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.

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'Anterroches ~,
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 dataflow. 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. Introduction
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. Computeraided 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

805

806

M.B.C. Afonso et al.

includes an analysis tool that helps to identify azeotropic systems for which solventbased 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

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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

Problem Type . Output Data
Input Data
Feasible molecular
Molecular
Building blocks for molecules; target
Design (CAMD) structures and their
properties and their upper/lower
corresponding properties
bounds and/or goal values
Mixture Design
List of feasible mixtures
List of candidate compounds to be
(CAMbD)
(compounds and their
used in the mixture; target properties
compositions) plus their
and their upper/lower bounds and/or
corresponding properties
goal values at specified conditions of
temperature and/or pressure
Process
Process flowsheet (list of
Desired process specifications (input
streams, product quality specificaDesign/Synthesis operations, equipments,
(PD)
their sequence and their
tions, process constraints, etc.)
design parameters)
Process-Solvent
Process flowsheet (list of
Desired separation process
operations, equipments,
specifications (input streams, product
Design
their sequence and their
quality specifications, process
design parameters) plus
constraints, etc.) and desired (target)
list of candidate solvents
solvent properties
Details of the molecular or formulated Product
Variable values defining
product (molecular structure or a list
Evaluation
the performance criteria
of molecules plus their composition
and state) and their expected function
Process
Performance criteria,
Details of the process flowsheet and
the process (design) specifications
Evaluation
sustainability metrics
Table 2. List of methods, alg orithms and software tools useful in pr ocess-product design
Method/Algorithm
Tools/Software
Problem Type
Molecular structure generation;
Molecular & Mixture
ProCAMD
Property preciction and database;
Design (CAMD)
Screening and/or optimization
Process Design/Synthesis
Process synthesis/design; Process
ICAS (PDS, ICASsimulation/optimization; process
sim, PA)
(PD)
analysis
Process-Solvent Design
CAMD-methods/tools; Process
ICAS (ProPred,
Synthesis/Design; Process
ProCAMD, PDS,
simulation/optimization; Process
ICAS-sim, PA)
analysis
Property prediction & databse;
Process Evaluation
ICAS (ProPred,
Product performance evaluation
ICAS-utility, MoT)
model; Model equation solver
Process synthesis/design; Process
ICAS (ICAS-sim,
Process Evaluation
simulation/optimization; Process
ICAS-utility, MoT)
analysis
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 solventrich 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 3 5 0 420 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 shortpath 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 q u e n c e o f p u r i f i c a t i o n s t e p s d e s i g n e d to m a t c h t h e d e s i r e d p r o d u c t p u r i t y . M o r e
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solvents.

4. C o n c l u s i o n s
B e c a u s e o f t h e n a t u r e o f t h e p r o b l e m s in t h e h i g h - v a l u e c h e m i c a l p r o d u c t s
sector (new chemicals, process reliability, reliable product performance and complex
phenomena),
models play a very important role and provide the basis for a wide range
of computer aided tools. In this respect, the paper highlights the important issues with
r e s p e c t to t h e i n t e g r a t e d a p p r o a c h as w e l l as t h e n e e d f o r a f l e x i b l e m o d e l - b a s e d
framework, the appropriate modelling tools, the importance and need for property
models, and the need for performance models for evaluation of processes and products.
F o r t h e i n t e g r a t i o n o f m e t h o d s a n d t o o l s to w o r k , r e l a t i o n s h i p s b e t w e e n t h e d a t a - f l o w ,
p r o b l e m t y p e s a n d m e t h o d s / t o o l s n e e d to b e p r o p e r l y e s t a b l i s h e d . C u r r e n t a n d f u t u r e
w o r k is d e v e l o p i n g a c o l l e c t i o n o f c a s e s t u d i e s o f w i d e r s c o p e a n d s i g n i f i c a n c e .

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