16th European Symposium on Computer Aided Process Engineering
and 9th International Symposium on Process Systems Engineering
W. Marquardt, C. Pantelides (Editors) 2006 Published by Elsevier B.V. 805 Computer Aided Methods & Tools for Separation & Purification of Fine Chemical & Pharmaceutical Products Maria B. C. Afonso 2, Vipasha Soni ~, Piotr T. Mitkowski 1, Loic d' Ant erroches ~, Rafiqul Gani ~, Henrique Matos 2 1CAPEC-Dep of Chem Eng, Tech Univ of Denmark, DK-2800 Lyngby, Denmark :Dep of Chem Eng-Instituto Superior T6cnico , Av Rovisco Pais, 1049-001 Lisboa, Portugal Abstract An integrated approach that is particularly suitable for solving problems related to product-process design from the fine chemicals, agrochemicals, food and pharmaceutical industries is presented together with the corresponding methods and tools, which forms the basis for an integrated computer aided system. The methods and tools are linked through the problems they are able to solve and the associated data- flow. The integrated computer aided system has been used to solve a number of industrial problems and summarized results from a selection, involving separation and purification issues, are presented. Keywords: Fine chemicals, agrochemicals, food, pharmaceutical products, separation, purification, methods and tools 1. Introducti on The fine chemicals, agrochemicals, food and pharmaceutical industries need a different set of processes and have different operational constraints than processes producing bulk chemicals. For example, they usually involve batch operations (low production rates) and usually handle chemicals that are temperature sensitive, difficult to separate (because of isomers), and have high purity requirements. Also, at the initial discovery step, the required processing steps need to be configured and tested very rapidly and at the final (clinical) trials, they need to be reliable and efficient. Computer- aided tools can provide significant savings in time and resources if reliable models for product-process evaluation were available and could be used in an integrated manner. The objective of this paper is a) to present a set of integrated computer-aided methods and tools that are particularly suitable for application in the synthesis, design and analysis of the separation-purification steps related to the production of high-value chemical products; b) to highlight the application of the developed methods and tools through a set of industrial case studies. The methods and tools include a large database containing pure component data of chemicals, solubility data of typical chemical products, azeotropic data of chemicals and many more. If the data for a chemical is incomplete, a property model program package is available to generate reliable data to fill out the needed missing properties. A unique feature of the property prediction method is its ability to predict missing model parameters from molecular structural information, without the need for additional experimental data [ 1 ] and is therefore able to handle a very wide range of compounds and isomers. Also, the azeotrope database 806 M.B.C. Afonso et al. includes an analysis tool that helps to identify azeotropic systems for which solvent- based separation is necessary and azeotropic systems for which it is not necessary. A solvent selection tool [2], integrated to the system, then finds the most appropriate solvents for the desired separation. The same is true for solid-liquid separations involving solution crystallization [3] and liquid-liquid extraction. In all these cases, the sequence of operations needed to achieve the desired separation/purification is identified through generic model-based tools (solubility model creation, generation of saturation curves, sequencing of operations, etc.) that can handle the complex mixture behavior of fine chemicals and pharmaceutical chemicals. The generated synthesis/design alternatives for the separation/purification steps are verified through an integrated modelling system [4] that can be configured to simulate various types of batch/continuous operations. Finally, a chemical system pre-analysis tool has been developed to identify the types of operation needed to achieve the desired separation or purification [5]. For example, should the separation/purification be achieved through batch distillation or short-path evaporation or pervaporation, if a vapor-liquid separation is feasible? Also, when should crystallization be used and under what conditions? Should solvents (and/or anti-solvents) be introduced? 2. Integrated Computer Aided System- ICAS For ICAS, a model-based framework (see Fig. 1) for product-process design has been adopted. A detailed description of ICAS can be found elsewhere [6]. I Chemical Product-Process Design I t Mol ecul ar [ , Structure? I ' t Mi xt ur e Composition? " Product Design . . . . . . 4 , . - Y . . . . Pro petty Models Product Models Process 1 I - I Performance? ] ,,t I ~rcess , I - - .I | Fl owsheet ? I J r "l " ' "] t Prduct Per f or mance' , ) Process Design i t ............... _1 I [ Process-Product .r , - " ,= p~. - - ~ Evaluation Process 'Synthesis/Design Tools Product Application Model Si mul ati on Engine Process Analysis Tools Figure 1: Framework for integration of product-process design For the integrated system (as shown in Fig. 1) to work, it is very important to identify the various tasks (problem types) and the methods and tools that need to be used to solve them. Also, the data-flow for each problem type needs to be identified and matched with the corresponding methods and tools. Table 1 provides a partial list of identified data-flow relationships with respect to problem types while Table 2 provides relationships between methods and tools to the problem types of Table 1. What is not shown in this paper, but is equally important, is the work-flow (or the sequence) in which the various methods and tools need to be used to solve the total problem (broken down into a collection of smaller sub-problems). This is briefly discussed in the next section where the solution of a selection of industrial problems are presented. Separation and Purification of Fine Chemical and Pharmaceutical Products 807 Table 1. Data flow for a selection of design problems Input Data Building blocks for molecules; target properties and their upper/lower bounds and/or goal values List of candidate compounds to be used in the mixture; target properties and their upper/lower bounds and/or goal values at specified conditions of temperature and/or pressure Desired process specifications (input streams, product quality specifica- tions, process constraints, etc.) Desired separation process specifications (input streams, product quality specifications, process constraints, etc.) and desired (target) solvent properties Details of the molecular or formulated product (molecular structure or a list of molecules plus their composition and state) and their expected function Details of the process flowsheet and the process (design) specifications Problem Type . Molecular Design (CAMD) Mixture Design (CAMbD) Process Design/Synthesis (PD) Process-Solvent Design Product Evaluation Process Evaluation Output Data Feasible molecular structures and their corresponding properties List of feasible mixtures (compounds and their compositions) plus their corresponding properties Process flowsheet (list of operations, equipments, their sequence and their design parameters) Process flowsheet (list of operations, equipments, their sequence and their design parameters) plus list of candidate solvents Variable values defining the performance criteria Performance criteria, sustainability metrics Table 2. List of methods, alg Problem Type Molecular & Mixture Design (CAMD) Process Design/Synthesis (PD) Process-Solvent Design Process Evaluation Process Evaluation orithms and software tools useful in pr Method/Algorithm Molecular structure generation; Property preciction and database; Screening and/or optimization Process synthesis/design; Process simulation/optimization; process analysis CAMD-methods/tools; Process Synthesis/Design; Process simulation/optimization; Process analysis Property prediction & databse; Product performance evaluation model; Model equation solver Process synthesis/design; Process simulation/optimization; Process analysis ocess-product design Tools/Software ProCAMD ICAS (PDS, ICAS- sim, PA) ICAS (ProPred, ProCAMD, PDS, ICAS-sim, PA) ICAS (ProPred, ICAS-utility, MoT) ICAS (ICAS-sim, ICAS-utility, MoT) The method and tools mentioned above have been integrated and fine-tuned to the needs of the fine chemicals, agrochemicals, food and pharmaceutical industries with respect to their product-process design problems. They have been successfully applied to interesting industrial problems (solvent-based separation of reaction products; 808 M.B. C Afonso et al. purification of the active ingredient (pharmaceutical product by short-path evaporation); sequence of crystallization steps to extract the solid product; vacuum batch (or membrane) distillation to purify aroma/food related compounds and many more. 3. Separation & Purification Problems & Solutions Separation processes employed for product development in the high-value chemical product sector are usually batch distillation (also including solvent-based and reacting systems), short-path evaporation, membrane-based separations (nano-filtration, micro-filtration, etc.), crystallization, chromatography, to name a few. As the chemicals involved are complex and have isomers, the separation tasks can be quite difficult. In the text below, a selection of typical separation-purification related industrial problems are discussed. More specifically, results from case studies involving product purification operations and solvent-based product recovery operations, are presented. Note, however, that these methods and tools have also been used to solve problems to improve product yields in specific reaction paths (through solvents and/or hybrid membrane contacting devices), for improved pesticide product performance (through formulation design for higher pesticide uptake through plant leafs), for increased recovery of fruit juice (through membrane distillation), and many more. Because of restrictions related to confidentiality and paper-size, specific details such as chemical names are not given. Instead, we will concentrate mainly on the problem definition, important solution steps and some of the important results. 3.1. Product purification problem A small amount of water needs to be removed from a solution containing an active pharmaceutical product (API), which is sensitive to temperatures above 350 K. Because of the nature of the reaction step, chemicals such as alcohols, acids, aldehydes and ketones cannot be used. At the operating pressure, the solvent must boil at lower than 350 K but should not be too volatile, as this will cause a VOC release. Two options could be considered. Option-1 could be to find a low boiling solvent that is miscible with the API but forms a low-boiling azeotrope with water. In this case, the water could be distilled off with the solvent by operating from the solvent- rich side. Option-2 could be to find a high-boiling solvent that does not form azeotrope with water and is only partly miscible (or immiscible) with water. In this case also, the water can be distilled off. The problem solution needs to predict the properties of the solvent, the solute and the mixture, needs data on azeotropes with water, needs simulation models for vapor-liquid separation operations (flash or batch distillation). Clearly, option-1 provides a better design altemative (w.r.t. ease of operation, reliability and economic criteria) as it means operation at lower temperatures and guaranteed removal of water. First a search of the database is made to find the chemicals forming azeotropes with water (excluding the chemical types listed above). For purposes of illustration only, Fig. 2 is included to highlight how the chemical type and carbon number of the candidate solvents are identified from plots of binary azeotropes. As shown in Fig. 2 (for alkanes versus carboxylic acids as an example), for a chemical type, an azeotrope may exist only between an upper and lower bound of carbon numbers for that chemical type. Also, azeotropes involving lower carbon numbers are likely to vary with pressure (meaning solvents may not be necessary for a separation task) while those involving higher carbon numbers are less likely to vary with pressure (meaning that solvents would be necessary). Using this information and generating pure component information on the solubility parameter, normal boiling Separation and Purification of Fine Chemical and Pharmaceutical Products 809 point and normal melting point of the API, it is possible to use the ProCAMD tool within ICAS [6] to identify solvents that are partially miscible in water, forms low boiling azeotropes with water, dissolves the API and has boiling points between 350- 420 K and melting point lower than 250 K. Using ICAS-utility and ICAS-sim, the removal of water from the API solution has been verified. 3.2. Recovery of API from reactor effluent through crystallization operations In this problem, a solvent (and/or an anti-solvent) that will promote the crystallization of the API at a specified temperature with the desired shape of crystals needs to be selected and its performance verified. A secondary objective is to add an anti-solvent so that an additional amount of the API can be crystallized out without further cooling at a reduced temperature. Two sub-problems are highlighted here. The first involves the creation of a customized solubility model, when the available model is not applicable. This is illustrated through a case study involving an API called Cemetidine [7], which is prescribed as a treatment for excessive stomach acid in conditions such as peptic ulcers. Solubility data in selected solvents (not necessarily optimal solvents) are available. First the necessary pure component data is retrieved from the database (Melting point= 412.4 K, Enthalpy of melting=44033 J/mol). The Hildebrand solubility parameter is predicted to be 29.2 MPa v2. This means that polar hydrogen bonding solvents would be more appropriate for Cemetidine. Using the available solubility data and creating a customized UNIFAC model, this result is verified through Fig. 3, where the solubility of Cemetidine in different solvents are plotted against the solubility parameter of the solvent. By definition, the solvent showing the highest solubility is the best solvent (as usually there is a clear maximum) and the corresponding solubility parameter value of the solvent also indicates the API value for this property (verifying, therefore, the earlier prediction). Primary and secondary alcohols have been found to be most suitable. The second sub-problem involves the selection of solvent-antisolvent mixtures for a sequence of crystallization operations. Using the decomposition method for CAMD proposed earlier [3], solvent mixtures have been identified for drugs like Ibuprofen and Paracetamol. In the case of Ibuprofen, the performance of the solvent and the formation of crystals have been validated through experiments [3]. 3.3. Separation of impurities from heat sensitive product An effluent from a multi-step reaction process consists of the API plus additives and impurities, which have lower boiling points than the API and additives. Vapor-liquid separation is feasible but not with distillation. One option is to use short- path evaporation, for which a new simulation model needs to be developed and validated through pilot plant data. Also, as the impurities, the API and additives are not present in the properties database, the needed properties (vapor pressure as a function of temperature, specific enthalpies, heats of vaporization, etc.) need to be predicted. The solution steps are as follows: generate a steady state simulation model, introduce new compounds into the database with their predicted properties needed for the simulation, validate model and adjust the model parameters to fit the plant data, and finally, use the validated model to identify the best sequence of operations that can achieve the desired separation (purity of product). Provide the developed model as a model-object that can be run from external software. Using the modelling toolbox (MOT) in ICAS, a model has been developed, model parameters identified and then a 810 M.B. C. Afonso et al. s e que nc e of pur i f i c a t i on s t eps de s i gne d t o ma t c h t he de s i r e d pr oduc t pur i t y. Mor e det ai l s of t he mode l c a n be obt a i ne d f r om t he a ut hor s or f r om t he I CAS r e f e r e nc e [6]. 1,0 0,9 0,8 0,7 0,6 ~j o,5 ~', 0,4 0,3 0,2 0,1 0,0 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 C number Fi gur e 2: Pl ot of bi na r y a z e ot r ope s of di f f e r e nt c a r boxyl i c aci ds ( di f f e r e nt c ur ve s i ndi c a t e di f f e r e nt aci ds ) as a f unc t i on of t he c a r bon numbe r of al kanes . 0.I- ........... .............. .................... ~ ...................... + ...................... + ................... ;+, .................. + .................. + ........................................... + ...................... ............................................ + ....................... + ............................................ + ..................... ...................... + .......... ....................................... ..................... + .................. . . . . . . . . . . . . . . . ~.......................... . : i~ i + i i ..... i .......... ~ ............. ........................................ i ............ + ..... i ......................................................... : ................... .............. ........... i ............ .......................... . ..... ~ . ............ ........................................ ~..............: ~. . . . . , .......................................................... ..... , . . . . . . ~ ....... :: ................ ........................ i i i+ ~, i i ..................................................... .................................................................................................................................... 0. 01. 4 .................. . . . . . . . . : ........................ + ........... + ........... + . . . . . . . . . . . :: ........... ...................... ........... + . . . . . . + . . . . . . . . . . . . . . . . :+............. .................. ~ ::::::: :i :+: ::i::::+:;:+: :i :;:i+i:::i:::11:11 :+:i.i+::::i;:.i~+ii :;11:+:::i :::.i0 i+:::i:;ii:;: i+i :i~ ;i::i :+: i : i:i :i+:::i:::.i .i+:ii :i: i : + i :i:::i:+i : : ii i ::i+:::i:i:::;:+: :::i: :;:::+i ====================================== s ooo14 .......... + .............. ............. :, ......... + ....... ++......... + ........... + ........... + ......................... ............ .............................................. + .......................... ....... 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' . . . i++.i.. ~+i+iiiii;i+i;iiii;iiiiiiiiiiiii;ii iiiiiiiiiii iiiiiiiiiiiiiiiiiiiiii II;IIIIY+II+IIIIIIIIIIIIIII+III151;iiii iiiii+ii;i;iiiiiiiiiii iiiiiii;iii+i/iiiiii++ii;iiiiiii; iii+iiii+ii iiii;iiiii iiiiiiiiiii]iiiii -, ~ + + + + + ; + + + ; + + + + + ; ~j 7 ................ +++..,:+ ............. p ......... + ....... + ........... + .......... + ................ p .................. + ............. + ...... + .......... + ........... + .............. + .................. + ................. + ......... + ....... +... 0.00011 ........... i ............ i .................. ~ ..................... i .................. i ............. i ........... i .......... t ......... i ............ l ............ i ............ i ............. i ........... i ............ + ............. 13 15 19 23 27 29 33 37 41 43 47 Solubiliy Parameter (MPa)^l/2 Fi gur e 3" Pl ot of s ol ubi l i t y of Ce me t i di ne ve r s us s ol ubi l i t y pa r a me t e r of di f f e r e nt s ol vent s . 4. Concl us i ons Be c a us e of t he na t ur e of t he pr obl e ms i n t he hi gh- va l ue c he mi c a l pr oduc t s s e c t or ( ne w c he mi c a l s , pr oc e s s r el i abi l i t y, r el i abl e pr oduc t pe r f or ma nc e a nd c ompl e x phe nome na ) , mode l s pl a y a ve r y i mpor t a nt r ol e a nd pr ovi de t he bas i s f or a wi de r a nge of c omput e r a i de d t ool s. I n t hi s r e s pe c t , t he pa pe r hi ghl i ght s t he i mpor t a nt i s s ues wi t h r e s pe c t t o t he i nt e gr a t e d a ppr oa c h as we l l as t he ne e d f or a f l exi bl e mode l - ba s e d f r a me wor k, t he a ppr opr i a t e mode l l i ng t ool s , t he i mpor t a nc e a nd ne e d f or pr ope r t y mode l s , a nd t he ne e d f or pe r f or ma nc e mode l s f or e va l ua t i on of pr oc e s s e s a nd pr oduc t s . For t he i nt e gr a t i on of me t hods a nd t ool s t o wor k, r e l a t i ons hi ps be t we e n t he da t a - f l ow, pr obl e m t ype s a nd me t hods / t ool s ne e d t o be pr ope r l y e s t a bl i s he d. Cur r e nt a nd f ut ur e wor k is de ve l opi ng a c ol l e c t i on of cas e s t udi es of wi de r s c ope a nd s i gni f i c a nc e . Ref erences [ 1 ] R. Gani , P. M. Harper, M. Host rup, I & EC Research, 44 (2005) 7262-7269. [2] L. E. K. Acheni e, R. Gani , V. Venkat asubr amani an, Comput er Ai ded Mol ecul ar Desi gn: Theor y & Pract i ce, CACE- 12, El sevi er Sci ence b.v., The Net her l ands, 2002. [3] A. Karunani t hi , L. E. K. Acheni e, R. Gani , Chem Eng Sci ence, 61 (2006) 1243-1256. [4] M. Sal es- Cr uz, R. Gani , in Dynami c Model Devel opment , Eds. S.P. As pr ey and S. Macchi et t o, CACE, 16 (2003), El sevi er Sci ence b. v., The Net herl ands. [5] L. d' Ant er r oches, Pr ocess Fl owsheet Generat i on, & Desi gn t hr ough a Gr oup Cont r i but i on Appr oach, PhD- Thesi s, t echni cal Uni ver si t y of Denmar k, Lyngby, Denmar k, 2005. [6] I CAS we b- a ddr e s s ( ht t p: / / www. c a pe c . kt . dt u. dk/ Sof t wa r e / I CAS- a nd- i t s - Tool s / ) . [7] P. Cr af t s , The r ol e of s ol ubi l i t y mode l l i ng a nd c r ys t a l l i z a t i on i n t he de s i gn of act i ve pha r ma c e ut i c a l i ngr e di e nt s , i n Ca s e St udi e s i n Che mi c a l Pr oduc t De s i gn, Eds K. M. Ng, R. Ga ni & K. Da m- J oha ns e n, CACE ( 2005) , El s e vi e r Sc i e i nc e b. v. , The Ne t he r l a nds ( i n pr es s ) .