STABILITY EVALUATI ON OF ph AND TEMPERATURE RESPONSIVE PARTICLES FROM STEADY-STATE RHEOLOGICAL MEASUREM ENTS

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1 STABILITY EVALUATI ON OF ph AND TEMPERATURE RESPONSIVE PARTICLES FROM STEADY-STATE RHEOLOGICAL MEASUREM ENTS An M. S. Mi, Prisil S. Curti, Nívi N. Mrques, Rosngel C. Bln* Universie Feerl o Rio Grne o Norte UFRN, Dep. Quími, LAPET, Ntl-RN ln@supero.om.r Copolymer ltex of rosslinke hitosn, N-isopropylrylmie (NIPAAm) n ryli i (AA) ws prepre using sopless ispersion polymeriztion. The inorportion of PNIPAAm n PAA onto hitosn hins ws onfirme y elementry nlysis. The effets of ph n temperture were evlute y stility tests n rheologil nlysis. It ws oserve tht the suspensions of the prtiles ontining PNIPAAm grfte onto hitosn presente etter stility in neutrl meium thn in i meium, n the rheologil nlysis inite ggregte formtion ove the LCST of PNIPAAm. With the introution of AA polymeriztion in the synthesis, the ph effet on the prtiles ws more signifint thn the temperture. In lkline meium, the suspension presente goo stility, ompre with the neutrl n i meium. The rheologil nlysis in high ph showe enhnement of visosity, tht n e expline y the presene of negtive hrges in the sie hins, stilizing the suspension n hinering the ggregte formtion, even ove the LCST of PNIPAAm. Keywors: thermoresponsive; ph responsive; stility; rheologil nlysis. Introution For more thn two ees, onsierle ttention hs een rwn to the so-lle smrt gels, whih n unergo oth reversile n isontinuous volume phse hnge in response to environmentl stimuli suh s ph, temperture, ioni strength, n so on. 1 These smrt gels hve potentil pplitions in iomeil n phrmeutil fiels. 2 One of the most well-known therml-responsive polymers is poly(n-isopropylrylmie) (PNIPAAm), whih exhiits lower ritil solution temperture (LCST) roun 32 ºC in queous solution. PNIPAAm hyrogels with rosslinke strutures thus n swell in wter elow the LCST n shrink ove it. 3 Reently, the interest on the evelopment of ul-stimuli-responsive hyrogels to e pplie s elivery vehiles tht respon to lolize onitions, suh s ph n temperture in the humn oy, hs een inrese. 4 They my e prepre y omining PNIPAAm with nother stimulussensitive polymeri omponent, to form opolymer gels. 5 The opolymer hyrogels re generlly synthesize y ril polymeriztion of NIPAAm with ryli i type monomers in the presene of rosslinking gent. The poly(ryli i) is goo nite euse exhiits ph responsive ehvior ue to the roxyli i groups long its hin, n these sme groups n e use for the onjugtion with proteins. 6,7 It woul e enefiil to introue other properties into the mterils, suh s ioomptiility, ioegrility n iologil funtions, in ition to the ul-stimuli-responsive property, espeilly when iomeil pplitions re esire. Chitosn hs een use in vriety of iomeil fiels euse it presents those properties ove mentione. Furthermore, this polymer hs oth retive mino n hyroxyl groups tht n e use to hemilly lter the polymer struture n properties uner mil onitions. 8 The im of this stuy ws: (i) to otin temperture n ph stimuli-responsive prtiles, whih woul lso present ioomptiility n ioegrility n; (ii) to hrterize the stility n rheologil properties of the otine prtiles in ifferent mei. Therefore, opolymers se on PNIPAAm, PAA n hitosn were use.

2 Experimentl Mterils Chitosn with 82% egree of eetyltion n molr mss of 9.1 x 10 5 g/mol 9 ws otine from Polymr S.A (Brzil), N-isopropylrylmie (NIPAAm) n N,N -methyleneisrylmie (MBA) were purhse from Sigm-Alrih, potssium persulfte (KPS) ws otine from Vete n ryli i (AA) ws kinly supplie y Oswlo Cruz Quími (Brzil). NOH, KCl, NCl, KH 2 PO 4 n N 2 HPO 4 were purhse from Synth. Aeti i ws otine from Cromoline n imethyletmie (DMA) ws purhse from Nuler. All regents were use s reeive. Sopless ispersion opolymeriztion The rosslinke hitosn-g-(nipaam-o-aa) prtiles were synthesize y the metho of sopless ispersion opolymeriztion 10 uner the onitions liste in Tle 1. The polymeriztion ws rrie out for 3 h t 50 ºC in nitrogen tmosphere. Then, the ltex prout ws hete to 60 C (ove the LCST of PNIPAAm) to preipitte the prtiles, tht were filtere. For the removl of the remining monomers n inititor, the prtiles were wshe with hot wter severl times n then rie in vuum oven. Tle 1 Conitions for synthesis of rosslinke hitosn-g-(nipaam-o-aa) prtiles. Regents Conentrtion (mol/l) Synthesis I Synthesis II Chitosn N-isopropylrylmie Aryli i N,N -methyleneisrylmie Potssium persulfte Elementry nlysis (EA) The opolymeriztion ws heke with elementry nlysis using Perkin Elmer CHNS/O 2400 Series II, t the omustion olumn temperture set of 925 ºC n seprtion olumn temperture of 640 ºC. The smple (out 2.7 mg) ws fille in tin foil n nlyze in syntheti ir using oxygen s the omustion gs n helium s the rrier gs. Copolymer suspension stility The opolymers were isperse t onentrtion of 2 % (w/v) in the following solvents: eti i 0.5 M (ph=3), phosphte uffere sline (PBS) (ph=7), PBS ontining NOH 0.25 % (ph=10) n imethyletmie (DMA). The suspensions were stirre for 24 h t room temperture n, in orer to reor the stility of eh suspension with the time, they were photogrphe y igitl mer Olympus, moel C-170. Rheologil mesurements The rheologil properties of the suspensions were mesure in RheoStrees RS 150 rheometer from Hke, t sme onitions, using onentri yliner geometry (DG41). The instrument ws equippe with thermostti th. The visosity t were otine over sher rte rnge of s -1 t ifferent tempertures (25 n 35 C). Results n isussion The prtiles synthesize in this work y the metho of ispersion opolymeriztion hve net negtive surfe hrge, in whih hitosn n PNIPAAm re homogeneously mixe, s expline erly y Lee n o-workers. 10 Tle 2 presents the EA results for the prtiles from synthesis I n II n the lulte vlues for the fee onentrtion. The mesure vlues re lose to the lulte vlues, for oth syntheses. These results inite tht the PNIPAAm ws inorporte into the prtiles for the synthesis I n oth PNIPAAm n PAA were inorporte into the prtiles otine in the synthesis II.

3 Tle 2 Molr perentge of C, H, N n O toms lulte from the monomers in the fee of retion system n from the elementry nlysis of the opolymers otine. Synthesis I Synthesis II Clulte Mesure Clulte Mesure C (%) H (%) N (%) O (%) From the ispersiility test results (t not shown), it ws verifie tht the prtiles from synthesis I n II presente some suitle kin of intertion in queous i, neutrl n lkline meium, s well s in DMA. Therefore, these solvents were use for the stility n rheologil mesurements. The pitures in Figure 1 show the visul spet of the suspensions otine from the prtiles synthesize, s funtion of the kin of solvent use. In ll ses, trnsluent or opque systems were oserve. This is n initive tht the suspensions were forme, ue to the retiultion of the PNIPAAm hins with MBAAm uring the synthesis proess. In this se, just smll egree of swelling ourre. Immeitely fter the preprtion, the suspensions presente opity in i, neutrl n lkline meium, n trnslueny in DMA. After 24 h of rest, the prtiles from synthesis I mintine the stility in the four mei use. This result inites tht the PNIPAAm inorporte into hitosn hins proue prtiles with improve stility in i, neutrl n lkline queous solution, s well s in DMA uring this time. After 96 h of rest, the prtiles from synthesis I still remine stle in i meium. In the other mei, it ws possile to oserve tht there ws grient of soli onentrtion from the top to the ottom tue. On the other hn, fter the sme time of rest, the suspensions prepre from prtiles otine y synthesis II presente visile improvement of stility y inresing the ph vlues. In the i meium (ph=3), just fter 30 minutes of rest, the prtiles preipitte in the ottom of the tue, there is ler seprtion etween the i meium n the seiment. Using PBS, the prtiles presente some stility. However, in the lkline meium (ph=10), the suspension showe stility n turne little less opque, ompre to the suspension in neutrl meium. These results inite tht the poly (ryli i) ws inorporte in the polymer prtiles uring the retion of the synthesis II. The higher stility of the prtiles from synthesis I n II in DMA is proly ue to the struturl similrity etween DMA n PNIPAAm hins. After 96 h of rest, it oul e verifie tht the stility of the prtiles from synthesis II ws still etter thn the stility of the prtiles from synthesis I. Figure 2 shows the pprent visosity of suspensions prepre from the prtiles in ifferent ph vlues. All ow urves exhiite non-newtonin sher-thinning ehvior, t 25 C. This my e srie to rerrngement of eformle prtiles uner shering to yiel system with lower egree of intertion etween the prtiles. The prtiles ontining only hitosn n PNIPAAm swelle more in PBS thn in the others mei, s inite y Figure 2. However, the prtiles lso showe some egree of swollen in DMA n in lkline solution (ph=10). A lower egree of swollen ws oserve in i solution (ph=3), proly euse of the preominne of negtive hrges onto the prtile surfe. 10 With the introution of poly(ryli i), the prtiles eme more swelle in lkline meium n prtilly i not swell in i meium (Figure 2). It is possile to oserve tht the prout of synthesis II ws less sensile to the sher rte. This oul e ttriute to the presene of negtive hrges on the prtiles surfe, leing to repulsion etween them, s well s to the higher totl monomer onentrtion in the synthesis, whih oul le to enser prtiles.

4 I initil time I fter 96 h of rest II fter 30 minutes of rest I fter 24 h of rest II initil time I fter 30 minutes of rest II fter 24 h of rest II fer 96 h of rest Figure 1: Pitures of the suspensions otine to the prtiles from the synthesis I n II in: () i meium (ph=3); () PBS; () lkline meium (ph=10) n () DMA, just fter the suspension preprtion, fter 30 minutes, 24 hours n 96 hours of rest. When the temperture ws inrese ove the LCST of the PNIPAAm, the prout of synthesis I showe rise in pprent visosity in queous meium, proly ue to the ggregtion of the prtiles (Figures 2, 2 n 2e). When the system ws oole to 25 ºC gin, the isperse prtiles in ph 7 n 10 immeitely reovere their originl forms, s oserve in Figures 2 n 2. The intertions of these prtiles with the i solution were not strong (Figure 2e), s inite y the low visosity. Proly, fter the heting n susequent ooling, the prtiles i Anis o 10o Congresso Brsileiro e Polímeros Foz o Iguçu, PR Outuro/2009

5 not reover the originl struture n the pprent visosity showe n inrese in the lower sher rtes. The prtiles otine from synthesis II showe LCST effet of PNIPAAm only in PBS (Figure 2f). In lkline meium, proly the roxyl moieties re full ionize n the ph effet preominte over the temperture one, stilizing the prtiles, n in the i meium the hins re lrey ompletely ontrte (t not shown). Therefore, these prtiles re not le of reovering their initil form when the temperture is oole to 25 ºC. As expete, the prtiles were not sensile to the temperture in DMA (t not shown), euse the LCST of PNIPAAm ours only in queous meium. Figure 2 Apprent visosity s funtion of sher rte for suspensions prepre from: () prtiles of synthesis I in ifferent solvents, t 25 C; () prtiles of synthesis II in ifferent solvents, t 25 ºC () prtiles of synthesis I in ph 7 t ifferent tempertures; () prtiles of synthesis I in ph 10 t ifferent tempertures; (e) prtiles of synthesis I in ph=3 t ifferent tempertures; (f) prtiles of synthesis II in ph=7 t ifferent tempertures. Conlusion The results of elementry nlysis inite the presene of PNIPAAm n PNIPAAm/PAA in the hitosn prtiles otine y synthesis I n II, respetively. From the stility test long the time n rheologil nlyses it ws possile to oserve the ph influene on the suspensions n swelling of the prtiles. The prtiles otine from synthesis I presente more stility in i meium. From the rheologil mesurements, it ws oserve the effet of the temperture in these prtiles. Aove the LCST of PNIPAAm, the ggregtion ourre, provoking n enhnement of visosity suspension. The presene of PAA in the prtiles of synthesis II turne the effet of ph

6 more signifint thn the effet of temperture, minly in lkline meium, proly euse of the repulsion mong negtive hrges. Aknowlegments Authors re grteful to finnil support from CAPES, n entity of the Brzilin Government irete towr the formtion of humn resoures n to NUPEG/UFRN for elementry nlyses. Referenes 1. Y. Qiu; K. Prk Av. Drug. Del. Reviews 2001, 53, N. A. Pepps; P. Bures; W. Leonung; H. Ihkw Eur. J. Phrm. Biophrm. 2000, 50, B. Jeong; S. W. Kim; Y. H. Be Av. Drug Del. Reviews 2002, 54, I. Dimitro; B. Trzeik; A. H. E. Müller; A. Dwork; C. B. Tsvetnov Prog. Polym. Si. 2007, 32, J. Zhou; G. Wng; L. Zou; L. Tng; M. Mrquez; Z. Hu Biomromoleules 2008, 9, C.-L. Lin; W.-Y. Chiu; C.-F. Lee J. Colloi Interfe Si. 2005, 290, Y. Yue; X. Sheng; P. Wng Europ. Polym. J. 2009, 45, N. M. Alves; J. F.Mno Int J Bio Mromol 2008, 43, S. S. Silv; S. M. C. Menezes; R. B. Gri Eur. Polym. J. 2003, 39, C.-F. Lee; C.-J. Wen; W.-Y. Chiu J. Polym. Si., Prt A: Polym. Chem. 2003, 41, 2053.