EFFICIENCY OF WATER REMOVAL FROM WATER/ETHANOL MIXTURES USING SUPERCRITICAL CARBON DIOXIDE

Transcription

1 Brazilia Joural of Chemical Egieerig ISSN Prited i Brazil Vol. 23, No. 02, pp , April - Jue, 2006 EFFICIENCY OF WATER REMOVAL FROM WATER/ETHANOL MIXTURES USING SUPERCRITICAL CARBON DIOXIDE M. A. Rodrigues 1, Ju Li 2, A. J. Almeida 3, H. A. Matos 1, ad E. Gomes de Azevedo 1* 1 Departmet of Chemical Egieerig, Istituto Superior Técico, Av. Rovisco Pais, Lisbo, Portugal. [email protected] 2 Departmet of Chemical Egieerig, Xiame Uiversity, Xiame , Chia. 3 Uidade de Ciêcias e Tecologia Farmacêuticas, School of Pharmacy, Uiversity of Lisbo, Av. Prof. Gama Pito, , Lisbo, Portugal (Received: October 20, 2004 ; Accepted: Jauary 28, 2006) Abstract - Techiques ivolvig supercritical carbo dioxide have bee successfully used for the formatio of drug particles with cotrolled size distributios. However, these processes show some limitatios, particularly i processig aqueous solutios. A diagram walkig algorithm based o available experimetal data was developed to evaluate the effect of ethaol o the efficiecy of water removal processes uder differet process coditios. Ethaol feedig was the key parameter resultig i a tefold icrease i the efficiecy of water extractio. Keywords: Water/ethaol mixtures; Supercritical carbo dioxide. INTRODUCTION New processes of particle formatio are becomig very attractive to the pharmaceutical idustry, where ihalable drug formulatios are gaiig importace. With the goal o delivery of isuli via the lugs almost accomplished by some of the major pharmaceutical compaies, it is expected that other formulatios will follow isuli i the emergig ew market of ihalable therapeutics. To eter the blood circulatio istataeously, replacig classic itraveous admiistratio, formulatios of ihalable drugs must reach deep ito the lugs, the site where these drugs act. However, lug brochioles are difficult targets because the trough ad its braches are physical barriers that ca retai most of the dose of the formulatio (Edwards, 2002). Very small particles with arrow size distributios are hard to achieve with the covetioal techologies, especially i the case of proteis due to their sesitivity to high temperatures, high shear stresses, ad orgaic solvets. Processes of particle formatio by supercritical fluids are cosistetly providig a solutio ad a competitive alterative to some of the established processes. The reasos for the relative success of supercritical fluid-based techiques are their ability to produce submicro particles with efficiet cotrol over size distributio i a sigle-step process, their exteded cotrol over the crystallie form of the products, ad their smaller evirometal impact sice this techology is potetially cleaer (Rodrigues et al., 2004). Carbo dioxide is the supercritical fluid that has bee most widely used due to its relatively low *To whom correspodece should be addressed

2 206 M. A. Rodrigues, Ju Li, A. J. Almeida, H. A. Matos, ad E. Gomes de Azevedo critical poit (7.38 MPa ad 31.1ºC), low cost, ad evirometal acceptability. However, because most of the therapeutic compouds, especially macromolecules such as proteis or ucleic acids, are sparigly soluble i supercritical (SC) CO 2, atisolvet techiques such as GAS, SAS, ad SEDS have the greatest potetial i the pharmaceutical idustry (York, 1999). Supercritical atisolvet procedures ivolve drug dissolutio i a liquid solvet that is further expaded by the dissolutio of the supercritical phase, forcig the drug to precipitate. I most cases the choice of solvet is the critical stage i processig biological macromolecules for therapeutic purposes. Ideally this solvet should dissolve large quatities of the drug without deactivatig it ad should also be highly mixable with the supercritical fluid. Such solvets have yet to be foud, but orgaic solvets such as DMSO or methylee chloride have bee reported to be able to precipitate several proteis. Orgaic solvets, however, are potetial deaturats for most therapeutic macromolecules, ad as a cosequece, the biological activity of the products ca be severely affected. Also, with this approach a dry protei reaget is required, which meas that the raw protei broth first has to be processed by other techiques, such as spray-dryig or lyophillizatio, which cosequetly raises questios o the purpose ad advatages of the supercritical fluid techology. Successful formulatios are therefore difficult to obtai without usig water i the productio process, which represets oe of the major difficulties i the processig of protei molecules with supercriticalfluid techologies. The reduced solubility of water i supercritical CO 2 makes atisolvet processes very iefficiet. The itermediate solutio of mixig water with ethaol i order to improve the miscibility with the SC-CO 2 has bee show to be somewhat reliable for may formulatios. May biological macromolecules are tolerat to moderate cocetratios of ethaol, ad small amouts of ethaol ca icrease the miscibility with the SC phase by several orders of magitude, thus icreasig the efficiecy of the process. Ethaol also shows some advatages over other solvets: low toxicity, FDA approval, ad cost. The use of water/ethaol mixtures has bee reported for GAS, SAS, ad SEDS. Briefly, the GAS process cosists i the ijectio of a drug/ethaol/water solutio ito a precipitator vessel, ad its pressurizatio with CO 2 util drug precipitatio occurs. The ethaol/water mixture is the removed by circulatig fresh SC-CO 2 util a dry powder is obtaied. I the SAS process, a aqueous solutio is sprayed cotiuously ito a flowig SC-CO 2 phase eriched with ethaol ad the particles precipitate readily as the water is dissolved i the SC phase. I SEDS the aqueous phase, the CO 2 phase, ad a ethaol phase are sprayed together through a multi-chael ozzle i such proportios that all compoets are miscible i the SC phase except the drug that precipitates. Despite the itese research i this area, supercritical-fluid techology has ot yet received widespread idustry acceptace for processes of particle formatio. To achieve a idustrial scale, the effects of SCF processig of biological macromolecules o aqueous-based therapeutic species have yet to be show ad specially most of the operatioal parameters that determie the efficiecy of the process have yet to be optimized. The aim of this work was to evaluate the effect of the water/sc-co 2 /ethaol system o the efficiecy of processes of protei microizatio with supercritical CO 2 from aqueous solutios. The low productivity associated with SC fluid atisolvet processes is due to the complete removal of water from the iitial aqueous solutio. This difficulty costrais the (aqueous solutio)/(sc phase) feed ratio to very small values, makig the process very time-cosumig. However this depeds o the process selected, GAS, SAS, or SEDS; o the ethaol feedig; ad o temperature ad pressure, amog other variables. A algorithm, referred to as diagram walkig, based o data preseted by Duarte et al. (2000) was developed to geerate the water removal profile for the GAS process depedig o the process parameters selected. Source of the Data MODEL DESCRIPTION Duarte et al. (2000) compiled available VLE data for the terary water/ethaol/co 2 system coverig a temperature rage of 35ºC to 70ºC ad a pressure rage of 10 MPa to 18.5 MPa. Uder these coditios the terary phase diagram is of type I ad, for a costat temperature ad pressure, the VLE curve is represeted by a cotiuous lie ad therefore ca be described by a polyomial fuctio with rectagular coordiates, 2 ν = au + bu + c (1) where Brazilia Joural of Chemical Egieerig

3 Efficiecy of Water Removal from Water/Ethaol Mixtures 207 v = z si( π /3); u = (2z + z )cos( π /3); C2H5OH CO2 C2H5OH ad a, b, ad c are costats obtaied by fittig the experimetal data at differet pressures ad temperatures. Duarte et al. (2000) also foud a liear relatioship betwee the tie lie-slopes (at costat temperature ad pressure) ad the tie-lie iterceptios with the VLE curve o the liquid side (u L ). A liear equatio is therefore suited to the tielie slope calculatio: m= b0 + b1ul + c (2) where m is the slope, u L is the abscissa for the liquid iterceptio betwee the tie lie ad the VLE curve, ad b 0 ad b 1 were obtaied by Duarte et al. by data fittig. Diagram Walkig Algorithm Assumig that the system is always i equilibrium (steady state), the algorithm proceeds i three steps. This three-step routie provides a path for water extractio that depeds o the coditios selected. Each path ca be observed if plotted i the terary diagram, as schematically show i Fig. 1. Figure 1: Represetatio of the calculatios with the diagram walkig algorithm for a geeric H 2 O/C 2 H 5 OH/CO 2 vapor-liquid-equilibrium curve at fixed P ad T. Step 1: Determiatio of the Overall Mole Fractio (z) of Each Compoet The routie starts with the calculatio of the overall compositio of each compoet (zco2, z H2O, zc2h5oh) ad of (u k,v k ) i rectagular coordiates. This requires a estimatio of the amout of CO 2 (loop i i Fig. 2). Because the volume of the liquid is always very small compared to the total volume, we estimate the CO 2 mole umber by V V = + = + (3) k,i k,i k,i T L k,i CO2 V,CO2 L,CO2 L,CO V 2 m,co2 I Eq. (3), CO 2, L,CO2, ad V,CO2 are respectively the total umber of moles of CO 2 ad the umber of moles of CO 2 i the liquid ad i the vapor; V T is the total volume; V L is the total liquid (water ad ethaol) volume; ad V m,co 2 is the molar volume of CO 2 at the selected pressure ad temperature. Superscript k deotes the iteratio umber whe equilibrium has bee attaied. I the first iteratio L,CO 2 is ukow. Therefore the iteratio for obtaiig the CO 2 mole fractio starts from a iitial guess for L,CO 2 = 0, as described i the block diagram show i Fig. 2. Brazilia Joural of Chemical Egieerig Vol. 23, No. 02, pp , April - Jue, 2006

4 208 M. A. Rodrigues, Ju Li, A. J. Almeida, H. A. Matos, ad E. Gomes de Azevedo Read costats: PTV,,, y, f, V, abc,,, b b T i,c2h5oh V m,co2 0, 1, ρ, H2O, C2H5OH Set: i = 0, k = 0 Set: ki, ki, ki, = 0; = ; = L,CO2 H2O H2O C2H5OH C2H5OH k k, i k, i = 0; = 0; from Eq.(3) out,co2 i,co2 CO2 Step 1 ki, z j j = CO 2,H2O,C2H5OH Step 2.1 Step 2.2 ik, x ik, j y j from Eqs.(1),(2),(4) from Eqs.(1),(5) k k, i = CO2 CO2 ki, ki, ; ; CHOH 2 5 HO 2 ki, CO2 from Eqs.(9)-(11),(3) ki, ki, ; C2H5OH L,CO2 from Eqs.(6),(7) ki, CO2 from Eq.(3) yes Is δ L,CO 2 >ξ? o k out, j from Eq.(8) Step 3 yes ki, ki, > y HO 2 HO 2 Is z? o Figure 2: Schematic represetatio of the diagram walkig algorithm. Superscript k is the iteratio umber whe equilibrium has bee attaied. Step 2: Calculatio of the Tie Lie, VLE Curve Iterceptios, ad Mole Fractios For clarificatio we separate the calculatio of the tie lie ad of the VLE curve iterceptios ito two further steps. Step 2.1 Because (u k,v k ) are already kow from step 1, the liquid-side iterceptio (u L,v L ) is determied by solvig Eqs. (1), (2), ad (4) for u L, v L ad for the tie-lie slope m: νl ν m = u u L k k The smallest solutio is chose as u L. Step 2.2 (4) With (u L,v L ) obtaied from step 2.1, the tie lie ad its vapor-phase iterceptio with the VLE curve, (u V,v V ) are determied from Eqs. (1) ad (5) with d = v L mu L : Brazilia Joural of Chemical Egieerig

5 Efficiecy of Water Removal from Water/Ethaol Mixtures 209 ν= mu + d (5) Recalculatio of the Ethaol Added Because the ethaol added ( i,c2h5oh ) depeds o the CO 2 itake, it must be recalculated for the CO obtaied i each iteratio i by usig 2 Eqs. (6) ad (7): k,i k,i k 1 k i,co2 CO2 CO2 out,co2 = + (6) k,i i,c2h5oh = k,i 1 i,co2 1 y y i,c2h5oh i,c2h5oh (7) where i,co ad 2 out,co are respectively the 2 mole umbers of CO 2 that etered ad left the system. We assume that the ethaol vapor compositio ( y i,c H OH ) i the vapor feed is costat. 2 5 Step 3: Removal of a Small Part of the Vapor A small fractio (f V ) of the vapor is removed ad replaced by fresh CO 2 ad ethaol. For each compoet the moles extracted are calculated from k k 1,i i 1 out,j V V j = f y (8) where subscript j refers to each compoet (j = H 2 O or C 2 H 5 OH or CO 2 ). The ext operatig lie is determied from Eqs. (9) ad (11); however this requires estimatio of the ethaol added to the system with Eq. (10): k,i k 1,i k H2O H2O out,h 2 O = (9) k,i k 1,i i,c2h5oh V = f y (10) V i,c2h5oh k,i k 1,i k k,i CHOH 2 5 CHOH 2 5 out,c2h5oh i,choh 2 5 = + (11) The correct amout of ethaol will be determied oly after the secod step of the ext iteratio because it depeds o the total amout of CO 2. EXPERIMENTAL To evaluate the experimetal reproducibility ad usefuless of the diagram walkig algorithm predictios, a GAS apparatus was used to obtai experimetal data. Each experimetal ru starts by ijectig a ethaol/water solutio of kow compositio ito a 460 cm 3 high-pressure visual cell, placed iside a temperature-cotrolled air box, as schematically show i Fig. 3. The cell is the pressurized with CO 2 (99.998% pure, supplied by Ar Líquido, Portugal) usig a motor-drive gas compressor (Newport Scietific, model ). The gas circulates first through a temperature-cotrolled cylider for temperature equilibratio. The workig pressure is cotrolled by a back-pressure regulator (Tescom, model ). Whe the workig pressure is reached, the backpressure regulator opes ad the liquid is extracted by the circulatig CO 2. The total amout of CO 2 cosumed is calculated based o flow meter readigs (Omega, model FLR 1000). Extractio is stopped whe oly oe phase is observed iside the cell. All the extractio rus were carried out at 10 MPa ad 40ºC with CO 2 flow rates from 3 to 7 g mi -1. Figure 3: GAS apparatus used i the determiatio of the efficiecy of water extractio by supercritical CO 2. Brazilia Joural of Chemical Egieerig Vol. 23, No. 02, pp , April - Jue, 2006

6 210 M. A. Rodrigues, Ju Li, A. J. Almeida, H. A. Matos, ad E. Gomes de Azevedo RESULTS AND DISCUSSION The Effect of Ethaol Fractio o Extractio Efficiecy Several extractio pathways were obtaied with the diagram walkig algorithm for differet iitial mass fractios of ethaol ad differet ethaol feeds. I Table 1 the variables that were kept costat are show. I Fig. 4 the higher selectivity of the CO 2 for ethaol i the terary system ca be see. It is evidet that without ethaol feed the icrease i extractio produced by the ethaol iitial fractio eds rapidly ad the system teds towards a biary CO 2 /water behavior. It ca also be observed that the efficiecy of complete water removal is little affected by iitial ethaol cotet. Efficiecy is defied here as the moles of water removed per mole of CO 2 cosumed. As Table 2 shows, a 35% icrease i efficiecy is achieved oly for ethaol mass fractios greater tha 0.7; however, these high-ethaol cotets are frequetly usuited for the processig of biological molecules ad i most cases the advatages of addig ethaol to the liquid feed do ot compesate the advatages of usig ethaol-free solutios. Table 2 shows that 5% (mass) ethaol i the CO 2 feed icreases the extractio efficiecy by over 500%, revealig that this is the key parameter for successful water removal. A importat drawback may however result from the ethaol feed; the ethaol cotet i the liquid fractio icreases durig extractio ad may reach values usuitable for successful formulatios. Stability of the active molecules i the terary liquid mixture is therefore the limitig parameter for ethaol feed ad cosequetly for extractio efficiecy. Table 1: Fixed variables. Pressure Temperature Vessel volume CO 2 desity Liquid desity Water cotet 10 MPa 40ºC 200 cm g/cm g/cm3 0.5 mol C 2 H 5 OH C 2 H 5 OH H 2 O CO H 2 O CO 2 Figure 4: Extractio pathways geerated by the diagram walkig algorithm for solutios with differet iitial ethaol mass fractios (0.7:, 0.5: ; 0.1: - - -) without ethaol feed (left) ad with ethaol feed (right). The straight lies are the iitial tie lies geerated for each mixture. Table 2: Compariso of efficiecies of water extractio from solutios with differet iitial ethaol mass fractios usig a CO 2 feed with or without ethaol at 10 MPa ad 40ºC. Ethaol mass fractio Without ethaol i CO 2 feed Efficiecy 10 3 Icrease i efficiecy (%) With 5% ethaol i CO 2 feed Efficiecy 10 3 Overall icrease i efficiecy (%) Brazilia Joural of Chemical Egieerig

7 Efficiecy of Water Removal from Water/Ethaol Mixtures 211 The Effect of P ad T o the Extractio of Water with Ethaol-Saturated CO 2 As described i Table 3, pressure ad temperature have a sigificat effect o process efficiecy. Depedig o the iitial ethaol cotet, a icrease of 4 MPa (or of 20ºC) results i efficiecies that are 20-30% higher or eve much higher with a simultaeous icrease i both pressure ad temperature. Experimetal Reproducibility of the Algorithm Table 4 compares the efficiecies of water extractio obtaied experimetally (at 10 MPa ad 40ºC) with those predicted by the diagram walkig algorithm. There is good agreemet betwee the experimetal ad predicted values, with a deviatio ot larger tha 10%. Moreover, we foud that this agreemet was slightly sesitive to chages i the solutio mass or i the iitial mass fractio of ethaol. Table 3: Compariso of efficiecies of water extractio from solutios with differet iitial ethaol mass fractios at differet temperatures ad pressures usig a CO 2 feed with 5% ethaol. 10 MPa, 40ºC 14 MPa, 40ºC 14 MPa, 60ºC Ethaol mass fractio Efficiecy 103 Efficiecy 103 Icrease i efficiecy at 40ºC (%) Efficiecy 103 Icrease i efficiecy at 14 MPa (%) Table 4: Compariso of efficiecies of water extractio obtaied experimetally (at 10 MPa, 40ºC) with those predicted with the diagram walkig algorithm. Mass of hydroalcoholic solutio (g) Mass fractio of ethaol Experimetal CO 2 Cosumed (mol) Predicted CONCLUSIONS A diagram walkig algorithm based o available experimetal data was developed to evaluate the effect of ethaol o the efficiecy of water extractio uder differet process coditios i supercritical fluid-based techiques. Ethaol feed was the key parameter for icreasig water extractio. The combiatio of the use of ethaol feed with a icrease of 4 MPa ad 20ºC icreased extractio efficiecy tefold, revealig that water extractio limitatios i supercritical atisolvet processes ca be overcome with the use of a third compoet such as ethaol. Compariso with experimetal results showed that the diagram walkig algorithm preseted here is a reliable tool for evaluatio of the effect of ethaol o the efficiecy of water removal with supercritical CO 2. Further work is beig carried out for a complete itegratio of the phase equilibria for the terary water/ethaol/co 2 system with the algorithm preseted here. Together they will allow a more geeral approach because this techique ca the be applied at ay pressure ad temperature. ACKNOWLEDGMENTS Fiacial support from FCT, Lisbo (Projects POCTI//EQU/34961/1999, POCI/EQU/55911/2004, ad postdoctoral grat BPD/5526/2001) ad the Europea Uio Programme FEDER is gratefully ackowledged. Brazilia Joural of Chemical Egieerig Vol. 23, No. 02, pp , April - Jue, 2006

8 212 M. A. Rodrigues, Ju Li, A. J. Almeida, H. A. Matos, ad E. Gomes de Azevedo REFERENCES Duarte, C., Aguiar-Ricardo, A., Ribeiro, N., Casimiro, T., ad Nues da Pote, M. N., Correlatio of Vapor-Liquid Equilibrium for Carbo Dioxide+Ethaol+Water at Temperatures from 35 to 70ºC. Separatio Sciece ad Techology, 35, 2187 (2000). Edwards, D. A., Delivery of Biological Agets by Aerosols. AIChE Joural, 48, 2 (2002). Rodrigues, M. A., Peiriço, N. M., Matos, H. A., Gomes de Azevedo, E., Lobato, M. R., ad Almeida, A., Microcomposites Theophyllie/Hydrogeated Palm Oil from a PGSS Process for Cotrolled Drug Delivery Systems. J. Supercritical Fluids, 29, 181 (2004). York, P., Strategies for Particle Desig Usig Supercritical Fluids. Pharmaceutical Sciece & Techology Today, 2, 430 (1999). Brazilia Joural of Chemical Egieerig