Cans A Modern Approach to Solvent Selection Although chemists’ and engineers’ intuition is still Rafigul Gani Technical University of Denmark Concepcion Jiménez-Gonzélez GlaroSritiKline Antoon ten Kate ‘Alze Nobel Peter A. Cratts, Mark Jones and Lyn Powell AstraZeneca John H. Atherton Britest Ltd, Joan L. Cordiner Syngerta Crop Protection clvents have been used for centu- ies aad in all trpe of industries the processing, manufactur. ing and formulation of goods, In the chemical process industries (CPD, solvents are used in various process- ‘operation steps such a8 seperation (of ens liquid andor soli), reaction (as re- action medium, resetant, and eazrier), degreasing, washing and many more. ‘As part of product formulations, sol- vents are used in paints, textiles, rub- ber, adhesives end thousands of other products found at work and home. In The cleaning industry, selvents are vused as cleaning reagents (dry clean- ing, washing) or as part of ¢ Cleaning product. This list is not exhaustive, ac solvents are used for many other indus- trial, seademie and research parpnses. While solvents have a very wide range of application, many of the commonly used solvents pose seri- as environment, health and safety (BHS) concerns, including human and -eco-toxiciby issues, process safety hax- ards and waste management issues, Furthermore, solvents are subject to increasing and contirnous regwatary scrutiny. One consequence is the need tw avoid the use of organie solvents whore possible. When elimination is not feasible, effar's should be made important, powerful tools are becoming available to reduce the effort needed to select the right solvent | %2 optimize, minimize and recycle solvents in order to reduce the EHS impact and move towards more sus tainable prartices by following green chemistry and engineering principles Ul (see alse p.7 in this issue), There fare, the drivs to develop cleaner tech- nologies with lower envirrumental impact hes led to increased research ‘an solvents, with spetia) emphasis on selecting the roost appropriate solvent and on developing now colvonts to moot targeted properties. Making achoice The appropriate selection of solvents depends to 2 large extent on the ap- plication — more specifically on what eds to he dissalved and under what cenditinns. Other considerations such assolvent recovery and covont release are gaining inereasing importance due to the stricter regulations on release and t0 increased competition Coosider, or example, the separa- Sion of phanol from water in process stream before itis released. Ifaselvent- based, ligaid liquid extraction process isto be nsod, then the solvent needs selectively dissolve phenol, should be ‘easy te recover and recyele, and should have very low water solubility so that selvent loss and environmental impact will be Jom. On the other hand, clean- ing a printing press from the ink may require the solvent to simply dscolve he iok iphus dirt) and then be washed with water (r dried with an absorber) In this cago, a solvent that dissolves the ink but is soluble in water and is velatilo could be a good candidate Ia the pharmaceutical and specialty chemical industries, tho use of sol- vents to promote reactions is very som- mon Here, solvents may be Used 85 = reaction meditum to bring teactants together, 65 £ reactant to react with a solute when it caanct be dissolved, ‘and 6 ¢ carior to deliver chemical compounds in solutions to their point of use in the required amounts, In ads dition, solvents are used to isolate & Product, as well as in the cleaning oF washing steps ofthe reaction stage. Other uses of solvents aS part of product formulations are abo very common. In paint formulations, the solvent moods to dissoive the past bat when the paint is applied, it should vaporize and leave the paint on the applied surface. The same is true for products such as adhesives and der mal products for skin care. Here, the solvent ie impertent not only to dbs- solve the active ingredient but also to have a desired evaporation rate to en: hance the produet behavior. In the pharmaceutical and chemical industries the amount of solvent roey- dled is small compared to the amount disposed by, les say, incineration, Ln the agrochetticals industry, only eol ‘eats approved by regulating agencies, such as the US. Environmental Protec tion Ageacy (BPA; Washington, D.C), ‘an be used, This restricts the choice, ‘while use of newly designed solvents raust watt until all data on safety have heen generated and boen accoptid by the regulating agencies. Consequently, solvent sélection and optimization and EHS impact are interrelated, ‘The introduction of cleaner, more sus- tainable technologges and sclvents has become more impartant. New solvents are being developed (suth as super- entical fluids ioni liquids, tailored sal vents, perfluorohydrocarbins, 9 maresor ck ‘scample functions 1 fow! in the hope that these might be less hazardous, whilst maintaining the roquired selveat properties. Presented below is a roview of dif ferent salvent-selecton techniques that are in current use, primarily in the chemical and pharmaceutical in dustries, as well asa diseussion of some of the future challenges. The methods and tools discussed are not the only onet available, but are ones in which the authors have experience in application. First the general sol vent selection problem is defined, fl- lowed by a set of guidelines on the so- lution steps Then, for a selected set of solvent selection problems taken from industry, the solution steps are illus- trated Uurough applications of meti- ods and toole that are currontly avail able, A brief overview of the methods and tools together with te important issues and needa corresponding to the solution stops are also included THE SELECTION PROBLEM ‘Tho solvent-selection problem is de- fined here in terms of the type of ap- plication for which the solveat will be ‘used Figure 1 Diustrates three selvent- selection problems in terms of their ap- plication type. Examples are given here for each epplication type and linked to the solvent function. type of products and recycie or release of solvents, Process applications Given the identity of a solute (or solutes), the task is to Bind a suit- able solvent(s) that can dissolve the selute(s) and that can be recovered and recycled with minimum solvent Joss. Solubility as wall as tha quantity to be dissolved or removed are im- [aes Aone Acotcaon noes pe aa FIGURE 1, ilustration of types of schent applications and corresponding solvent portant, The solute(a) may be eolids liquids or gases and be present alone or es part of a mixture. The function cof the ealvent could be to separate or extract the solute(s) or to promote one ‘or more reactions. Additional selection ceniteria ore that tho solvont(e) should be stable, should be low-cost, should be readily available and should have ‘an acceptable eavironmeatal impact Speeifie examples of process-related applications are: Find solvents to pro- duce high purity ethanol by separat- ing it using distillation from an aq ous mixture that is obtained through a fermeniation process; find solvents te separate aromatics (benzene, tolu- ene, xylenes) from paraffins (pentane, hexane, heptane, Os" by liquid-liquid ‘extraction; Sind neutral solvents to in- crease the product yield in the conver- sion of S-octanol to 3octanone. Product formulations Given the identity of an active ingre- dient (Golute or solutes), the tasic is to find 2 suitable solventis) that can not only dissolve the solute(s) but also achieve a desired product behavior during application of the product. The solvent is not recovered or recycled and is released during the applica- tion of the product. Additional selec- tion eritaria are that the solvent(s) should be stable, low-cost, readily available, and in compliance with any applicable regulations (such as the guidelines from the International Conference on Harmonization (ICH) 2), and should have accoptable envi- ronmental impact. Specific examples for product-for- ‘mulation applications are: Find mini- ‘mum-cost solvent mixtures that, when f added to a paint or printing ink iplus additives), will match a de- sired evaporation profile and prod: fact seosty. find solvents that F will dissolve the active ingredeat during an encapsulation prooss; [find solvents that when added to a solid active ingredient will frm an tmnulsion of desired activity. Cleaning and washing ® Hero, the task is to find a suitable ‘solventis) that ean remave (or lean or wash) undesired material (sol- ‘te or solutes). The solute may be consist of known chemicals, or it may be unfamiliar. The solute\s) may be a solid, liquid oF gas and present alone fo as part of « mixtare, The function of the solvent is ta remave all solutes. The selvent is not recovered or reey- led and the solvent-based cleaning is usualy followed by a washing step, typically with water. Additional selec- ‘on criteria are that the solventis) should be stable, inexpensive, and readily available and should have ac- ceptable environmental impact. ‘Specific examples of cleaning and washing are: Find solvents to remove unwanted material (chemical identity andior composition unknown) from process equipment or surfaces. A GENERAL PROCEDURE ‘A four-step procedure for solvent selec- tion for te problems described above i shown in Figure 2. Fach of the stops are deseribed here. 1, Problem identification ‘The fist step in solvent selection is ta identity the actual problem and identify the direction required te solve the problem. An additional question ask at this point is whother the use of iret is necessary, o whether the abjecive can be mot by some otber ‘means, such as physical separation ot selventive reaction An example of this ctep might bo the identification of product that does not meet specifica tions (an off spec produc, The solution direction identiBiod might be to extract ‘contaminants out ofthe product 2. Search criteria definition In this step, the requirements that need to be met by the solvent are de-Cece fined. The criteria used are related to lin arbitrary order) » Paysical and chomical properties (pure-solvent properties) + EHS characteristics (eolvent EHS properties) + Operational properties (solvent scl ute properties) ‘+ Fumeticnal constraints (solven!- function properties) + Economic figures final selection er teria) Examples of this step might be: Toe solvent should dissolve high amounts of contaminant, ut bitte uf tbe prod- uct; the solvent shoal be im:niceible with the product, the solvent shoald be a liquid at operating conditions: the solvent should act be tosis; the solvent should be available at aecept- able costs, and, preferably, be already sn use at the plant. ‘The role af the properties is shown in igure @. We start with a list of chemivals some of which may be suit- able as solvents, The properties of the pure eolvent are used to help 10 nar- row down the soarch spoce until the chemicals satisfying a tho target properties for the soivents have been matched 9. Performing the search ‘The third step in solvent election is to identify and rank potential solvent candidates according to the enteria ‘The search can be performed in a spurnber of ways" + Benchmarking: What can we adopt from the same or similar processes? What can we learn from systems with the same or similar com- pounds? ‘= Expertise snd oxperienco: What kind of eompounds would we think of booed on our chemical intaition and aur technical experience? + Database search: Can we find com. ‘pounds in some database that Aufl! ‘She set criteria? = Computational approseh: Can we “saleulate” compounds that_meet the eritoria? There are two distinct computations] approaches: 2 Generate 4 predefined list of can- didates and rank their spplicabil- ity according to the enteria 2 Employ molecular design (sof- ware builds {olen solvent salection the compoundis) “from scratch" to meet the eviteria} ‘To apply the benchmarking approach, check which solvent(s) was (were) used for a similar produet and puri- fication process. To apply the exper- tise and experience approach, first establish the type of solvent needed and then search a databace to find a match with the same pattern, To apply the computational approach, ‘quantify the solrent pattern in terms of quantitative property values. and then use malecular design methods to generate and evaluate chomical structures that atch the desired properties. 4. Verification of results ‘The Snal stop in solvent selection is to ‘verify that the suggested candidates actually work as expected. First, a computational validatia, may be per- formed: for example, by simulating the ‘extraction step using process-simula- tion software. Experimental validation of the sclvent candidate is required at all stages of process development, from laboratory and pilot scales to ac- ‘ual plant trials comm sii li a cas sesuhitinnt Note that the four-step guidelines given above can, in general, be up- plied to almost all sclvent-selection problems, and the approach is sinilar tw that recently proposed fer ebemical product desiga [5]. Note also that, for ‘agiven preblom, uct all the steps may bbe necessary Also, in performing the search, a datobase maybe necessary for all four ctaps listed above. If tov many feasible alternatives are found, the search-eriteria definition could be tightenod and Step 9 repested 1 re- uce the number of alternatives. On tthe other hand, if too few of no alter natives are found, the search-eriteria deficition could be relaxed and Step 3 repeated to generate more alterna- tives. If only experimental data based generation and evaluation of alterza- tives are mace in Step 2 then Step 4 ‘may not be necessary. IMPORTANT ISSUES Some of the important Issues related to the four-step goneral procedure for solvent sélection are now discussed. These issues adtiress finding the an- swers to quostions ouch as: Which aroperties and finetions define theI ETION TOOIS USED BY THE AUTHORS “SOLVENT SELECTION TOOLSUSED BY THE AUTHORS [riven epcrabiby 26 PNFSCS Ras oils [acti coefcion! uceds of the solvent? How do we ob- tain the solvent properties and func: tion values? How do we generate and evaluate solvent. alternatives? How can we verify and test selected solvent alternatives? Properties & functionsneeded In general, the properties and Fune- tions aeeded for a epecifie solvent tclection problem can be chosen from the four classes of properties shown in Figure. 3: pure-solvent properties sclvent-EHS properties, solvent-sok- bite propersies and solvent-function properties Pure-solvent properties. These are pure-componestproperties ofa chemi- ‘al through which its function as a sol ‘vent can be established. For example, the melting point and the boiling point of a chemical establish if the sclvent ‘would exiet as a liquid at the condition of operation of the solvent-based pro- cess, The most commonly used proper- fies of thie type are! + Primary pure-zomponent properties \single value per chemical), such as ‘ormal boiling peint, normal meit ing point, the heat of fusion at 298 KK. the heat of vaporization at 208 K, the specific heat at 298 K, the Hil: debrand solubility parameter at 298 K. and the Hansen solubility param eters + Functional purecompenent proper ties (properties that are depeadent ‘on temperature or pressure, or bath), ‘such a8 vapor pressie, viscosity, en thalpy, and heat of vaporization Solvent-EES properties. These are ‘leo usually pure component proper ties of a chemical but are separately TABLE Saag Ns ate, ae Sevens to eS elect tt caning choi gone (en se Ts ope a (eehon Geico: [sven sorecton too nghightng EHS esate Bo ‘mained based on segrroat cortrbullors, Poditive ved ong \Aseitorofcekssany dete he elect method Yeo sts. Vsti or cyetstision, Scent slacton and oxerds to Uf end VE nee lrofes mas be gorercted rina UCT ‘a ee fie tie ties, the next important issue is te eb- classified because they do not directly tain reliable values of these properties define the aeed of the solvent. Instead, they are used ta screen solvent candi. | for tbe solvent as well as the solute( Gates in terms of properties relawed to | There are several alternatives. For ¢x- environment, health end safety: Some | ample, one can measure the required ‘exaxiples of propertias of this type | properties, use a database of proper: fare, toxicity, odor. biodegradability, | ties of chemicals (or solvents), or, use ‘Gooue depletion potential (ODP), and | property models to estimate them. flash point, "The most important issue here is ‘Solvent-solute properties, These are | the accuracy of the obtained property data (moasared or estimated). Note usually solution properties where the mounts ofthe chemicals solvent and | also that it is easy 1 find measured folate) in solution play ard together | solveat-pure and solvent EHS proper swith the temperature and pressure | tics in databases as they only require Of the operation, The most common | a one-dimensional search, For solvent property of this type is the solubility | solute and solvent-furction properties, br the solute as a function ofthe cor- | tho soarch ix moze difficult as they position af the solute-solvent mixture. | require a two: or higher-dimension Other useful properties are satura- | search. Also, it is usually more dif tion points (er soli, liquid, gas) as a | Geult to find measured data because function of temporatare and pressure: | such information may not be available surface tension, solution wscasity;and | for the epeifc solvent eolute system ‘diffusion cveffcien:. These properties | of interest. Ancther issue with respect Gefine the principal solvent neods. | to solvent-function data is that mea- ‘Soleent-fumetion properties. Taese | sured data may be available only for are usually properties that are ob- | existing procestes sved as the solvent or solvent based | ‘Therefore, for a majority of slvent- formulated product is applied. For eX- | solute and solvent-function properties, Ample. the amount of solute removed | both predictive and reliable models ainlsclved in the solvent, he solvent | are needed. Group contribution based lest from an extraction process, the | models 14, 5] are quite useful when produdt yield from a reaction, product | they match the required accuracy Behavior as 2 function of evaporation | Models basad on statistical thermo, Pato and the environmental impact. | dyaamics, suck as SAT (@, 7}, and ‘These properses define the perfor: | quantum mechanics, such as COSMO trance Unetuding economical and en- | [8], are also finding increasing wse In ‘ronmental impacts) of the solvent | solvent-solute properties calculations. based application In Table 1, salvent-coloction tools om- pleying property prediction are pr. Properties & functions values | vided. See also Table 8 for a list of ‘Once the needs of a solvent-selection | databases that may be used in solvent probiem have been defined in terms of | soloction as well as for developine uentitative values of a set of proper- | property models. CHEUICAL ENGINEERING WORN OHECOM MARCH 008 33Ceneratefevaluate aliernatives An efficient soarch procedure is re- ‘quired in arder to generate yotential solvent alternatives and t9 evaluate them. Four poasible approaches are considered below Basically all ap- proaches for generation and evalua Bon of solvent altematives perform some kird of search as ilustrated in Figure 3, Note, however the order of the serening in terns of property types may be diffront, and some cans putational approsches may consider a Simultancoas rather than an ordered: sequittial sppriach. Benchmarking. As mentioned above, it is sometimes gossible to selet sol ‘ent candidates by analogy wit simi- lay processes. From the vast eange of tontbooks on solvent related published Inerature it ix frequently possible to find a elose analogy to the process under study. It must be recognized howevor that the eriteria of te ayn- thetic chemist with respect to solvent selection may be very different from hose required to provide a satisfac tory industrial process. For example, chemists working i the area of prot. vet discovory are mainly interested in maximizing the ease of laboratory scale synthesis, and at this staze of de- ‘velopment the EHS iesues associated with large seule manufacture are uch always considered, Taus, for example, dichioromethane Gequently features sn small scale synthases, and hao tobe ‘designed out” during the development procoae This is discussed In more de- tail later by meas of an example. Database search. Direct search: This principally. in- volves searching a database for com pounds having properties similar to the desired solvent. properties. The search could be ordered such that Ast solvent-pure properties sre used in the aourch, followed by oalvent- SHS, followed by solvent solute and finally solventfunction. This order ensures that the most relisble and easy-to- search data are used first. Note that in many eases, tho selvent-sohuto data and the solvent function data will e- ther need to be measured or estimated sbrough a suitable simulation model In this way, the computationally inten- sive and timo consuming sters handle svaller number of alternatives TOGETHER WITH THEIR R TABLE USTOF SOME own sons iz [Nii * aa 5 grande [Ame mD Tere ‘Seen (gross scaptal NEB sar FIGURE 4. Principal component analyst ‘As an ecample, consider tie prob- lem of finding solvent replavements for benzene that are environmentally more acceptable, The following x vent-pare properties and soleen!-EHS Droperties may be used to identify the benzene replacements: normal beil- ing point (252.2 FO, normal melting point (278.7 Ki, Hildsbrand eolubility parauieter (18 MP8) and loglg (a measure of taxicity; < 3) In addition. ty confining the search only ta acyclic ron-ehlorides, candidates with poton- tally unacceptable EHS properties can be indirectly removed. Note that the first three properties are of the NE = eonsectreyc ohaat B= Sdeami ntact eeceb PD 3748 eae a gereatolge rs eral mean pk Sa Par Beran alice in pou Sa Pay of sive prysteal rebates pure-solvent type and 30 the database search could bo used to first propare a list of compounds that match theoo properties. Then, the lis could be re- ‘dyond in size by removing those com- pounds that do not match the solvent EHS properties (logLCzp and chemical type). At this point, the solvent selec- tion problem has been solved unless details of the solutes) and solvent functions aro provided. Again, a da- tabase search could be made for data related to any of the sted solvents and the spocified colute.Ifno data are available, they will need to be mea- sured or estimated, The same is traeTABLE. LIST OF SOME WELL-KNOWN DATABASES: [ERC Haecteok of hems Frond res zi [DEGAMR ceri Bos, lgeney to eons Rieivrecechema.defCOSNIml get Tete en ETA ff rm me for the solvent-funetion properties. Statistical-design methodology: This ‘methodology is based on the evalua tion of a range of selected solvents to representa widerange of volvent prop- trties. The authors of Reference (9 de- scribe a statistical approach based on 1 principal-componest analysis (PCA) ofa rango of aclvents using eight com- ‘mon solvent descriptors. PCA of 82 solvents, using as descriptors malting tnd boiling point, dielectric constant, refractive index, Reichardt's solv tochromic parameter (a color-ceded acheme to categorize solvent's. polar: ity, (34), specifi gravity and logP val- nes gave an esceatially 2D response surface. Figure 4 shows some of the solvents listed on the response sur face, to ilustrate the way in which sol- vents are differentiated "The ty axis correlates with polarity Aeseriptors and the ty axis with polar izability descriptors. The ares covered by the response surface is referred 0 as the solvent space; for selection purposes, it is recommended that this ‘space be explored using & statistical design approach to identify those sol- ‘ven: types which give the best results for the process in question. Although the plot is not intended to be used to Ini ww cope i ctsk/Softwere/ICAS-cndteToos select « single solvent, it allows the identification of solvents with similer properties. Therefore, if solvent is al- ready known te be a good candidate, ‘the map can be used to suggest other possibilities. Expertise and experience. An under- standing of the chemical mechanism, together with the experience and inte- ition of the chemist, can sometimes be ‘used to deduce the most appropriate solvent type, This approach could also be described aa a knowledge-based ex- port system. An important element for this approach is classification of eol- ‘vents according to important and well Anown solvent properties (hydrogen bonding, polarity, Hildebrand solu Dility parameter, among others) that are able to deseribe the pattern (char- acterizing properties) of the desired solvent. The expert lor experienced ‘user) then employs a pattern-match- ing procedure ta identify the solvents that best match the specified pattern, Experts withia the chemical process industries routinely apply this ap- ‘proach, In most cases, it helps to gen- trate quick results, but not necessar- fly the best ones. Two examples af this approach are given below. For solvent selection problems not involving chemical reactions, the E | pattern of the desired solvent is es- tablished through analysis of the sol- tte, application type, and other con- =| straints, For example, specifying that || the solvent should remove a contami rant (characterizod by its solubility parameter value) from water, should be environmentally benign, should be ‘easy to recover and there should be 2 ‘minimum loss, means that the solvent should be non-hydrogen bonding, prof E| erably immiscible with water, have 1 low logLCyp value, provides @ pat ter (target) for the desired solvent. Duce this is eatablishod, a database of known solvents can be used to Kentify the solvents that mateh this pattera.A umber of useful databases are listed in Table 3. An example of the GSK sol- vyent-selection guide is also provided in Table 4 ‘On the other hand, when chemical reactions are involved, the approach is based on transition state theory and requires consideration of the relative solvation energies of the reecianis, products and transition states, and thus requires knowledge of the reac: tion mechanism. Chemists will usually have a good understanding of this. ‘A protocel derived by Britest Lid Ghttp/worwbritest.couk) seeks to ‘use mechanistic principles to guide solveat selection (soe Figure 6) The bjective is to follow the arrows. &- cording 10 the problem definition and search criterion until an end-point fs reached, identifying the group-type of the candidate solvents. Then the solvents listed in a solvents database (@c0 Table 2) under the corresponding ‘group-type are evaluated and a final selection made. Hybrid computer.cided techniques. ‘These techniques integrate databases, property-estimation models, and f- ficient polvent-acarch procedures ita ‘an integrated and powerful emputer- ‘aided tool for solvent selection, design ‘and evaluaticn. One example of these techniques is the computer-aided mo- lecular design (CAMD) methodology developed by Gani and cowerkers at APEC, Department of Chemical Ea- gineering, Technical University of Dea. ark, Figure 6 shows the main steps of tho CAMD approach. CAMD problems are defined as: Start with a given sot CHEMICALENGINEERING WHIW.CHE.COM MARCH 2006 38of building blocks and a specified set of | target propartios. Thea, determine the molecule oF molecular structure that matches these properties ‘This approach i the reverse of that used by property rredietion methed- logis, which start with the identity cf the molecule andor the molecular structure, and then a sot of targot properties is calculated, CAMD may be performed at various levels of size and complexity of moleeular structure representation. Figure 6 (Irom Refer. fence [20)) illustrates a typical group contribution based CAND mothod, where the predesigm phase defines the basic aceds, the design phase de- tecmines the Feasible candidates (gene erates molecules and tests for desired properties and the postdesign phase Serforms highenievel azalyoin of the molecular structure and the final se lection ofthe sclvent. The post-design hase may also address the question ofthe per‘ormance ofthe designed sol- vent. CAMD methods based on mae- roscopie properties are. suitable for design of relatively smaller molecales, sicher az solvents or a8 additives (or Ingredients) for formulated products, ‘Assuming thatthe target properties ave been identifed andl their geal values have boon specified, the main issues with all types of CAMD meth ods are the flowing ‘How to genarste molecular struc- tures? ‘How to represent the molecular stractare? + What level of molecular structural information will be used? ‘How the target properticn will be sbiained (calenlated andor mes sured)? ‘The complexity of the problom may be understood from the nambers of iso- ters that can be generated as s fune- tion of carbon number. As the carbon aumbers for each molerular type in- exease, oo dues the number af possible inomers. So, to address the questions above, one needs to consider very eare- fally, the molecular siructural param- stors that ald be used to represent the molecoles These same parameters will also need to be used for estimat ing the target properties. Itcan be noted that most group-con. tribution based methods design small eon Fees hot in Gime mad tae f ew BES date bree a molecules and therefore, do mot need to handle too many iscaners However unless the groupe are able to distine fuish between isomeric structures, those methods would not be able ta consider thers Also, eince many differ ent oypes of molecules are investigated in this case the number of candidates may sill bo quite large ‘The design of large complex mol- ecules, on the other hand, mainly depends on differences in molecular structures of somers or of molecular conformations of a particular moleet- lar type. Thorofore, i this case, molec Solent a ido ae fo ar her et: oe ed {ES he ae arid snd Sond atl pendant fy sie tees mt bece iden (sds area nay be wort staung het aoe ape Beis Caran penal ey Changed ange sare pede should rable then some elvan ny cage law | lar structures are represented at the mesoscopic and/or microscopic level, and property estimation methods that vce these variables are seeded. fn this, ‘ease, the aumber of candidates is like- wise very large because there may be Yoo many isomers. ‘Tho corresponding needs for a CAMD method are the following: + Atool for molecular structure repre- sentation at different scales ‘+ A tool for moleenlar structure gen- eration (based on a get of rules that will enzuro the generation of feasi- ble chemical structures)aprot por S aalomiton Somtin | —-cees noun: i lan Sees, Se ; nS a Cees =f Coons] Ceara | Soret FIGURE 5. Mechanism + Tuols for analyzing molecular struc- tural stability «+ Tools for target property estimation > A tool for property estimation ‘method selection (including iden- thfying whieh properties can be es tated for which database andi for experimental techmiques that ‘need to be nsed) ‘A brary of property estimation tmodele (methods and tools) that tare particularly suitable for eom- puter aided applications ‘+ A method of solution for the CAMD problem (the two mner steps of the design process) Since it appears that multiple-property rnedels at different scales or levels of molecalar structural variables will reed to be considered if the isomers ‘andlor multiple conformations are also faping to be considered, a communica- tion (link! between lower level medeling tools and higher leveling model tools ‘also need to be established. Harper ‘and Ganj [£1] established ouch a link for their hybrid CAMD method. The idea is to first establish the molecular type in the search/desiga through mac- _raseopie properties and then to lnk the promising candidates to higher-level ‘mesoscopie or microscopic methods for ‘more detailed analysis. ‘One starts with 2 molecular de- scription at the group level, which is then conversed to a 2D atomic repre- sentation at the atomic level. This is then passed to molecular modeling software that converts the atomic rep- resentation to a 3D model. which is then optimized to obtain the fiasl 3D structure. Once the optimized struc- tre bas been obtained, a whole range of descriptors and properties may be estimated. ‘The CAMD techniques have been applied with success for selection of solvents for separation processes (in- cluding liquid-liquid estroction, cepa Fation of azcotropie mixtures, solid separation, and washing, cleaning and drying operations (12), as well as in organie synthesis (231 Verify and test the selections ‘The approuches meationed above will of course need to be corroborated via ‘experimentation of the systems at hand. One of the advantages of arriv- ing to a preselected set of potentially feasible solvents is the likely reduc- ‘ion of experimental time and cost, since only a reducod set of options will need te be validated. Ideally the experimental testing of solvents will be carried out using docign-of-erperi- ments techniques to better identify in- terrelationships between parameters ‘in an experimental setting. Solvent-selection tools Several solvent selection techniques, uidelines and software have also ‘beon developed during the last decade. Most of these are integrated with da. tabases az well as property estimation ‘models. Table 1 lists some of the s0l- vent-selection tools that are available ‘and have been used by the suthers SELECTED EXAMPLES In this section, the four step approach tosolvent selection is demonstrated by means of five solvent-selection prob- Jems from the pharmaceutical and spo- ialty chomicals industries. Additional example problems from the chemical, petrochemical, and washing, cleaning and drying sectors (and many more), can be found in References (14-23) Find another reaction solvent Step 1: The objective for this example ‘sto replace 1,2-diethoxyethane (DEE) tas the primary solvent in the reaction stop ofa batch pharmaceatical process, ‘pesee solvent selection procedure (Britest Lid - wwve.britest.co.uk) ‘currently in the early stages of process development. The replacement work is driven by toxicity concerns and the probability of a more restrictive clas- sifeation for DEE in future environ mental legislation. In addition, DEE thas a relatively low auto-ignition tem- perature and is not compatible with ‘some electrical equipment in goneric ppreduction eazets. The following sec- ‘Goa describes how the reaction solvent ‘was successfully changed, and how an tunexpected effect on the downstream product erystallization step required f second solvent to be changed in the process to realise the original goal ‘This case stady clearly highlights the need for a holistie approach to solvent ‘selection for batch process design. ‘This stage of the synthesis is a cou pling reaction in DEE between a pri- mary pharmaceutical intermediate and ‘a omaller side-chain component that is to be attached. The reaction involves & fluoride displacement and io mediated ‘bya strong organic base, The end-of-re- action liquor contains the desired prod ‘uct together with residual side-chain (used in excess) and sodium fluerie. Both of these impurities are removed by adding a water wasi to the batch reecior,fellowed by a liquid-liquid sep- aration and removal of the lower aque- ‘ous phase. The majority of the product remains in the top organic phase znd ‘the residaal side chain and NaF are removed with the aqueous phase. The ‘original DEE solvent is exchangod in a ‘seriea of *put-and-take” distillatons (a technique frequently used in the phar- ‘maceutical and related industri), in ‘order to achieve 2 solvent composition ‘that is almost pure ethyl acetate ‘Ethyl acetate was the only solvent that was found to support nucleation and crystallization of the product in fa laboratory screening experiment, It should be noted, howover, that ethyl CCHENICAL ENGINEERING WWALCHE.COM MARCH 2006 37FIGURE 6. Hybrid computer alded techniques tora acetate cannot be used in the reaction step because it would hydrotyre with the base. A small quantity of water is added to erytalizo tho preduct as 0 sable hydrate during cooling. Previous Iaberatory work bad shown that the product will only form a stable crystal Iattice in the presence of water, irr spective of the crystallization solvent and reaction conaitions-This is a com mon feature of pharmeceutical inl caus, which are oRen eonformationaliy flexible and dificult to crystallize. Step 3 Tre replacement selvent must achieve a yield and purty profile that is oiilar io, or botter than the existing proses and improve the EHS profil. ‘The solvent must be inert to the chem: istry, stalize the reaction inarwedi- ates and form a seporate iquid phase With water to allow the removal of re. sidual side-chain and NaF impurities Step 3: on solvents were initaly se lected using knowledge of the reaetion ‘mechanism, a known immiscibiity with wate and a table of EHS prop- erties similar to that iz Table 4. The solvent effets oa the reaction were seroened at the I gram seale in test tubes on « Radley's Carousel, Analysis was performed by HPLC to quantify the extent of reaction and ascess the levelof elated impunties. Theresults were evaluated qualitatively against Parkers solvont taxonomy [24) using SMSwin software (see Figure 7), This revealed @ clear trend in reactimty: Better than DEE — intermediates, Similar to DE¥ — spolaraproties; Worse than DEE ~ dipolar-aprotics and the protic solvent. Based on these resclts and using the multicriteria databese-search capabilitios of SMSwin, a Sacther four solvents were selected and sereened All of these solvents were equivalent to, or beter than DEE. ‘At this point it would have bees beneficial to sercen ll ofthe solvents lusing @ predictive medal for liquid liquid equllibris, to enable selection based oo the partition efficiency be- tween the desired product and re sidual side chain, Unfortunctely the UNIFAC binary parameters were snising for several Functional groups on both the product and side chain, and use of this method was not. pos” ible. solubility data were avéllable for these compounds. then parameters coulbe fied locally to UNTFAC using SojuCALC from ICAS (see Table 1) xe the recently developed NRTLSeg- sent Activity Coefficient model from ASPEN (25). The ab-initio methods of COSMO-RS [| and COSMO-SAC (26) could also be considered. An accarate predictive medel ofthis system, which includes tho effects of the disaociated Naf, is still beyond the proves eapa- bilities of moder thermodynamic models. A gew electrolyte extension to NRTLSAC 127] may help to fil this 2p in the near future. ‘Sep 4 Tet ary alcohol was selected ‘or further evaluation at a S-gram laboratory scale, This solvent is used in the preceding synibesia stop and sffers an obvious synergy — the ce- action profile was also better than in DEE, The aqueous miscibility wae eo- timated using SMSwin (Figure 8) and the distillation behavier was predictod ving the Proceso Design Stadio too OTICAS (Figure 9) The results show aa acceptable range of immisebility with water to facilitate NaF removal, Figure 8 also shows that a relatively small quantity of the slvent will be lost to the aqueous stream, wich is ‘important from az enviroamontal perspective, It was quickly discovered in the laboratory thet following the original proveas description with the new replacement solvent cated the product to cryptallize as a sticky gum, 38 OENICALENGINEERING WWLCHECOM MARCH ance smabve generation and evaluation rather than the previous sugertike, free-flowing crystals, This problem was traced to residual f7t amyl aloo- hol that remained after the distllstion step, and which hindered the crystalli- ration. Such a precsce would be wnac- ceptable on staleup. The residue curve (Figure 9) identifies ethyl acetate as an unstable node and so, while pure ethyl acetate will be reached eventa- ally by a “putand-iake" distillation, the process will be inefficient and take a significant amount of time and large volumes of fresh ethy! acezate. This snalysis explained the appearence of the gam and the high lovols of tert- amyl alcohol Two options were considered to remedy the prolom. Use bates distil- lation taking into aczount the residue curve paths, or, replace ethyl acetate fas the crystallization solvent (dis- cussed below in the second example The batch distilletion option is feasi ble bacause water i a stable aedo (see Figure 9) and cculd be reached easily ‘as the end point in the batch st, pro- vided that tho starting composition is on the watar side of the water-iert- amyl alcohol azeotrope, After success- fal removal of the tert-amyl alcohol then the water-ethyl acetate axeotrope could be used with another “put-and- take” distillation to remove the water and move the stil contents into ethyl acetate. This option was however dis- carded, over concerns that both the preduct and Nai would precipitate out of an aqueous solution and ag- slomerate on the vessel interaals, Crystallization solvent Step 1: In order to overcome the problem of the poor (gunimy) crystal: lization, a second solvent replacement problem was defined, this time to re place othyl acetate az tho erytalisa- ‘ion solvent. The replacement musting 72 : —— ; ill crystallize the product in its hy- dérated form and thus have a reason~ able degree of miscibility with waver. Tt must also improve on the distilla- tion performance and minimize the residual levels ofcer-amyl alcohol. Step 2 The replacement oolvent should havo the following properties: #8 liquid at normal plant tempers- tures to facilitate easy handling #A relstivoly high volatility to pro- mote fast drying of the isolated product +The vapor pressure should not be 0 high thet fugitive emissions are ‘a problem from the standard -15°C condensers that is used for primary VOC abatement + Partial miscibility with water to pro smote the hydrated form of the ery: tallized product and enable water ‘washing ‘Ability to promote the removal of ‘water and iert-amyl aleshol during the distillation. This was achieved by specifying @ minimum-boiling azeotrope for both water and tert. ‘amyl alcohol with the new crystal~ lization solveat (this io « acessoary condition ifthe boiling point of the new solvent is below that of the ‘ther two solvents, but aot essential if the aew selvent is higher boiling) + Promote nucleation of the stable hy- ddrated form of the product ‘+ Be compatible with previous chem- istry and reagents Step 3: Tae theory of solvent effects ‘on nucleation and crystal growth is an active area of carrent research. and, to the authors’ knowledge, there are 0 prodictive methods available at this time. There is some literature proce- ence to suggest the use of Hansen solubility parametorain predicting the impact of solvent type on crystalliza FIGURE 7. Screen shot from SMSwin (sae Tabla 1) showing Parker's clacafication of solvents. ‘perature forthe water tion [28], This approach was adopted through the ProCAMD tol in ICAS (see Table 1), by sereening the selectod solvents to those that are within twa units of the Hansen dispersive, polar and hydrogen bonding parameters of the original ethyl acetate solvent. Step The ProCAMD results identi fled n-propyl acetate as the most ap- propriate replacement. The residue furve plotted with ICAS-PDS showed ‘that the new crystallization solvent is now @ stable node an the plot as de- sired, and will thus be more efficiont in removing residual ter-amyl alcohol wihea following tbe original process. ‘This was confirmed in the laboratory at the 5-f scale where excellent-qual- ity product was delivered at the first ‘attempt The process wae later scaled up ta a fel, reactor and followed by a successful 250-L pilot plant carapaign. Solvents for organic synthesis This problem invalves the selection of neutral solvents for the oxidation of 3.0etanol to 3-octanone, and has boon previously reporved in Refereace {13} ny Steps Addn th sh oe ‘tion to provide an inert reaction me- dium by dissolving the reactants and ety benrieceae oferta he eal re See sraeser pee oat Se wae Sas treraie oe Spell taal rose 2a wre theeis aa ease sel tar Se crs dle methane does not satisfy the require- Sen paths BOs FIGURE 8. Calculated aqueous immiscibility as a function of tem- Wvont binary mibaure faith SMSwin) cbjective is to find a replacement. Step 2: "The solvent. needs to dissolve Boctanol and Soctanooe, must be inert and must be liquid at tho ro. acting condition (temperature of 288 1). Also, it must have favorable BHS proportion and muat have a dancity cle ta that of water Table 5 lists the properties and their values needed to match the desired solvent pattern Step 8: Based on the above problem definition, alist of candidate solvents are generated through ProCAMD. Figure 10 shows a sereon shot from ProCAMD providing a breakdown of amber offeasibiechemicals that have been found by ProCAMD. ProCAMD generated 2.751 + 2,185 molecules out of which 215 were found to satisfy the specified solvent property constraints, One of the feasible solvent candidates is 2-penianone, whose properties as calculated by ProCand are alo shown inthe screen shot of Figure 10 Tt can be seen from Figure 10 that 215 chemicals (solvent. candidates) have boon gonerated. From ‘his list, some of the most promising solvents are: 2-pentanone, secbuty! acetate, Doxepanone, ganma-valeralactene, Dethary ethylacetate and many more. ‘Among these solvents, 2 pentanone appears to be the most environmen tally friendly STEP 4: Tac verification step for this example has not boon completed at the time of writing, Water removal ‘Step 1: The objective of this example is to Gind a replacement for tetrahy- drofarar (THF) as tho solvent during the early development of a pharma- ceutical process. THF does not. sup- port the procese chemistry and there are safely concerns associated with (CHEMICAL ENGINEERING VPWW.CHE.COM MARCH 2006 38tho use of this sivest. The hey reac tian step in the process is hyéropho. big, so complete water removal from tho solvant prior reaction is crucial ‘The Active Pharmacvutical Ingredient (APD must be highly solobe in he se- lected aolvent Due to the relatively small amount of waner present and the desire to maximise product yield, dstftion sins dented as tho preferred rothod of water removal. To options were considered during solvent selection: Formation of woivont water, low boiing-inary azeatrope + Use ofa higher boiling solvent (rela. tive to water) Step 2: The search criteria defition ineludes che following poets + Tho solabiity ofthe APT aclecule ‘was characterized tirongh the Hil Gebrand solubility parameter, The range as predicted by ProPRED (Go Table 1) wa eed as te sargot range fo the candidate solvents + Atinfinie solventdiltion, the activ ity coefficient with respect to water must be a8 high as possible. While this requirement was act used to afin apesfic target forthe candi. date solvents it did enable solvents to be ranked +The APT is known tadograde et high temperature ard soa vacvtim ope sting presvure was selec for the Gistllacon. Tho propored vacuum level waskenown tobe resilyachiew able in existing plant equipment +A target rango was set fr the nor tal boiling point of the eandidste solvents, The solvent must not be tcovolatilethattcistillsofin pref rence to water (or the binary arco trope), but mast bol readily enoeh 1» avoid degradation ofthe APT mol- tale at the distillation pressure + Previous experimental work indi cated thot the flowing classes of Procors colvont should ot be con- sidered: aeohols, acids, sldehydes fad stones ‘Step Tho ProCAMD too} was weed te search fr candidate soivents based om the criteria defined above. The sat- ‘pare goneratd a lst of 41 candidate slventsin tal, including sumers, The ‘host promising arycic solvents were srbutylaostate, n-propyl aczate, ethyl ‘gcetate and n-pentyl acetate, with telu- ‘ene and the xylenes the most suitable aromatics. Tho software predicts that all of these solvents form a low-boil: ‘ngebinary azeotrope with water at the Aistillation pressure considered. ‘Step 4:"The-coareh results wore veri ‘ied by plotting Tx. curves (tempera- ture and mole fractions in the Liquid ‘and vapor phase) for all of the eardi- ave solvents with water. Ia all eases. the pesition’of the azeozrype matched closely the prodiction made by Pro- CAMD. For example, for the x-propy} acetate-water system at 300 mbarfa), a lew boiling azeotrope with boiling pains of approximately 50°C is formed at 3 tole fraction af n-propyl acetate close ‘ta 0-4, The solvent bailing point is ap rox. 65°C, which is below the tamper- ‘tare at which degradation of the API molecule ia typically observed. Further experimental trials aro required to verify the solubility of the APT mol- ‘cule in the candidate solvents, as well as the compatibility of these solvents ‘with the process chemistry. (CHALLENGES & OPPORTUNITIES Predictive methods are eritial for chenical and pharmacouticl process development, especially when very few smsnsured data are available, Usual, in early staguo of developrent there ‘3 ver litle mformation forthe main prdvet and isolated invermetistes ard ¢ften no data at all for related impari- ties. Particularly in case of pharmacou- teas aac a solvent hes been proven inthe laboratory itis move dificult wo justify move to & ner but potentially better solvent because of the mereased Aovelopment risks en ffir. Solvent effects om ceastions could be better understood with predictive models, embedded in tools like Pro- CAMD, Efforts should be continued to refine and validate methods that optimize eolvent selection and use, while potentially enhancing the de. sired reactions early in the develop- ‘meat process. In a related vein, there v2 an angoing chellonge to find suit- able replacements for organie solvents that pove EHS and other operational concerns via predictive modeling and ‘targeted experimentation SoemReersnasy pee ee es “WKeiraBencen (avon Eee ae Sera Seah Sane iageemaces rs ital project, senda Se ee {Rr ving produ inves ced sania Specter Eom aes ee Rioarenetien tat Eh ene ress cnamtercy fou inet Calley Loncen, aad PS carponme weber atIn the design of formulations, sol- vents play an important role in the comples arena of surfactant stabilized aetive ingredients that are cormally hydrophobic into a formulation that hhas to remain stable for a number of years. Typical agrochemical formula- tons have a number of curfsetanis and wettors that all need to work with the selected solvent to improve the praduct perfurmanee. The challenge Shi sh Atari i cue lg “ee {ley Prins “apeechonial Aap of Proves Deedgamene 00, anda chaos ented St feat Sohctin (rte EX denne Caper 12 oe Giang ait “Chematey ote Resim on, Laon” Roca 1008, Front 1099 cr 300; Sistema speek cam Se ns PEO Cats tinversy. ans mow coum ioc, IMESU, Manerey oso and + 2 nema Roser ene eheretaaes See facets FIGURE 10. Sersen | sho's from ProCAMD | highlighting the gen- | ‘eration ofthe lst of foatible solvents for ‘step ) ‘is to model the complex behavior suf. ciently accurately to identify the solventa that bave the best chance to sueceed 80 that the experimental ef fort epuld be directed towards only the best solvents ‘Some additional opportunities for the development of methods or tools on solvent selection are: © Predictive models for new solvents ssuch as ionic liquids Anions ten Kate gesiue ing a ine Cheicals Pe. Seas SB Aro Phen ‘ae Rail stds Ne Gre Bex oa, kb Ben Netherland itige See soes 3ifesee-sern, fir blorastal waste deseractionSinen U0 {ee Kae ae eee enone Akzo Nebel ‘Worleng oth in he Netherlands and the (8 Relsatmember of Use Royal Dutch Chemieal Fete Crate a ppl Seo SCV ‘Prosees BAD Ba {Cho 10, Sik Base Businaee fate § (ease n, Tea * Predictive electrolyte models for phar toaveutical salts, inorganic solvents two-phase (liquid) systems with water ‘nd inorganie salts ike NaC] + Obeaining a better understanding of he science behind the effects of sol- ‘vents on polymorph formation dar- ing erystllization # Integrated software environments for laboratory data analysis, prop- ecty model generation and predic- ‘ton, validity testing and thon bate’ process synthesis and design + Evaluation of EHS lifecycle impacts ‘of new solvents to ensare that tbo impacts are minimizod and that any potential “cleaner” claims are justi- 5c Por en Siiceaee ca+ Extonsion of current predictive models (such as ProCAMD) vo the search for solvent mixturos,and tho subsequent eveiuation of their fea sibility ‘Translation from built candidate to actual, economically feasible candidate in some of the existing predictive tools (such as automated search for similar compounds as identified candidates in “vendor catalogues") Conclusions Organic solvents have been ssed in many industries for conturies, but the methods and cools to select op- imal solvents while minimizing their adverse environment, health, safety and operational concerns are still evolving, This paper highlights some of the approaches, software, databases, and tools used currently in industry and academia to aid in tolveat selection. Some application examples are given and ongoing challenges in the area of optimizing solvent selection aro described Research to address thoce chal lenges and improve tools for solvent solertion and optimization is still rreeded.. The implications a solvent will have in fullseale operations need to be bettor understood at the development stage end integrated in the selection process. life-cycle ap- proach is needed when selocting and evaluating new or existing solvents, to avoid shifting the potential issues instead of addressing them. Improved tools will enable greater influence of early siage process de- velopment, ideally at the oyntheaio route selection stage, with fast and accarate prediction of solvent effec, process feasibility and eventual plant performance, A good level of coopera- tion and coordination between the chemist and the chemical engineer at all stages of development is instru- mental to address the EHS impac> of solvents at the manufacturing scale, While solvent selection for major, large-volume petrochemical and chemical processes may be fairly standard today due to the well tested modals.and tools, lhe same is not true for pharmaceutical, egrochemical or specialty chemical’ process-produet development, One of the main rea- sons is the lack of available data and, consequently, lack of predict» ‘models. Also, for the chemicals and petrochemicals industries, solvent substitution with new solvents that can provide significant improve- sents, lack data 2nd models for fur- ther dovelopment. Until true green chemistry is achieved, solvents will be neaded, Therefore, efficient and Aorible golvent selection procedures supported with the necessary data, models and tools aced to be devel oped, maintained and updatod. Edited by Gerald Ondrey Circle 22 on p. 72 oF go to adlinks.che.com/S827.23Molla; De | 28 cher, Gc. Song, soln Yoosing ‘Weel TV Conrad References | BNR RR AROo SEARS | * Sie a pang Tanduay Geen Cheme | AE Sy Herta ba Tg Sera ibe epic zeg ggens Oar EO | 5 Ge TmdaGmmden md Comatin | Ber tn op oe aah HO sive Bad SeMidree ie streets | 9 Ln 8 wd bade 2 pace Cairn ermine, | sate rea zs om gin ecemenera fi ERERSTR GE CST Eales nt: Sas : = ata Secs oat = SEG or iene” | |, Renate oH ie « 2% atl Ghia Gay, Ga | ache SS eo EIS, Hesse Goyette Sarg ed Sher, Sparta ed foe Cae Bug vo 28 pp 248. 18. Bindory 7, sad cry Spree pe 4 Neel Gey 8 Grin Cnn | Ror, % sects Senin ce] RHEIN Sp ian Echo Riedie waa aeor | 4 22 Kannan, AT, Actetie, [Read me ae 18 Kogan er ad Be Cie | ROAD tn et ea etn 8 Regs ng 108 andes | BE npn lien rb Fiaioe of Mire Poperace om | yy, Rv Pm HEE arere ey rig ad Send ortar Gro Cenrmations | Yaga, pp FH a0. 2. Ope and Cera, Basse A Var fee the (lfc Medel Za oy ites ESO | a erat 26 Does ya avons OP Hi Wl al 9 300,00 6 Haag SL toad nd Bag Chm Seige Sas Oe Sd Hlafed Solvent, Org. Cher Vl 8, Kee cer SESS ie cei: | mate Se 1. Grose. apd SapumeGIné & Ere Chom | yo, aaewic VI. Tends in Anatol Chena, | 80. arms 4D andContabe, IC. Sant ESR pp ABE as ioe ee age rns. | 30. Gorrie: eich Go tothe Unagrnaee ol Eoctowseeu leat and Sefer 2, Kant, A. and Baker, F, COSMOS: A ‘Noval acd Bisons Method fr the a Por Prmcton of orinapiyal Date of Lag ‘ios Flaud Phace Bylivi, VO 17, 7p ver Aided SEE | Roca Sd Memes, Yo pp. 02-96, 31 Findnwe Conse, ere Baa Gonztles, ani, othe ine ae 21 Ness, KK, Rational Solvent Selection for 1 See tant Tw At, | 2 Hay oe al iv Sn | * Bato, oo es Rene ar, tang Ftd ee | dead mobeset |” Giieenten toe ras Symthaaie, Actas Charice vviza, Vol cee ng Solection, J of Cleo, ‘and Envi- ‘E39, No 9, pp. 79-91, 1986. -— oe ean Ror o Ri gg ogre ‘ronmental Policy, Vol 7, Pp. 42-80, 2096, ao epee Gans &.. Kolar, P. and ishi- et sake ==! ry | 82.ICAS documentatica, Internal Report, Teridbce ie egms | Eerie ace? Ss | Os, eames ae Eid ce do es a Gores eae 15 ketung 9 ody 0 a ania 0, |g Se it Uae ama 3S Geen ea meas eet sepia gi ema | wo "3 < deeper escent stpand| Renee eect forren | bl arg Cogn aaa oe Hei ree Spin | 7 a oe ‘St ap O78. + | 24, Paoker, A, Rafe of Salvation 0 the Prop nardt, ©, “Solvents and Solvent Effects an ee en auan, | geese isinete Sse Us, |“ Rtremns Ghtery ACES ar mE = f Quart, Ren, Vol. 16, pp. 163-187, 1962 Germany, 2902. Take advantage of our experience in the Chemical Process Industry in ts comprebensive range of physical models, STAR-CD from CDvalapco ges you the ability to simulate a wide range of flow Processes n the CP, inctedng oubble coum, maing vessels, Cyclone SeFAIONS, Nulled Deds, neat eICTengers and chemical reactor. \Witn 25 years e@etence in te Chamisa! and Pracese Idus, you can rly on CO-adapco 1 ofr you the fl spactrum soutin that youveed. We wont just offer you CAE software; we wl back you up win Trahing, Consutng and Engen Serces. Optimize your desis, imarove your rrocess and meet your legal reuiremerts; ak to us tay > fre out Rew you can Beret Rom our exparence. Your CAE Partner for Success worw.ed-odlapoo.com (eD-adapeo of Clrele 24 on p- 72 oF go te adlinke.che.com/6027-24 ‘CHEMICAL ENGINEERING WWWCHECOM MARCH 2006 43