm (Table 1).

2. Experimental 2.1. Material N-isopropylacrylamide (NIPAAm) monomer, and diethyl ether were purchased from Acros (Belgium). N,N0 azobisisobutyronitrile (AIBN) was purchased from Fluka (Belgium). Acrylamide (AAm), Methacrylamide (MAAm), N-methyl-N-vinylacetamide (MVA), N-vinylacetamide (NVA), N-vinyl-2-pyrrolidinone (VPL) and 4-acryloylmorpholine (ACMP) were purchased from Aldrich (Belgium). Unstabilized 1,4-dioxane and Nhexane were purchased from Lab-Scan (Belgium). D2 O was purchased from Cortec (France). The other materials were of analytical reagent grade. 2.2. Preparation of the copolymers

Table 1 Chemical structure of NIPAAm monomer and the dierent used comonomers

Main monomer Comonomers

H2C CH N C CH3
H2C CH N H2C C CH2
CH C O

CH3 O

(MVA)
O

H 2C

CH C NH O

CH2
H2C

(VPL)

NH2

(AAm)
O

CH H 3C CH3

H2C

C(CH3) C NH2

(MAAm)

H2C

CH NH C CH3 O

(NIPAAm)

(NVA)
O

H2C

CH C N

H2C H2C O

CH2 CH2

(ACMP)

N-isopropylacrylamide (NIPAAm) was puried by recrystallization from N-hexane, the other materials were used as received. PNIPAAm copolymers were prepared by free radical polymerization in 1,4-dioxane. About 2.5 g of each copolymer was prepared. AIBN was used as an initiator (1 mol%) and polymerizations were carried out under nitrogen atmosphere and magnetic stirring at 70 C (67 C for MVA) for 5 h. Prior to polymerization, the monomer solutions (1 mol/l) were bubbled with nitrogen for 20 min in order to remove the remaining oxygen. The comonomers percentages incorporated in the reaction media were as follows: 2.6, 5.2, 7.8, 10.4, 15.6, 20.8, and 31.2 mol% for VPL; 3.9, 7.8, 11.8 and 15.7 mol% for AAm; 3.3, 6.5, 9.7, 12.9, 19.0, and 24.9 mol% for NVA; 2.8, 5.7, 8.5, 11.2, 16.8, 22.2, 27.6 and 32.8 mol% for MVA; 3.3, 6.5, 9.7, 12.9, 19.0, 24.9, 30.1 and 36.3 mol% for MAAm; 2.0, 4.0, 6.1, 8.2, 12.4, 16.7, 21.1 and 25.6 mol% for ACMP. After polymerization, the obtained polymers were precipitated by adding the polymeric solutions to an excess volume of diethyl ether (5:1), under agitation at room temperature. The suspensions were ltered and washed with diethyl ether and the recovered polymers were dried in a vacuum oven at 60 C. They were then further puried by dissolution in acetone (110 g/l) and precipitation in diethyl ether (5:1) [22].

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The copolymers whose phase transition temperature is slightly higher than 37 C were also synthesized by using higher batch sizes (about 100 g of monomers were involved) and subjected to an additional purication process. For this purpose, they were dissolved in water (280 g/l) at room temperature and precipitated by heating the polymer solutions at 42 C. At this temperature, fractions of the polymer samples having a phase transition temperature higher than 42 C were still soluble and were eliminated by ltration. The process was repeated twice, and after drying, the puried polymer samples were dissolved in acetone (110 g/l) and precipitated in diethyl ether. 2.3. 1 H NMR analysis The chemical composition of the synthesized copolymers was determined by 1 H NMR The comonomer ratio was calculated by integrating the peaks pertaining to each of the comonomers. Spectra were recorded at 300 MHz on a Brker Avance 300 spectrometer, in u D2 O at 25 C. 2.4. Phase transition determination 2.4.1. Dierential scanning calorimetry (DSC) DSC method was used for the examination of the phase transition phenomena of the copolymers in aqueous solutions. The Td value was arbitrarily taken as the abscissa of the maximum of the endothermic transition peak (average of two measurements). DSC analyses were performed using a Perkin Elmer DSC-7 dierential scanning calorimeter/TAC-7 thermal analysis controller with an intracooler-2 cooling system (Perkin Elmer Instruments, USA). Aluminium sealed pans containing 10 ll of the various polymer aqueous solutions (56 g/l) were heated at a scanning rate of 2 C min1 , using nitrogen as blanket gas. Calibration was performed using cyclohexane and indium as standards. The glass transition temperature (Tg of the copolymers was also determined by DSC. Pans containing about 3 mg of solid polymer were heated from 50 to 200 C at 5 C min1 , cooled back to 50 C at 10 C min1 , and heated again to 200 C at 5 C min1 . Tg (average of two measurements from the second heating segment) was considered at the mid-point temperature of the endothermic drift in the heating curves. 2.4.2. Transmittance measurements The phase transitions were also evaluated by performing transmittance measurements of the polymer solutions (in duplicate) at 500 nm, using a Shimadzu 160 spectrophotometer (Shimadzu Corp., Japan). The temperature of the polymeric solutions (14 g/l), was raised by 0.1 C steps, using a Cell positioner with a Peltier

temperature controller (Shimadzu CPS-240A). The cloud point (CP) value (average of two measurements) was determined as the abscissa of the inexion point of the transmittance versus temperature curves [20]. 2.5. Molecular weight evaluation The molecular weight characteristics of copolymers were studied by gel permeation chromatography (GPC). An Agilent 1100 GPC (Agilent, USA) apparatus equipped with a refractive index detector and with two Ultrahydrogel 2000 and 250 columns (Waters, USA) was used. The analyses were performed at 20 C, using a 0.1mol/l NaNO3 aqueous solution, at a ow rate of 0.6 ml min1 . Monodisperse polyacrylic acid standards (Waters, USA) were used for calibration.

3. Results and discussion 3.1. Characterizations of the copolymers The copolymerization was easy to perform and conversion yields from monomers to copolymer were in the range 8090% (Table 2). They were however lowered after the second purication step, mainly due to handling. The chemical composition of the polymers was determined by 1 H NMR by integrating the signals pertaining to each monomer. As an example, Fig. 1 shows 1 H NMR spectra of PNIPAAm-co-VPL. The signals pertaining to NIPAAm are found in d 1:5 (CH2 CH); 2.1 (CHAC@O); 3.9 (NCH(CH3 )2 ); 1.1 (CH(CH3 )2 ) ppm. And the signals pertaining to VPL are found in d 1:6 (CH2 CH); 3.8 (CHN<); 3.3 (NCH2 CH2 ); 2.0 (CH2 CH2 CH2 ); 2.4 (CH2 AC@O) ppm. The appearance of the proton peaks at 2.4 and 3.3 ppm, which increase steadily as the content of VPL increases in the copolymer, indicates the reality of the copolymerization. NMR results can be read from Table 2. They show a good accordance between the comonomer composition in the feed and in the copolymers, except for VPL and MVA-copolymers for which losses of ca. 50% can be observed. For PNIPAAm-co-VPL, this loss originates in the purication treatment of the copolymer, and more precisely in the dissolution step in acetone. The polymer fractions with the higher VPL-contents were not soluble in acetone and were removed from the process. Besides, NMR analysis of a copolymer which has been precipitated only in diethyl ether showed that the comonomer ratio in the copolymer was roughly the same (29.5%) than that of the feed (31.2%). For PNIPAAm-co-MVA, the loss could be due to the low value of the velocity of the copolymerization reaction. But as the copolymerization

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Table 2 Properties of the synthesized copolymers Copolymers PNIPAAm-co-VPL % in the feed 2.6 5.2 7.8 10.4 15.6 20.8 31.2 3.9 7.8 11.8 15.7 3.3 6.5 9.7 12.9 19.0 24.9 2.8 5.7 8.5 11.2 16.8 22.2 27.6 32.8 3.3 6.5 9.7 12.9 19.0 24.9 36.3 2.0 4.0 6.1 8.2 12.4 16.7 21.1 25.6 % calculateda / 2.1 3 5.5 8.5 11.7 18.3 3.3 7.4 11.9 15.3 4.5 8 10.8 13.9 18.5 22.3 / / 5.1 5.6 8.7 / 14.7 16.2 / 5.9 9.2 11.5 19.1 20.1 36.7 / 4.4 6.4 / 13.6 17.7 20.0 25.5 Yield 1b (%) 88 95 86 89 83 83 85 91 88 89 90 78 92 88 86 88 96 80 80 76 72 78 81 74 72 84 88 84 82 78 86 76 84 84 84 84 88 78 84 86 Yield 2c (%) 72 80 77 65 69 72 70 80 76 72 81 74 74 76 64 78 90 62 63 61 52 58 60 60 58 76 74 72 72 64 68 60 72 68 78 65 74 72 66 70 Td (C) 31.8 32.6 33.1 34.2 35.7 37.2 40.0 36.1 38.3 40.3 42.5 33.2 35.7 37.2 38.6 42.1 45.4 32.4 32.5 33.4 34.2 35.8 37.6 38.9 41.2 34.9 37.6 38.9 41.8 / / / 31.9 32.1 32.3 32.6 33.1 33.8 34.1 35.2 CP (C) 32.2 32.7 33.6 34.3 35.7 36.9 39.6 34.6 36.3 38.7 40.0 33.8 35.6 36.8 38.2 41.2 43.5 33.2 33.5 34.1 34.7 35.8 37.0 38.1 39.1 32.4 33.8 34.7 35.4 / 37.8 43.2 31.1 31.6 31.8 32.3 33.2 33.8 34.1 35.3 Tg (C) / 139.2 140.4 139.2 139.9 139.0 142.0 138.5 140.6 144.1 148.3 / 137.2 137.2 137.7 / 140.9 137.4 136.1 136.5 136.5 135.2 134.3 135.1 135.5 141.1 144.4 146.3 150.1 151.3 153.7 160.1 / / 140.7 140.0 141.1 141.4 142.5 143.0

PNIPAAm-co-AAm

PNIPAAm-co-NVA

PNIPAAm-co-MVA

PNIPAAm-coMAAm

PNIPAAm-co-ACMP

By NMR. After the rst precipitation. c After the second precipitation.

b

constants are unknown, this should be regarded as just a hypothesis which the relatively low reaction yields obtained (Table 2) tend to corroborate. All the copolymers have shown a single glass transition temperature Tg (Table 2), located between the Tg of the two corresponding homopolymers [13,2327]. This is an indication that the copolymers are most likely statistical [24]. The Tg of PNIPAAm-homopolymer

synthesized in [22] was found to be equal to 139.0 C, what is in relatively good agreement with the results published in the literature [13,24]. 3.2. Phase transition properties of the copolymer solutions As already discussed, aqueous solutions of PNIPAAm-homopolymer have a phase transition tempera-

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Fig. 1. 1 H NMR spectra of PNIPAAm-co-VPL in D2 O. A 0% VPL; B 10.4% VPL; C 20.8% VPL; D 31.2% VPL.

ture of about 32 C [1315], which can be determined by both DSC analysis, giving the endothermic transition peak and by spectrophotometric analysis, giving the cloud point value. The thermal analysis method measures the heat resulting mainly from the breaking down of hydrogen bonds between water and polymer, while the photometric method visualizes the clouding of the solution due to the precipitation of the polymer, when phase separation occurs. The mean Td and cloud pointvalue of PNIPAAm in pure water were respectively found to be 31.9 C [22] and 32.4 C. Both methods were also used to examine the phase transition temperature of the synthesized copolymers. As stated before, it is desired to select copolymers on the one hand with a Td slightly higher than 37 C, considering that they have to be soluble at that temperature, and on the second hand with a sharpness of the phase transition comparable to that of the homopolymer viz. with a width of the DSC endothermic phase transition peak suciently small, what is tantamount to a sucient

steepness of the curve of transmittance versus temperature in the neighborhood of the cloud point [20]. Unfortunately, these two requirements are in a certain sense contradictory. Indeed, as shown in Fig. 2, the rise of the Td obtained from the increase of the comonomer content in the copolymer is accompanied by an increase of the width of the transition peak and, with the exception of PNIPAAm-co-AAm and PNIPAAmco-MAAm, by the appearance of an asymmetry of the peaks whose tail could even extend to innity for the higher comonomer-contents. The rst phenomenon is probably due to a non-uniformity of the distribution of the comonomers over the molecules of the polymers, what results in a non-homogeneity of the copolymers samples, all their molecules not having the same phase transition temperature. The second phenomenon could be a result of the (unknown) polymerization kinetics constants of the respective monomers, so polymer molecules with high hydrophilic comonomer contents are formed, those molecules making up the right part of the transition peak. DSC phase transition peaks of PNIPAAm-co-AAm and PNIPAAm-co-MAAm copolymers remain, on the other hand, quite symmetrical (what could be explainable by the, still unknown, monomers respective polymerisation kinetics constants). The broadening phenomenon is more important for PNIPAAm-co-MAAm as even samples with Td higher than 37 C (9.7 and 12.9 mol%) possess fractions, in a nonnegligible amount, with phase transition temperatures far inferior to 37 C. The phase transition, which was a very sharp phenomenon for aqueous solutions of PNIPAAm [20], is here spread out over a wide range of temperatures. The Td is, as mentioned above, still arbitrarily chosen as the abscissa of the maximum of the phase transition peak, but the whole transition phenomenon tends to take place over a still wider temperature range. The loss of sharpness of the phase transition can also be clearly observed in Fig. 3 which shows the results of cloud point analyses of PNIPAAm-co-VPL aqueous solutions. It can be observed that the phase transitions are spread over an increasing temperature range when the VPL content is increased. Fig. 4, which summarizes the DSC-analyses results, shows the inuence of the percentage of comonomer (in the feed) on the Td of the various synthesized copolymers. If one considers the ratio of the Td -rise to the comonomer percentage as an eciency index of the comonomer, the following ranking results: AAm $ MAAm > NVA > MVA $ VPL > ACMP. As it was expected, this ranking is determined by the hydrophilicity of the comonomers, the most hydrophilic one, AAm, bringing about the most signicant Td -rise, and the less hydrophilic one, ACMP, raising only slightly the Td (incorporation of 15.7% of AAm makes the Td -rise of ca. 10 C while incorporation of 16.7% of ACMP makes the Td -rise of ca. 2 C).

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Fig. 2. DSC thermograms of aqueous solutions (56 g/l) of the synthesized copolymers.

Fig. 3. Cloud point analyses of PNIPAAm-co-VPL aqueous solutions (14 g/l).

3.3. Selection of the copolymers For the intended application, PNIPAAm-co-ACMP was evidently discarded because the comonomer hydrophilicity is not sucient to raise the Td of the co-

polymer to an acceptable value. As shown in Fig. 2, the DSC peaks become broad and asymmetrical when the amount of ACMP is increased, but the Td (abscissa of the maximum of the transition peak) never reaches 37 C.

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Fig. 4. Eect of the comonomer percentage on the Td of the copolymers.

Although Td -values of PNIPAAm-co-MAAm with comonomer contents of about 10% are satisfactory ($39 C), the copolymer was also discarded because the width of its transition peak is too high (Fig. 2). If the additional purication process was applied at 42 C (as it was for the other cases) and at 37 C, in order to eliminate respectively the polymer fractions with high and low phase transition temperature, a drastic decrease of the overall yield would have been implied. The remaining fractions would have been so few that it seemed preferable to discard that copolymer for drug delivery purposes. However, copolymers with respectively 31.2% VPL, 11.8% AAm, 12.9% NVA, and 27.6% MVA can be retained as being perfectly adequate for the intended application, their Td being slightly higher than 37 C (respectively 40.0, 40.3, 38.6 and 38.9 C). 3.4. Additional purication process As mentioned before, an as uniform as possible comonomer distribution over the sample molecules is

asked. This is precisely the object of the additional purication process described in 2.2. and which globally consists in eliminating the sample fractions with high comonomer content, viz. those with the higher phase transition temperatures. The thermograms of PNIPAAm-co-VPL from polymer samples subjected or not to the additional purication process are shown in Fig. 5. The improvement of the sharpness of the transition peak is evident: the transition peak, relative to the sample having been subjected to the additional purication, has now become more symmetrical. This proves that the sample fractions with the higher VPL content (those with the higher phase transition temperatures) have well been removed, as conrmed by the thermogram relating to the ltrate. Analogous improvements were obtained for the other selected copolymers. The main characteristics of the four puried copolymers can be read from Table 3. It can be seen that the purication process was accompanied with a decrease of the calculated comonomer content and entailed

Fig. 5. DSC thermograms of PNIPAAm-co-VPL (31.2% VPL) aqueous solutions with and without additional purication.

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Table 3 Properties of the copolymers with additional purication. % calculateda PNIPAAm-co-VPL 31.2% PNIPAAm-co-Aam 11.8% PNIPAAm-co-NVA 12.9% PNIPAAm-co-MVA 27.6% PNIPAAm homopolymerd
a b

Yield (%) 36 46 40 35 95

Td (C) 40.2 39.9 38.6 38.6 31.9

Tg (C) 144.8 149.6 147.3 143.6 139.0

M nb 20 100 10 900 20 400 26 200 3900

M wb 57 800 52 000 79 500 62 300 50 100

M w =M n b 2.9 4.8 3.9 2.4 13

M nc 3750 4500 6900 1400 /

M wc 42 600 32 700 51 300 13 400 /

M w =M n c 11.3 7.3 7.4 9.8 /

12.8 11.4 9.1 10.6 /

By NMR. Relating to puried samples. c Relating to non-puried samples. d From Ref. [22].

a severe reduction of the yield. Indeed, due to the removal of fractions containing higher comonomer contents (those with the higher phase transition temperature values), the average comonomer contents of the whole samples are consequently decreased. Finally, it has to be remarked that, as is shown by GPC analyses results presented in Table 3, the molecular weight of the copolymers are roughly the same as that of the homopolymer [22], and that in this respect few changes are brought about by the copolymerization. It has however to be pointed out that the number average molecular weights M n of the puried copolymers are higher than that of PNIPAAm-homopolymer, leading to a reduction of the polydispersity index M w =M n . Moreover, comparison of the molecular weights of the puried and of the non-puried samples (Table 3) show that the non-puried samples have quite lower molecular weights, particularly the M n values. This means that the fractions with a high comonomer content eliminated by the purication process had low molecular weights, entailing consequently an increase of the average molecular weights of the puried samples. This is also illustrated by the higher Tg values of the puried samples than those of the non-puried ones, in accordance with the FloryFox equation, viz. Tg Tg1 A=M n [23]. Besides, except for the width of the transition peak, the additional purication process leaves the Td , of the copolymers invariant. The same goes for the scale range (2.5 and 100 g) of the reactions which moreover proved to be reproducible n P 2.

four of the considered copolymers, by subjecting them to an additional purication. Those four copolymers will be used as controlling agents in a new drug delivery system based on the use of thermoresponsive polymers. That work is currently underway and results will be presented in a further paper.

Acknowledgements Financial support from the Rgion Wallonne (cone vention no. 14403) is gratefully acknowledged.

References
[1] Bae YH, Okano T, Kim SW. Temperature dependance of swelling of crosslinked poly (N,N0 -alkyl substituted acrylamides) in water. J Polym Sci 1990;28:92336. [2] Fujishige S, Kubota K. Ando I. Phase transition of aqueous solutions of poly (N-isopropylacrylamide) and poly (N-isopropylmethacrylamide). J Phys Chem 1989;93: 33113. [3] Hahn M, Grnitz E, Dautzenberg H. Synthesis and o properties of ionically modied polymers with LCST behavior. Macromolecules 1998;31:561623. [4] Idziak I, Avoce D, Lessard D, Gravel D, Zhu XX. Thermosensitivity of aqueous solutions of poly (N,Ndiethylacrylamide). Macromolecules 1999;32:12603. [5] Durand A, Hourdet D. Thermoassociative graft copolymers based on poly (N-isopropylacrylamide): eect of added co-solutes on the rheological behaviour. Polymer 2000;41:54555. [6] Liu HY, Zhu XX. Lower critical solution temperatures of N-substituted acrylamide copolymers in aqueous solutions. Polymer 1999;40:698590. [7] Plat NA, Lebedeva TL, Valuev LI. Lower critical solution e temperature in aqueous solutions of N-alkyl-substituted polyacrylamides. Polym J 1999;31(1):217. [8] Okano T, Bae YH, Jacobs H, Kim SW. Thermally ono switching polymers for drug permeation and release. J Control Rel 1990;11:25565.

4. Conclusions Rise of PNIPAAm-Td was obtained by copolymerization with hydrophilic comonomers. Five of the six evaluated comonomers brought the Td to values slightly higher than the physiological temperature. DSC thermograms of the copolymers showed that their phase transitions can be lacking of sharpness. However, quite satisfactory results could be obtained in this respect with

F. Eeckman et al. / European Polymer Journal 40 (2004) 873881 [9] Ichikawa H, Fukumori Y. New applications of acrylic polymers for thermosensitive drug release. STP Pharma Sci 1997;7(6):52945. [10] Yoshida R, Sakai K, Okano T, Sakurai Y. Drug release proles in the shrinking process of thermoresponsive poly (N-isopropylacrylamide-co-alkyl methacrylate) gels. Ind Eng Chem Res 1992;31:233945. [11] Chee CK, Rimmer S, Soutar I, Swanson L. Manipulating the thermoresponsive behavior of poly(N-isopropylacrylamide). In: Stimuli-responsive water soluble and amphiphilic polymers. ACS Symposium Series, 780. 2001. p. 22337. [12] Kikuchi A, Okano T. Intelligent thermoresponsive polymeric stationary phases for aqueous chromatography of biological compounds. Prog Polym Sci 2002;27(6):116593. [13] Heskins M, Guillet JE. Solutions properties of poly (Nisopropylacrylamide). J Macromol Sci-Chem A 1968;2(8): 144155. [14] Kubota K, Fujishige S, Ando I. Single-chain transition of poly (N-isopropylacrylamide) in water. J Phys Chem 1990;94:51548. [15] Schild HG. Poly (N-isopropylacrylamide): experiment, theory and application. Prog Polym Sci 1992;17:163249. [16] Xue W, Champ S, Huglin MB. Thermoreversible swelling behaviour of hydrogels based on N-isopropylacrylamide with a zwitterionic comonomer. Eur Polym J 2001;37:869 75. [17] Shibayama M, Mizutani S-Y, Nomura S. Thermal properties of copolymer gels containing N-isopropylacrylamide. Macromolecules 1996;29:201924. [18] Jones MS. Eect of pH on the lower critical solution temperature of random copolymers of N-isopropylacrylamide and acrylic acid. Eur Polym J 1999;35:795801.

881

[19] Schild HG, Tirrell DA. Microcalorimetric detection of lower critical solution temperature in aqueous polymer solution. J Phys Chem 1990;94:43526. [20] Eeckman F, Amighi K, Mos AJ. Eect of some physioe logical and non-physiological compounds on the phase transition temperature of thermoresponsive polymers intended for oral controlled-drug delivery. Int J Pharm 2001;222:25970. [21] Schild HG, Tirrell DA. Interaction of poly (N-isopropylacrylamide) with sodium n-alkyl sulfates in aqueous solution. Langmuir 1991;7:66571. [22] Eeckman F, Amighi K, Mos AJ. Evaluation of a new e controlled-drug delivery concept based on the use of thermoresponsive polymers. Int J Pharm 2002;241:113 25. [23] Brandrup J, Immergut EH, Grulke EA. Polymer handbook. 4th ed. Wiley; 1999. [24] Liu H, Avoce D, Song Z, Zhu XX. N-Isopropylacrylamide copolymers with acrylamide and methacrylamide derivatives of cholic acid: Synthesis and characterisation. Macromol Rapid Commun 2001;22:67580. [25] Fitzpatrick S, McCabe J-F, Petts CR, Booth SW. Eect of moisture on polyvinylpyrrolidone in accelerated stability testing. Int J Pharm 2002;246:14351. [26] Nishio Y, Koide T, Miyashita Y, Kimura N, Suzuki H. Water-soluble polymers blends with partially deacetylated chitin: A. Miscibility characterization. J Polym Sci Part B: Polym Phys 1999;37:15338. [27] Matsud S, Tsuchiya S, Homma M, Hasegawa K, Nagamatsu G, Asano T. Thermally-reacted poly (methacrylamide) as a positive electron beam resist. Polym Eng Sci 1977;17(6):4103.