Study on Polymer-Surfactant Interactions for the Improvement of Drug Delivery Systems Wettability

Transcription

1 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) 405 Stuy on Polymer-Surfactant Interactions for the Imrovement of Drug Delivery Systems Wettability I. De Simone, a N. Coceani, b R. Farra, b S. M. Fiorentino, b G. Grassi, c R. Laasin, b D. Hasa, a B. Perissutti, a M. Grassi, b an D. Voinovich a,* a Deartment of Chemical an Pharmaceutical Sciences, University of Trieste, Piazzale Euroa 1, I-3417, Trieste, Italy b Deartment of Engineering an Architercture, Piazzale Euroa, I-3417, Trieste, Italy c Deartment of Life Sciences, Cattinara University Hosital, Straa i Fiume 447, I-34149, Trieste, Italy Original scientific aer Receive: June 8, 01 Accete: July 4, 01 One of the ossible causes of failure of the mechanochemical activation of oorly soluble rugs relies on the scarce rug wettability. Inee, the mechanochemical rocess comorts the isosition of rug nano-crystals an amorhous rug, generate by the estruction of original rug macro-crystals, on the surface of the carrier (acting as stabiliser), usually reresente by crosslinke olymeric articles. Accoringly, the scarce rug wettability can reuce the beneficial action of mechanochemical activation (nano-crystals an amorhous rug are characterise by a higher solubility with resect to the original macro-crystals). In this light, this aer is focusse on the use of surfactants for the increase of elivery system (rug lus carrier) wettability. In articular, the surfactant-olymer systems are characterise for what concerns their bulk an surface roerties. This allows to select the best surfactant an to exerimentally verify its effect on the release kinetics of a oorly soluble an wettable rug. Key wors: Wettability, mechanochemical activation, surfactant, surface characterization. Introuction * Corresoning author: vojnovic@units.it; Tel: ; Fax: Oral osage form reresents the most common route for rug aministration into human boy because it leas to a better atient comliance an it is very versatile for what concerns osing conitions 1,. Unfortunately, however, oral osage form can be not so effective ue to oor rug solubility in aqueous environments such as hysiological meia. Inee, solubility is an imortant requirement to ensure goo boy absortion after oral aministration. In other wors, harmaceutical system bioavailability, efine as the rate an extent to which the active rug is absorbe from a harmaceutical form an becomes available at the rug action site 3,is heavily influence by rug solubility that becomes the absortion rate etermining ste for class II rugs (goo ermeability, oor solubility) accoring to the Amion bioharmaceutical classification 4. While an ieal rug (100% bioavailability) gets the site of action unmoifie without unergoing metabolism an elimination athways, a real one, esecially if slightly bioavailable, has to be aministrate in high ose to ensure a minimum effective concentration at the site of action. In this case, consequently, the aearance of ose-eening sie effects can be robable. A ossible strategy to imrove solubility an, thus, bioavailability, without moifying rug chemical structure, strictly connecte to theraeutic roerties, is to act on rug hysical roerties. Inee, it is well known 5 that the smaller the rug crystal, the higher its solubility in a liqui system. This statement, a little bit intriguing, neither reresents a araox, nor confutes thermoynamic theory. Inee, at fixe temerature an ressure, rug solubility in a solvent is a unique value escening from the rincile of minimal energy that translates into the equality of all secies chemical otential in the liqui an soli hase. In virtue of the minimal energy rincile, however, this efinition of solubility imlicitly assumes that the soli hase is reresente by crystals of infinite imension, this being the most stable configuration the soli hase can assume. If, on the contrary, it were ossible to realise the equilibrium between a liqui hase an a soli one mae by very small crystals (nano-crystals or, more recisely, crystallites), it can be thermoynamically emonstrate that rug solubility is eenent on crystals size 5. However, as nano-crystals reresent a metastable conition for the soli hase an they

2 406 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) ten to assemble together to get the most stable infinite crystal conition, it is not exerimentally ossible to achieve a two hases equilibrium in resence of a nano-soli hase. Nevertheless, in the resence of articular stabilising agents, the metastable nano-crystals conition can be stabilise an, at least for a limite erio, it is ossible to take avantage of the increase solubility 6. Obviously, the amorhous rug conition can be viewe as a nano-crystal of vanishing imension which cometes the highest solubility in a solvent at fixe temerature an ressure 7. In this sense, both nano-crystals an amorhous hase reresent an activate state for the rug. It is now clear the necessity of choosing a roer stabilising agent to have a reliable an effective elivery system able to take avantage from the above iscusse nano-crystals roerty. Deening on rug hysicochemical characteristics, articular olymers (tyically crosslinke amhihilic ones) can stabilise nano-crystals an amorhous rug hase by traing them insie their three-imensional network or on their surface. Inee, ue to olymer rug interactions an to the hysical resence of the olymeric chains (rug macro-crystals can form on conition that the ry network meshes be sufficiently wie), macro-crystals formation, at least in the ry state, is ractically hinere 5,6. On the contrary, when olymeric articles come into contact with the external liqui environment, solvent iffusion insie the olymeric network gives rise to the swelling rocess an to rug issolution, coule with nano-crystals an amorhous rug re-crystallisation into macro-crystals. The resence of the solvent an the enlarge imensions of the network meshes make negligible the olymer stabilising action. Practically, release kinetics evelos as the issolving rug were characterise by a ecreasing solubility, sanning from a higher value to a lower one, characteristic of the macro-crystal 8,9. As re-crystallisation is not instantaneous, on average, rug release kinetics is imrove 5, 6. Although ifferent techniques exist to iserse the rug insie the olymeric network (solvent swelling 6,10 an suercritical fluis 11,1, for examle), in form of very small crystals ranging from the nano-scale to the virtually zero-imensional crystals reresenting by the amorhous state, co-grining rove to be a reliable strategy Moreover, it has the consierable avantage of not requiring the use of solvents whose elimination from the final formulation can often reresent a very exensive an elicate stage. Inee, solvent must be eliminate without extracting the rug an without moifying rug istribution insie the olymer as it is well known that this istribution can sensibly affect the release kinetics 16,17. Unfortunately, however, when the rug is highly hyrohobic an its abunance in the co-groun system is relevant (rug-olymer ratio 1/3 w/w) elivery system wettability can be very low 18. In this case, esite of goo rug activation, bioavailability can be eresse an the use of surfactants becomes unavoiable. Accoringly, aim of this work was to stuy olymer-surfactant interactions in orer to select the best caniate able to confer the highest wettability to the carrier system (olymer) which, in turn, reflects on the imrovement of the whole rug-olymer system wettability. Firstly, olymer-surfactant bulk roerties were stuie in orer to measure surfactant solubility in the olymeric bulk hase. Then, attention was focusse on the olymer-surfactant system surface roerties. Inee, it is essential to evaluate whether surfactant isoses at the soli surface or not as system wettability moifications are only ue to the suerficial surfactant fraction. Finally, in vitro release tests were use to evaluate the macroscoic effect of surfactants on release kinetics. Materials an methos In the light of its amhihilic nature an of its wie use as rug nano-crystals stabilizer 5,6,10,15, olyvinyl-yrrolione (PVP) was chosen as olymeric carrier. In articular, two PVP tyes were use: the linear one (K90, Kollion BASF) an the crosslinke one (olyvinyl-yrrolione, PVP-CL-M.) Investigate surfactants were soium lauryl sulfate (SLS, anionic, Sigma Alrich), tetraecyl trimetyl ammonium bromie (TTAB, cationic, Sigma Alrich) an oloxamer 407 (Lutrol, not ionic, Sigma Alrich). All of them are arove for oral aministration an frequently emloye in formulations 19,0. Nimesulie (Helsinn, PambioNoranco, CH), a tyical non-steroial anti-inflammatory rug (NSAID), was consiere as moel rug as it belongs to the Amion class II (low solubility an high ermeability rug) 4 an for its low wettability 1. Determination of bulk roerties K90 aqueous solutions (7% w/w) containing ifferent surfactant amounts, were reare, oure in aluminium ans an there rie (rying overnight uner air flux followe by 40 minutes at 80 C in a oven) to get films. Differential scanning calorimetry (Perkin Elmer DSC 7, Perkin Elmer, Norwalk, CT) was then le on these films to etermine the olymer-surfactant hase iagram an, thus, surfactant solubility in the olymer reach hase (temerature calibration was mae, at the

3 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) 407 same heating rate, using Hg an In as stanars). In orer to eliminate water traces, films unerwent a first heating ste le at 10 C/min (SLS, from 50 C to 190 C; TTAB, from 0 C to 110 C; Lutrol from 0 C to 180 C) followe by an analogous cooling. Then, 1 minute isotherm (SLS 50 C; TTAB 0 C; Lutrol 0 C) recee the efinitive heating (SLS, u to 00 C; TTAB u to 190 C; Lutrol u to 190 C) at 10 C/min. DSC scans were erforme uner N stream (0 cm 3 /min) to revent samles from oxiation. DSC analysis was firstly aresse to etermine the variations of olymer glass transition temerature (T g ). Inee, T g, characteristic of each amorhous olymer, ecreases with increasing surfactant concentration because of surfactant lastic agent action. Then, first orer transitions (melting), characteristic of crystalline surfactants, were consiere in orer to iniviuate the eventual resence of a surfactant reach hase, being the olymer reach one the only hase existing until surfactant solubility in the olymer was not exceee. X-Ray iffraction analysis (Stoe 500, Siemens, Germany, equie by a Cu K source (40KV, 0 ma)) allowe getting information on ossible film crystalline structure ue to the resence of a surfactant reach hase.the scanning angle range from 5 to 35 of, stes were of 0.05 of, an the counting time was of 5 s/ste.this technique was use to suort what foun by means of DSC analysis. Determination of surface roerties K90-surfactant films, characterise by ifferent surfactant mass fraction (u to 7% for SLS an u to 9% for TTAB. This characterisation was not erforme in the case of Lutrol for the reasons exose in the results an iscussion section), were reare by casting the olymer-surfactant aqueous solution on a glass suort. Water evaoration was erforme uner controlle conitions in orer to get a homogeneous surface free from cracks an bubbles. Films surface roerties were firstly etermine by measuring the contact angle (tensiometer G10, Kruss, GmbH, Hamburg, D; sessile ro technique) relative to a olar solvent (istille water) an an aolar one (iioomethane). Then, in orer to verify the existence of one or two hases on film surface, the Cassie-Baxter equation was use: cos a =f 1 cos 1 +f cos (1) where a is the aarent contact angle measure on film surface while f 1 an f are the surface fractions occuie by the two hases, each one characterize by its own contact angle ( 1 an ). As, obviously, f 1 +f = 1, eq.(1) becomes: cos a =f 1 (cos 1 cos ) + cos () which exresses a linear eenence of cos a on f 1. Thus, if the exerimental tren of cos a is not linear with f 1, it is not ossible that two suerficial hases exist on film surface. To further characterize films surface roerties, their soli-liqui ( sl ) an soli-vaor ( ) surface tensions were etermine. At this urose, Young equation 3 was use: lv cos = sl (3) where is the contact angle an lv is the liqui-vaor surface tension cometing to the robe liqui use to wet film surface. As in eq.(3) is unknown, its value was estimate accoring to the Wu aroach 4. This aroach relies on the hyothesis that is the sum of two contributes: where = + is the isersional comonent an (4) is the olar comonent. In aition, assuming that the mean interaction otential relative to the two immiscible hases (the liqui an the soli hase, in our case) is given by the harmonic mean of the interaction otential of each hase, Wu got the following relation: lv (1+ cos ) = 4 lv 4 lv lv lv (5) where lv an lv are, resectively, the isersional an the olar comonent of lv. While lv, lv an lv can be foun in literature for many liquis 18, an are unknowns. Accoringly, their etermination imlies the simultaneous solution of two equations of the eq.(5) tye relative to two ifferent liquis. In so oing, the balance among equations an unknowns ( an ) is achieve as, obviously, an o not een on the liqui use but they een only on the soli film surface characteristics. In articular, in this work, two ifferent liquis were consiere: istille water an iioomethane. Inee, while water is essentially olar, iioomethane is essentially aolar. Once an are known, eq.(4) allows the etermination of. On this basis, eq.(3) yiels sl when the soli-liqui contact angle ( ) has been exerimentally etermine. Knowlege of is not only imortant er se, but it is also essential for the etermination of the film surface comosition in relation to ifferent surfactant concentration in the film bulk. Inee, for a two comonents (1 = olymer, = surfactant) system mae u by a vaor (v) an a soli (s) hase in equilibrium, Gibb-Duhem equations hol 5 :

4 408 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) v v v v n1 1 n 0 (6) s s s s n n (7) where n v 1 an n v reresent, resectively, the moles of olymer an surfactant in the vaor hase, n s 1 an n s reresent, resectively, the moles of olymer an surfactant in the soli hase (film) while v s v s an are, resectively, the infinitesimal variation of olymer an surfactant chemical otential. Eqs.(6) an (7) can be coule with the Gibb s equation ertinent to the soli-liqui interface : 1 1 (8) where 1 an are, resectively, the so calle excess of olymer an surfactant on the soli-vaor interface. Accoring to the Gibb s theory, when i (i = 1 or in our case) is equal to zero, the surface an the bulk comosition of comonent i th are equal, i.e, the excess (or efect) of comonent i th on the surface is zero. Exressing 1 eenence on accoring to eq.(6) an substituting this exression into eq.(8), we get: or: n 1 s n 1 B s 1 (9) n n s s 1 B (10) Remembering the relation existing between the chemical otential an activity ( = RT lna ; where T inicates the absolute temerature, R is the universal gas constant an a is the surfactant activity), we have: 1 RT ln 1 B a ( ) (11) As in the case of ilute solutions (surfactant concentration less than 0.1), surfactant activity (a ) can be aroximate by its concentration (c ), eq.(11) can be aroximate by: 1 1 B RT ln c (1) Relying on eq.(1), it is easy to verify the valiity of the following relations: 1 B B B (13) (14) Polymer-surfactant interaction in aqueous solution In orer to investigate the olymer-surfactant interaction in liqui hase, ifferent aqueous solution (olymer concentration = 10 mg/cm 3 ) with increasing surfactant concentrations (sanning from 10 to g/ml) were reare. Then, liqui-vaor surface tension was measure by means of a tensiometer G10 (Krûss GmbH, Hamburg, D, enant ro technique). In the case of imortant interactions between the olymer an the surfactant, variations in the lv versus ln(c ) shoul be etecte 6. Both K90 an PVP-Clm were use. Obviously, in the case of PVP-Clm, we were in resence of isersions an not of solutions ue to cross-linke nature of PVP-Clm. Prearation an calorimetric investigation of co-groun samles Nimesulie/PVP-CL-M/surfactant hysical mixture (ratio 11:3:1 (w/w)) an Nimesulie/PVP-CL-M hysical mixture (ratio 11:33 (w/w) were co-groun for hours in a lanetary mill (Pulverisette 7, Fritsch GmbH, D)) setting the rotational see to 530 rm. Mill vials, mae u by agate, containe seven agate balls (1 cm iameter) lus 1.5 g of hysical mixture. The lanetary mill was chosen as it is efficient an its ynamic behaviour, jointly with the energy transfer to co-groun materials, is well unerstoo 7. The co-groun material was sieve (60 mesh 50 m). Pure nimesulie an ifferent co-groun systems were characterise by means of DSC. The samles were ut into aluminium ans (about 6 7 mg in the case of co-groun systems an about mg in the case of ure rug) an then scanne uner a N stream of 0 cm 3 /min at a heating rate of 10 C/min. In orer to eliminate water from the co-groun materials, a four ste roceure was alie: 1) heating from 0 C to 90 C ) cooling from 90 C to 70 C 3) resting at 70 C for minutes 4) heating from 70 C to 160 C. Release test Drug an olymer Release tests, erforme in trilicate in not sink conitions, were le in 600 cm 3 water (V r )at 37 C. At time zero, 00 mg of hysical mixture (nimesulie/pvp-cl-m, 11:33 weight ratio, simly mixe) or co-groun systems (nimesulie/pvp-cl-m, weight ratio 11:33, mixe an then subjecte to co-grining; Nimesulie/PVP-CL-M/surfactant weight ratio 11:3:1, mixe an then subjecte to co-grining) were ae to the release environment. The reason for choosing this rug-olymer ratio relies on the fact that lower ratios are not

5 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) 409 robably connecte to wettability roblems ue to olymer abunance. On the contrary, higher ratios woul reflect in oorly stable systems ue to the olymer lack. Drug In the case of ure nimesulie, 50 mg of rug were ae to the release environment (600 cm 3 water (V r ) at 37 C). In so oing, the rug ose is the same use in the test erforme on the rug-olymer system. Oerative conitions Uniformity conitions were ensure by means of an imeller (rotational see 00 rm). The use of an otical fibre aaratus (HELLMA, Italy), connecte to a sectrohotometer (ZEISS, Germany, wavelength nm), allowe the etermination of nimesulie concentration (C r ) without erturbing the release environment (each release test laste 0 minutes). Moreover, this methoology allowe to easily overcome the roblem connecte to rug concentration measurement in resence of a isersion of soli articles. Inee, while the maximum nimesulie absortion occurre at nm, the scattering effect ue to olymeric articles uniformly occurre at every wavelength. Accoringly, the real absorbance relate to nimesulie concentration was the ifference between the absorbance measure at nm an that measure at 500 nm (at 500 nm nimesulie oes not absorb). Results an iscussion Bulk roerties Fig. DSC attern of SLS. Enothermic eak is uwar Figure 1, showing the DSC behaviour relative to K90, reveals that this amorhous olymer is characterise by an inflection with a mioint at 174 C, attributable to its glass transition temerature (T g ), followe by a relaxation enotherm. At the same time, Figure shows that two thermal events characterise the DSC attern of SLS: the first, occurring at 87 C, reresents a soli-soli transition while the secon, ositione at 196 C, inicates the soli-liqui hase transition. These consierations were suorte by the hot stage microscoy stuies (FP 5 Mettler, Greifensee, CH, connecte to a temerature controller FP 5 Mettler) (ata not shown). Inee, while no liqui hase was visible at 87 C, an evient liqui hase aeare at 196 C. The information containe in Figure 1 an reresent the initial (0% SLS content) an final art (100% SLS content) of the K90-SLS hase iagram reorte in Figure 3. Figure 3 was realise by erforming a DSC analysis on ifferent K90-SLS systems characterise by an increasing content (mass fraction X 100) of SLS 1. Accoringly, all the thermal events characterising the ifferent K90-SLS systems were recore an reorte in the hase iagram of Figure 3. It can be seen that, u to a SLS content of about 9%, only one hase exists an the Fig. 1 DSC attern of K90. Enothermic eak is uwar Fig. 3 SLS-K90 hase iagram

6 410 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) increase of SLS content simly reflects into a reuction of the T g cometing to the K90-SLS system. This is reasonable as SLS, acting as a lasticizer agent, enhances K90 molecules mobility. Obviously, once temerature T excees T g, the glass hase transforms into a rubber hase. As soon as SLS content excees 9%, DSC analysis reveals the resence of a bi-hasic system comose by a K90 reach hase an an SLS reach hase. Inee, other three thermal events a to the original one referring to the glass-rubber transition. Accoringly, u to 87 C (ure SLS soli-soli transition) we have the coexistence of a glass hase, rich in K90, an a soli hase, rich in SLS, enominate olymorhic 1. A temerature increase inuces the transformation of the SLS-rich hase in the olymorhic state while being unaffecte the glass hase. Deening on the SLS content, this secon bihasic region sans from 87 C to C. Once this threshol is overcome, the glass hase becomes rubber while no moifications are observe in the SLS-rich hase (olymorhic ). A further temerature increase reflects into the formation of new SLS-rich hase enominate soli 3. This bihasic region sans between 167 C an 196 C, regarless of SLS content. As the soli 3 hase cannot be etecte in the ure SLS (no thermal event occurs aroun 167 C, see Figure ) we shoul suose that soli 3 is inuce by the resence of K90. After 196 C, the coexistence of a rubber, K90 rich, hase an a liqui, SLS rich, hase takes lace. In orer to suort the existence of only one hase for SLS < 9% an the existence of two hases for higher SLS content, X-ray iffraction attern were recore for K90, SLS an two ifferent K90-SLS systems (SLS = 5% an SLS = 8.6%). Figure 4 an 5 show, resectively, the comarison Fig. 5 X-rays attern relative to K90-SLS 8.6% an SLS systems between the X-ray attern relative to the coules (K90 an K90-SLS 5%) an (SLS an K90-SLS 8.6%). It is clear that in the K90-SLS 5% system the eaks characteristic of SLS are not visible while a iffraction attern very similar to that of K90 aears. This means that, in this case, no soli hase is resent an only one amorhous hase exists. On the contrary, in the K90-SLS 8.6%, some of the eaks, characteristic of ure SLS, are resent an this witnesses the resence of a soli hase rich in SLS. In aition, the X-ray attern relative to the K90 rich hase is etectable. The hase iagram relative to the K90-TTAB system, reorte in Figure 6, was built accoring to the same roceure followe for the etermination of the K90-SLS hase iagram. We can see that for TTAB contents lower than 10% only one hase exists an system T g, correctly, ecreases with in- Fig. 4 X-rays attern relative to K90-SLS 5% an K90 systems Fig. 6 TTAB-K90 hase iagram

7 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) 411 creasing TTAB concentration. Once this threshol is exceee, a bi-hasic conition occurs: a K90 rich hase coexists with a TTAB rich hase. Inee, the DSC trace shows the aearance of the TTAB soli-liqui transition (aroun 100 C) lus another eak that inicates the T g of the K90 rich system. Accoringly, when TTAB content excees 10%, a temerature rise gives origin to the hase transformations reorte in Figure 6. For TTAB content exceeing 60%, the hase iagram is not so clear ue to the isaearance of the T g eak. Anyway, this region is not of ractical interest ue to the very high surfactant content. Obviously, also in this case, the X-ray analysis, erforme on three ifferent systems (K90-TTAB 3%, 7% an 50%), reveale that only one hase exists for TTAB contents lower than 10% while a two-hase system aears for higher concentrations. Finally, Figure 7, showing the K90-Lutrol hase iagram, makes clear that the solubility of this surfactant insie K90 is very limite (aroun 0.5%). Accoringly, its use in combination with K90 seeme not romising. Table 1 Water contact angle ( HO ) ± stanar eviation, iioomethane contact angle ( CHI ) ± stanar eviation, olar ( lv ) an isersional ( lv ) liqui-vaor surface tension relative to water an iioomethane, soli-vaor surface tension ( ), olar ( ) an isersional ( ) soli-vaor surface tension relative to K90-SLS films characterize by increasing amount of SLS (mass fraction X 100). All ata refer to room temerature (0 5 C). SLS (%) H O ( ) CH I ( ) 0 55 ± 1 17 ± ± 3 5 ± ± 4 ± ± 55 ± ± 4 64 ± ± 3 64 ± ± 3 55 ± ± 5 59 ± H O CH I ata from ref 17 lv =51 lv = 1.8 lv = 1.3 lv = 49.5 Fig. 7 Lutrol-K90 hase iagram Surface roerties Table 1 reorts the water ( HO ) an the iioomethane ( CHI ) contact angles relative to K90-SLS films characterize by increasing amount of SLS u to 7%, i.e., just below SLS solubility in the K90-SLS system (see Figure 1). These ata reveal that while the increase of SLS amount oes not reflect in systematic variations of HO, SLS increase imlies an increase of CHI. In aition, it is easy to verify that the tren of cos( ) versus %SLS (= f 1 ), for both water an iioomethane, oes not follows a linear tren as it shoul be accoring to the Cassie-Baxter equation (eq.()). Thus, we can conclue that only one hase exists at the K90-SLS film soli-vaor interface. This is in agreement with what foun by means of the bulk characterization (see K90-SLS hase iagram reorte in Figure 1). Table 1 also shows that, accoring to eq.(5), the increase of SLS reflects into a convex variation of (minimum value aroun 4%) while the olar comonent ( ) increases an the isersional comonent ( ) ecreases. The aition of SLS makes the surface more hyrohilic an, consequently, more wettable by water. On the basis of the eenence on the amount of SLS (see Table 1), it was ossible evaluating the excess of olymer ( 1 ) an surfactant ( ) on the soli-vaor interface accoring to eqs.(1)-(14). At this urose SLS content, exresse as mass fraction X 100, was converte into molar concentration (moles/m 3 ) knowing that olymer an SLS molecular weights are, resectively, 10 6 an 88.4 an that film ensity is, in the range 0 < SLS% 7%, aroximately equal to 885 Kg/m 3. Thus, the resulting vs. ln(c ) curve was fitte by the following equation: = A (ln(c )) 3 + D (ln(c )) + E (ln(c )) + F (15) an the values of the fitting arameters were: A =9.3, D = 110.4, E = an F = Relying on eq.(15), ( /ln(c )) was etermine an, consequently, (see eq(1)) coul be evaluate for all s s the exerimentally teste B ( n n1 c c1 ) values. The seuo-exerimental tren of versus B was fitte by the following equation:

8 41 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) l m B B (16) an the values of the fitting arameters were: l = , m = an = The evaluation of the sloe an intercet of the tangent to (B) in each exerimentally consiere B value, allowe to etermine the excess of olymer ( 1 ) an surfactant ( ) on the soli-vaor interface as reorte in Figure 8. Figure 8 shows that while 1 is almost zero whatever the SLS content, is negative for %SLS < % an then becomes ositive. This means that the olymer surface concentration is always equal to the bulk one, while the SLS surface concentration is lower than the bulk one for %SLS < % an it is bigger than the bulk one for SLS %. Accoringly, for a bulk concentration %, the surfactant shoul exert its action at best. Table Water contact angle ( HO ) ± stanar eviation, iioomethane contact angle ( CHI ) ± stanar eviation, olar ( lv ) an isersional ( lv ) liqui-vaor surface tension relative to water an iioomethane, soli vaor surface tension ( ), olar ( ) an isersional ( ) soli-vaor surface tension relative to K90-TTAB films characterize by increasing amount of TTAB (mass fraction X 100). All ata refer to room temerature (0 5 C). TTAB (%) H O ( ) CH I ( ) 0 55 ± 1 17 ± ± 8 ± ± 1 ± ± 1 6 ± ± 1 19 ± ± 6 ± ± 9 ± ± 5 19 ± H O CH I ata from ref 17 lv = 51.0 lv = 1.8 lv = 1.3 lv = 49.5 Fig. 8 Tren of the olymer ( K 90 ) an surfactant ( SLS) surface excess versus the SLS mass fraction X 100 The stuy of the surface roerties was also erforme in the case of TTAB, while it was not erforme in the case of Lutrol as this surfactant showe to be almost insoluble in K90 (see Figure 7). Table reorts the water ( H O) an the iioomethane ( CH I ) contact angles relative to K90 TTAB films characterize by increasing amount of TTAB u to 9%, i.e., just below TTAB solubility in the K90-TTAB system (see Figure 6). It can be seen that the aition of TTAB imlies a general reuction of H O an a general increase of CH I. Data shown in Table reveal, also, that the tren of cos( ) versus TTAB% (= f 1 ), for both water an iioomethane, oes not follows a linear tren as it shoul be accoring to the Cassie-Baxter equation (eq.()). Consequently, we can conclue that only one hase exists at the K90-TTAB film soli-vaor interface. This is in agreement with what foun by means of the bulk characterization (see K90-TTAB hase iagram reorte in Figure 6). Table also shows that, accoring to eq.(5), the resence of TTAB causes an increase of but this increase seems ineenent on TTAB concentration (TTAB%). In aition, while the isersional comonent ( ) is un-affecte by the resence of TTAB, the olar comonent ( ) increases, but this increase is ineenent on TTAB%. As the isersional comonent is always bigger than the olar one, we shoul conclue that the effect of TTAB on surface wettability is smaller than that of SLS, where the olar comonent resulte similar, if not bigger, than the isersional one for SLS% 4%. On the basis of the eenence on the amount of SLS (see Table ), it was ossible evaluating the excess of olymer ( 1 ) an surfactant ( ) on the soli-vaor interface accoring to eqs.(1)-(14). At this urose TTAB content, exresse as mass fraction X 100, was converte into molar concentration (moles/m 3 ) knowing that olymer an TTAB molecular weights are, resectively, 10 6 an an that film ensity is, in the range 0 < TTAB% 9%, aroximately equal to Kg/m 3. As is, substantially, constant with TTAB% (see Table ) an, thus, with ln(c ), it turns out that also is constant with B. Accoringly, we foun that 1 = 0 an = 4.*10 5 moles/m. This means that there is no excess of K90 on film surface, i.e. K90 surface concentration is equal to

9 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) 413 the bulk one. On the contrary, TTAB surface concentration is bigger than the bulk one. The comarison between TTAB an SLS surface behavior inicates that for SLS% %, the surface excess cometing to SLS is aroun 300 times that cometing to TTAB. A further comarison between SLS an TTAB erformance can be le by evaluating their behavior in aqueous solution/isersion in resence of K90 (water soluble; 10 mg/ml) an PVP-CL-M (water insoluble; 10 mg/ml). In articular, Figures 9a an 9b, show, resectively, the variation of the liqui-vaor surface tension ( lv ) referring to SLS an TTAB aqueous solution containing K90 or PVP-CL-M. Figure 9a reveals that the resence of K90 sensibly alters the tren of lv versus the molar concentration of SLS. This means that there is an interaction between K90 an SLS. On the contrary, as the resence of PVP-CL-M oes not affect the tren of lv versus the concentration of SLS, we can conclue that interaction between SLS an PVP-CL-M is negligible. Figure 9b, conversely, emonstrates that the interaction between TTAB an K90 or PVP-CL-M is negligible (no moification of the lv tren versus TTAB molar concentration). Desite both SLS an TTAB emonstrate to sensibly reuce the water contact angle on nimesulie (69.5 ± 9) when ae to water at 1% (w/w) ( SLS =1±; TTAB = ± ), in the light of the above consieration an those relative to the surfactant-olymer films, we ecie to exlore the effect of SLS on nimesulie release kinetics from nimesulie/pvp-cl-m/sls co-groun systems (11:3:1 w/w). It is worth unerlying that in this ternary system, the SLS mass fraction relative to the PVP/SLS system is 3%, i.e., the minimum surfactant mass fraction ensuring the maximum effect of surfactant (see Figure 8). Figure 10 shows the release kinetics relative to five ifferent elivery systems. Gray line, reresenting the release kinetics (issolution) of ure nimesulie, shows that nimesulie concentration is very low an only after, about, 13 minutes it can be etecte. Correctly, nimesulie concentration in the release environment (C r ) never excees the water solubility that is 9 g/ml 5. Dashe thin line shows the behavior cometing to the hysical mixture comose by nimesulie/pvp-cl-m. It is evient that the aition of the olymer, although cross-linke an, thus, insoluble, can consierably increase the release kinetics (this effect has been observe also for many other crosslinke olymers). Accoringly, after 0 minutes, C r aroaches nimesulie solubility. Correctly, the hysical mixture obtaine by aing SLS to nimesulie an PVP-CL-M shows a higher release kinetics (otte thick line). Inee, nimesulie issolution takes now avantage not only by the res- Fig. 9a Variation of the liqui-vaor surface tension ( lv ) referring to ure SLS aqueous solutions (black circles) an to SLS aqueous solutions containing K90 (gray circles) or PVP-CL-M (white circles) at a concentration of 10 mg/ml Fig. 9b Variation of the liqui-vaor surface tension ( lv ) referring to ure TTAB aqueous solutions (black circles) an to TTAB aqueous solutions containing K90 (gray circles) or PVP-Clm (white circles) the scarce wettability Fig. 10 Release kinetics relative to the five ifferent elivery systems stuie. C r is the nimesulie concentration in the release environment, while t is time

10 414 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) ence of the olymer but also by the resence of the surfactant. It is clearly evient that when the hysical mixtures mae u by nimesulie/pvp-cl-m an by nimesulie/pvp-cl-m/sls unergo co-grining, the release kinetics is enormously increase (thick an thin continuous lines, resectively). The ifferences existing among these two release atterns can be exlaine in terms of surface an bulk roerties. Inee, the resence of SLS, increasing system wettability, reflects into a higher release kinetics u to 40 secons. Then, nimesulie/pvp-cl-m exhibits a higher release kinetics. This can be exlaine remining that, in this system, nimesulie is resent only in nano-crystalline or amorhous form (as emonstrate by DSC analysis, ata not shown) an it is well known that nano-crystalline or amorhous rug are associate to higher solubility 4,5,7. On the contrary, in the nimesulie/pvp-cl-m/sls system, art of the rug is still resent in the original macro-crystals (as emonstrate by DSC analysis, ata not shown). As macro-crystals solubility is consierably lower than that cometing to nano-crystals an amorhous rug, the global riving force governing the release kinetics is smaller than that cometing to nimesulie/pvp-cl-m. Finally, Figures 11 shows a icture of the nimesulie/pvp-cl-m/sls system after h co-grining. It is ossible to istinguish the small acicular nimesulie crystals from the olymer-surfactant globular structures. Fig. 11 SEM icture of the nimesulie/pvp-cl-m/sls after h co-grining Conclusions This aer roves that the aition of a roer surfactant can enhance the erformance of co-groun rug-olymer systems reucing the roblems connecte with system wettability. Obviously, aart from other imortant asects (rug solubility, article size istribution an so on), the release kinetics eens not only on surface roerties (wettability) but also on bulk roerties (rug status: macro-crystals, nano-crystals or amorhous). At this urose, the surface roerties lay a more an more imortant role when the rug amount increases. Tyically, wettability can be a rate limiting factor when the rug/olymer ratio is 1/3. Of course this is not a general rule as this threshol eens on the wettability of the rug. In general, this limit is soun for rug characterize by a contact angle with water aroun 70. The selection of the roer surfactant requires the stuy of both the bulk an surface roerties of the olymer-surfactant system. Tyically, DSC an X rays are useful techniques to stuy bulk roerties as they allow etermining the solubility of the surfactant in the olymer. Conversely, contact angle measurement is funamental for the etermination of the olar an isersional comonents of the soli-vaor surface tension jointly with the excess of olymer an rug at the soli-vaor interface. References 1. H. van e Waterbeem, in: J.B. Dressman, H. Lennernäs (Es.), Oral Drug Absortion, Preiction an Assessment, Dekker, New York/Basel, 000, Cha. 4.. Quintavalle U., Voinovich D., Perissutti B., Seroz F., Grassi G., Dal Col A., Grassi. M., Eur. J. Pharm. Sci. 33 (008), Pharmacos 4, Euralex Collection, Meicinal Proucts for Human Use: Guielines. Volume 3C, Amion, G.L., Lennernas H., Shah V.P., Crison J.R., Pharm. Res. 1 (1995) Coceani N., Magarotto L., Ceschia D., Colombo I., Grassi M., Chem. Eng. Sci. 71 (01) Grassi M., Colombo I., Laasin, R., J. Contr. Rel., 68 (000) Murane S. B., Pikal, M. J., Shanker, R. M., Bogner R. H., J. Pharm. Sci. 99 (010) Nogami H., Nagai T., Yotsuyanagi T., Chem. Pharm. Bull. 17 (1969) Grassi G., Hasa D., Voinovich D., Perissutti B., Daas B., Farra R., Franceschinis E., Grassi M., Mol. Pharm. 7(5) (010) Carli F., Colombo I., Magarotto L., Torricelli C., Int. J. Pharm. 33 (1986) Debeneetti P.G., Tom J.W., Yeo S.D., Lim G.B. J. Contr. Rel. 4 (199) Kikic I., Lora M., Cortesi A., Sist P. Flui Phase Equilibria, (1999) Colombo I., Grassi G., Grassi M. J. Pharm. Sci. 98 (009) Voinovich D., Perissutti B., Grassi M., Passerini N., Bigotto A. J. Pharm. Sci. 98 (009) Hasa, D., Voinovich D., Perissutti B., Bonifacio A., Grassi M., Franceschinis E., Dall acqua S., Seh M., Plavez J., Invernizzi S., J. Pharm. Sci. 100 (011) 915.

11 I. De SIMONE et al., Stuy on Polymer-Surfactant Interactions for the, Chem. Biochem. Eng. Q. 6 (4) (01) Lee P. I., Polymer 5 (1984) Lee P. I., J. Contr. Rel. 4 (1986) M. Grassi, G. Grassi, R. Laasin, I. Colombo. Unerstaning rug release an absortion mechanisms: a hysical an mathematical aroach, CRC Press, Boca Raton (FL, USA), 007, American Pharmaceutical Association: Hanbook of Pharmaceutical Exciients (II e), ages , , an M. I. Ash: Hanbook of Inustrial Surfactants, (III e), Synase Information Resources, Inc, De Simone I., Stuio ell interazione olimero-tensioattivo er l incremento ella baganabilità i sistemi olimerici attivati er uso orale, Grauating thesis, Deartment of Pharmaceutical Sciences, Aamson A. W., Gast, A. P., Physical Chemistry of Surfaces, 4 th e., Wiley, New York, Kwok D. Y., Neumann, A. W., Avances in Colloi an Interface Science 81 (1999) Wu S. J., Polym. Sci., art C, 34 (1971) Prausnitz J.M., Lichtenthaler R.N., Azeveo E.G., Molecular Thermoynamics of Flui-Phase Equilibria, thir e. Prentice Hall, Englewoo Cliffs, N.J. 6. Goar E. D., J. Soc. Cosmes. Chem., 41 (1990) Burgio N., Iasonna A., Magini M., Martelli S., Paella F., Il Nuovo Cimento 13 D (1991) 459.