Computers and Chemical Engineering 34 (2010) 1030–1035

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Computers and Chemical Engineering

journal homepage: www.elsevier.com/locate/compchemeng

Process modeling and optimization of batch fractional distillation to increase

throughput and yield in manufacture of active pharmaceutical ingredient (API)
Yubo Yang ∗ , Rosalin Tjia
Abbott Laboratories, Manufacturing Science and Technology, Building R-13, Department 045B, 1401 Sheridan Road, North Chicago, IL 60064, United States

a r t i c l e i n f o a b s t r a c t

Article history: An active pharmaceutical ingredient (API) is purified by fractional batch distillation to achieve a high
Received 18 August 2009 purity drug substance. This work is to improve the process throughput and to increase the yield using
Received in revised form 9 February 2010 batch distillation modeling and engineering principles to better understand the process so high quality
Accepted 31 March 2010
product can be produced consistently. A batch of the drug substance was produced in about 7 days by
Available online 10 April 2010
batch distillation using a packed column with approximately 32 theoretical plates. Process improvements
were required to decrease the cycle time. Based on process modeling and other engineering principles,
Keywords:
four process improvements have been made to increase the manufacture throughput. After improve-
Fractional batch distillation
Process modeling
ments the average cycle time has been reduced to 2.5 days from an average of 7 days process originally.
Pharmaceutical API purification Furthermore, the yield is also increased. This was achieved with the original equipment. Since the changes
are within the regulatory filings for the process, they are implemented quickly in commercial production.

© 2010 Elsevier Ltd. All rights reserved.

1. Introduction (1) low-boiling fraction, consisting of product and low-boiling

impurities,
An active pharmaceutical ingredient (API) is purified at the final (2) product fraction, and
step by fractional batch distillation to achieve a high purity for (3) high-boiling tail fraction, collected after the product fraction.
an injectable formulation. The purpose of this work is to improve
the process throughput and to increase the yield using process
The low-boiling fraction typically contains more than 95% of
modeling tools and other engineering principles to fundamentally
product and the product fraction consists of >99.5% of API. In com-
understand the process so a high quality product can be produced
mercial production the distillation column is held at total reflux
consistently in commercial production.
under vacuum to reach vapor–liquid equilibrium. The system is
The API was separated by a fractional batch distillation col-
then switched to front-cut distillation to separate the low-boiling
umn with 32 theoretical plates, which was validated and filed
impurities. The distillate is sampled, tested, and collected in the
with regulatory agencies over 15 years ago. Approximately 7
product receiver once the fresh distillate (collected from the con-
days of cycle time were required to manufacture a batch of drug
densate line without mixing with the content in the front-cut
substance in the original process. Fundamental engineering under-
receiver) contains not less than 99.4% of API by gas chromatogra-
standing of the batch distillation process was limited in the original
phy (GC) analysis. The distillate is collected in the product receiver
development led by chemists. To meet the increased commer-
until the purity of fresh distillate drops to <99.4%. The decision to
cial demand of this drug substance using the existing equipment,
switch the distillate to product receiver is based on the In-Process
better fundamental understanding of the process and improve-
(IP) GC analysis.
ments were required to decrease the cycle time for throughput
Batch distillation is utilized extensively in production of high
improvement. The batch distillation process generates three
value-added, low-volume pharmaceuticals and fine chemicals
fractions:
(Perry & Green, 1997). The flexibility of batch distillation, combined
with its unsteady nature of the process, poses challenging design,
operation and optimization problems for engineers (Diwekar,
1995). A rigorous model for the batch distillation involves solving
∗ Corresponding author at: Manufacturing Science and Technology, Abbott Lab-
stiff ordinary differential equations. The development of accurate
oratories, Building R-13, Department 045B, North Chicago, IL 60064, United States.
models for batch distillation processes is a difficult task. The objec-
Tel.: +1 847 937 2316. tives for this work are to model the batch distillation using the
E-mail address: Yubo.Yang@abbott.com (Y. Yang). rigorous model BatchFracTM from Aspen Technology (Aspen Tech

0098-1354/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.compchemeng.2010.03.019
 Y. Yang, R. Tjia / Computers and Chemical Engineering 34 (2010) 1030–1035
Fig. 1. Flow diagram of the batch distillation process.
Inc., 2004) that has been validated by other researchers in litera-
ture for batch distillation simulation (Cook, Engel, Zehnder, Landis,
& Tedeschi, 2004; Jimenez, Basualdo, Gomez, Toselli, & Rosa, 2002),
to determine the key parameters affecting the separation efficiency
and yield, and to develop strategies to reduce the low-boiling frac-
tion to achieve a better yield.
2. Process description
The schematic of process flow diagram for the batch distillation
is illustrated in Fig. 1.
The key points for the manufacturing process that was filed with
regulatory agencies are:
1. Charge approximately 150 kg of the crude starting material
(feed) to reboiler under nitrogen.
2. Obtain ≤16 mbar vacuum, and maintain the vacuum for ≥1 h
before heating.
3. Heat the reboiler to 60 ± 5 ◦ C, then ramp up at 5–10 ◦ C/h until the
still pot (reboiler) temperature stabilizes. The system is equili-
brated for 1–2 h at total reflux before starting of distillation.
4. Set the front-cut reflux ratio at about 45:1 and start the front-cut
distillation until the fresh distillate purity reaches ≥99.4% by GC
analysis.
5. Set the product-cut reflux ratio at about 10:1 and start the
product-cut distillation until the distillate purity decreases to
99.4% by GC analysis.
6. Collect the tail-cut if necessary at a reflux ratio of 3:1 until dis-
tillation completes.
7. Product-cut material is filtered, tested, and packaged.
8. Column residue is drained to reboiler and reboiler residue is
disposed of as waste.
The main challenge for the distillation process is that the front-
cut took very long time (up to 50 h) to achieve the required ≥99.4%
purity since this product was introduced to, mainly due to one
impurity (Impurity A). Nevertheless, the existing batch distilla-
tion column had been able to produce a high quality product for
many years, and there were no urgent requirements to improve
the process. However, due to an increased commercial demand,
more capacity in the existing plant is needed. After cycle time anal-
1031
ysis of each operating steps, it was realized that the cycle time in
the front-cut was too long. If the separation efficiency for key low-
boiling impurities can be improved, the cycle time for the front-cut
could be significantly shortened that would lead to an increased
throughput to meet the increased demand. This led the study to
generate ideas for improvement, quantify the benefits, validate the
feasibility and implement the solution.
3. Modeling of the batch distillation to improve efficiency
The vapor–liquid equilibrium (VLE) is the key parameter to
determine the separation for a given mixture. The liquid and vapor
phases consist of same components but in different compositions.
The more volatile (low-boiling or light) components tend to be
enriched in the vapor phase while the less volatile components
(high boiling or heavy) tend to stay in the liquid phase. As the
mixture moves up along distillation column, vapor phase becomes
richer and richer in the volatile components while liquid phase con-
tains more and more heavy components as it cascades down the
column.
The VLE data are typically determined by experiments under a
fixed pressure or vacuum at total reflux or estimated by modeling.
The VLE curve for the major low boiling Impurity A and product is
shown in Fig. 2. The symbols are the experimental data obtained
under vacuum of approximately 16 mbar. The pink curve is the cal-
culated VLE using UNIFAC and group contribution method in the
built-in property estimator of AspenPlus® (Aspen Tech, 2004). The
required parameters for UNIFAC (boiling point, heat of formation
and Gibbs energy) on the two components are calculated using the
build-in chemical property calculation of ChemDraw (ChemDraw,
2003). Normal boiling points are calculated using the Joback frag-
mentation method modified by S.E. Stein; heat of formation and
Gibbs energy is calculated using the Joback fragmentation method.
The T–xy diagram of product and Impurity A is shown in Fig. 3
at 16 mbar vacuum, which is calculated using the UNIFAC and
group contribution method with the build-in property estimator of
AspenPlus® (Aspen Tech, 2004). The measured boiling temperature
of pure product is approximately 118.6 ◦ C at 16 mbar, very similar
to the calculated value of 119 ◦ C. The good agreement between the
calculated values by UNIFAC and measured data is not surprising
since the molecular structures of product and Impurity A are very
similar.
1032 Y. Yang, R. Tjia / Computers and Chemical Engineering 34 (2010) 1030–1035
Fig. 2. Vapor–liquor equilibrium diagram of Impurity A and product at 16 mbar.
The mean relative volatility of Impurity A and product is calcu-
lated to be ˛ = 1.13 according to the following equation from the
VLE curve in Fig. 2:
yi /xi
˛=
yj /xj
where ˛ is the relative volatility of the more volatile component i
to the less volatile component j; yi and yj is the vapor–liquid equi-
librium concentration of component i and j in the vapor phase,
respectively, and xi and xj is the vapor–liquid equilibrium con-
centration of component i and j in the liquid phase, respectively.
Relative volatility is a measure comparing the vapor pressures of
the components in a liquid mixture that is widely used in design
of distillation processes. The closer the relative volatility to 1, the
more difficult it is to separate the two components by distillation.
It is also determined experimentally that other low-boiling
impurities are more volatile than Impurity A and can be easily sep-
arated into the front-cut. For modeling purpose, it is assumed that
the entire low-boiling components are Impurity A since it domi-
nates the amount of low-boiling impurities and it has the lowest
relative volatility, which represents the worst case situation. The
model simulation, based on such an assumption, would be slightly
Fig. 3. T–xy diagram of Impurity A and product at 16 mbar vacuum as calculated by
AspenPlus® .
Fig. 4. Dimensionless time  to reach equilibrium as a function of relative volatility.
different from that by considering the exact composition of the
low-boiling components.
In the original manufacturing procedure the distillation col-
umn was held at total reflux for 1–2 h after the temperature in the
reboiler reached the boiling temperature under vacuum. Since the
relative volatility of Impurity A and product is very small, the tem-
perature at top of the distillation column is nearly constant after
2 h of total reflux. However, close examination of the temperature
charts along the column revealed that the column did not reach
complete equilibrium after 2 h of total reflux. Due to the low rel-
ative volatility of Impurity A, it is very difficult to separate it from
the product. Additionally, the specification for this impurity in the
product is low (≤0.1% in the product). Theoretical calculation indi-
cated that at least 4–5 h of total reflux is required for the column to
reach 99% of equilibrium after the reboiler has reached the boiling
temperature. Only after the equilibrium for the distillation column
is reached, will the separation of the low-boiling components from
the product become efficient.
The time required for a distillation column to reach equilibrium
can be calculated by the following equation (Robinson & Gilliland,
1950):
nh
tequi = 
vvap
where tequi is the equilibrium time, n is the number of plates, h is
the liquid hold-up per plate, vvap is the boiling rate of vapor, and  is
the dimensionless time (a function of relative volatility and degree
to equilibrium).
Fig. 4 shows the dimensionless time  to reach 95% and 99% of
equilibrium as a function of relative volatility (Robinson & Gilliland,
1950). It indicates that it takes longer time to reach a high degree of
equilibrium for components with a small relative volatility. Fig. 5
illustrates the total reflux time required for the commercial column
to reach 99% of equilibrium as a function of relative volatility (using
the actual hold-up and boiling-up rate for the commercial column),
which implies that it takes 4–6 h after total reflux to reach 99% of
equilibrium for Impurity A—product pair with a relative volatility
of 1.13.
The front-cut typically took 2 days with 1–2 h total reflux prior
to the front-cut in production. Since a longer total reflux time yields
better equilibrium, it will be beneficial to increase the total reflux
time prior to the front-cut based on this analysis. To evaluate the
benefits of better equilibrium on the efficiency of Impurity A sep-
aration, the batch distillation process is modeled with a rigorous
distillation model.
 Y. Yang, R. Tjia / Computers and Chemical Engineering 34 (2010) 1030–1035
Fig. 5. Reflux time required to reach 99% equilibrium for the production column.
A rigorous model for batch distillation involves solving several
stiff ordinary differential equations (Diwekar, 1995). For the model-
ing purpose, the commercial available software, BatchFracTM from
AspenPlus® , was chosen and used for this work due to its flexibility
and availability although other commercial software are available
(such as CHEMCADTM BATCH and HYSYS.Plant® ). BatchFracTM is a
rigorous model for modeling batch distillation with multi-stages
from AspenTech (Aspen Tech Inc., 2004) that has been verified and
validated by researchers in literature (Cook et al., 2004; Jimenez
et al., 2002). Thus, validation of the accuracy of batch distillation
simulator is not subject of this work since it has been done else-
where. BatchFracTM uses a robust and efficient algorithm to solve
the unsteady-state heat and mass balance equations that describe
the batch distillation processes. BatchFracTM is flexible and can han-
dle a wide variety of batch distillation problems. In addition, the
property estimation/correlation of AspenPlus® is integrated with
BatchFracTM , simplifying the modeling task.
In batch distillation modeling the equilibrium composition
along the column has to be calculated first. Equilibrium or steady
state under the batch mode distillation at total reflux can be very
different from the continuous mode distillation, since liquid hold-
up and amount of low-boiling impurities in the hold-up needs to
be considered, especially for a low level of low-boiling components
in the feed. Impurity A concentration is about 0.23–0.25% in typical
feed material. Impurity A along the column at equilibrium is cal-
culated using BatchFrac® and is illustrated in Fig. 6 for the column
used in manufacturing (33 theoretical plates with a total 9.6 kg of
liquid hold-up). Plate number 1 and 32 in the figure corresponds to
Fig. 6. Impurity A along column after reaching equilibrium.
1033
Fig. 7. Comparison of model simulation and In-Process test results of Impurity A in
distillate.
top and bottom of the distillation column, respectively, and plate 33
corresponds to the still pot. It is evident from this figure that liquid
hold-up in the column has a dramatic effect on the impurity pro-
file along the column. Impurity A along the column at equilibrium
with 50% of the nominal hold-up (4.8 kg) and 200% of the nomi-
nal hold-up (19.6 kg) in Fig. 6 indicates that the larger the hold-up
is, the less efficient the separation is for the low-boiling compo-
nent due to lower Impurity A concentration at top of the column.
After the low-boiling component moves to the top of the column
in the equilibrium process, its concentration in the still pot starts
to decrease that affects the level of low-boiling impurity on all the
plates above the still pot. The model simulation indicates that if
a better equilibrium is reached, Impurity A at top of the column
could be enriched from 0.23% in the feed to approximately 8% at
the top of the column. Thus, better equilibrium in principle would
significantly increase the separation efficiency.
Simulation result of Impurity A concentration (weight/weight
percentage) as a function of distillation time in fresh distillate is
illustrated in Fig. 7 (solid curve) using the actual reflux ratio of
40:1 for the front-cut, 8:1 for the product-cut, boiling-up rate of
41 kg/h and total column hold-up of 9.6 kg for the distillation col-
umn. The deflection point at 16 h of distillation is due to the change
of reflux ratio from 40:1 to 8:1, resulting in less efficient separa-
tion of Impurity A that reduces its concentration in fresh distillate
after reducing the reflux ratio to 8:1. The model simulation indi-
cates that the front-cut distillation should be completed in 12–14 h
using the production column with a typical 0.23% of Impurity A in
the feed, starting from which the fresh distillate should meet the
In-Process specification of ≤0.6% of low-boiling impurities as mea-
sured by GC analysis. This is far less than the typical 48 h of front-cut
distillation observed in production with 1–2 h of total reflux prior
to the front-cut. Based on the model simulation and engineering
understanding, the total reflux time for the production column was
increased to approximately 5 h prior to the front-cut. For a com-
mercial run with a typical 0.23% of Impurity A in the feed, fresh
distillate samples from the condenser line were taken and tested
by GC analysis every 2 h from beginning of the front-cut distillation.
The In-Process GC testing results of Impurity A (square symbols in
Fig. 7) show a good agreement with the model prediction for both
the front-cut and the product-cut distillations. This demonstrates
that the efficiency of Impurity A separation from product can be sig-
nificantly enhanced with an increased in total reflux time to about
5 h, which results in over 60% of cycle time reduction for the front-
cut distillation. It has been shown in the commercial column that
further increase in total reflux time to more than 5–6 h has a mini-
mum effect on the enrichment of Impurity A at top of the distillation
1034 Y. Yang, R. Tjia / Computers and Chemical Engineering 34 (2010) 1030–1035
Fig. 8. Effect of reflux ratio in front-cut on Impurity A removal with 0.23% of Impurity
A in the feed.
column since an equilibrium has been reached, thus dismissing the
return of even longer total reflux time on the efficiency of Impurity A
removal.
After the distillation model has been verified by the plant data,
it is of interest to utilize the modeling tool to understand the effect
of reflux ratio in the front-cut on Impurity A removal and the effect
of Impurity A level in the feed on the cycle time of front-cut dis-
tillation. Fig. 8 shows the effect of reflux ratio in the front-cut on
Impurity A removal with a typical 0.23% of Impurity A in the feed
as a function of percentage of feed distillated. As the reflux ratio
is reduced from 40:1 to 20:1 in the front-cut, the percentage of
feed to be distilled is actually reduced from 7.7% to 5.2% for the
fresh distillate to meet the specification of ≤0.6% impurities due
to a less degree of purification for the low volatility Impurity A at
a low reflux ratio. However, the overall percentage of Impurity A
removed at end of the front-cut is reduced from 65.6% to 55.3%
with a reduced reflux ratio from 40:1 to 20:1. Fig. 9 illustrates the
effect of reflux ratio in the front-cut on Impurity A removal with
a doubled amount of Impurity A in the feed (0.46%) as a function
of percentage of feed distillated. For this elevated level of Impu-
rity A, the percentage of feed to be distilled is almost the same at
approximately 17% for 20:1, 40:1 and 60:1 reflux ratios to meet the
specification of ≤0.6% impurities in the fresh distillate. However,
the overall percentage of Impurity A removed at end of the front-
cut is reduced from 88.4% for 60:1 reflux ratio to 84.2% for 40:1
Fig. 9. Effect of reflux ratio in front-cut on Impurity A removal with 0.46% of Impurity
A in the feed.
Fig. 10. Front-cut cycle time before and after increasing equilibrium time.
reflux ratio and 73.7% for 20:1 reflux ratio with the corresponding
front-cut cycle time of 38 h, 26 h and 13 h, respectively. It should be
noted also that 73.7% removal of Impurity A in the front-cut with
20:1 reflux ratio may not be sufficient to meet the specification of
≤0.1% of Impurity A in product. To balance the overall Impurity A
removal and cycle time in the front-cut, 40:1 reflux ratio in the
front-cut is appropriate even with Impurity A doubled in the feed.
The enrichment of low-boiling impurities (mainly Impurity A)
in the front-cut with a longer total reflux time (about 5 h) can be
further explained in Fig. 10 by comparing the low boiling concentra-
tion in the fresh distillate with 1–2 h total reflux (original process)
and those with approximately 5 h total reflux prior to the font cut
(after process improvement). The total low-boiling impurities in
the feed material for these five production runs were very similar.
Distillate samples were taken every 5 h (if the previous samples
contains ≥1% of low-boiling impurities) and every 2 h (if the pre-
vious sample consists of <1% of low-boiling impurities) to test for
low-boiling impurities by GC analysis after starting the front-cut
distillation, until the low-boiling impurities are ≤0.6% in the fresh
distillate. In the original process, the first sample after 5 h of front-
cut distillation normally contains 5–6% of low-boiling impurities in
distillate and the impurities gradually decreased with a very long
tail due to insufficient equilibrium prior to the front-cut distilla-
tion (three production lots with dotted lines grouped as “original
process” in Fig. 10). After process improvement with about 5 h of
total reflux, low-boiling impurities are much enriched in the top
portion of the distillation column due to better equilibrium. This
results in a much higher concentration of the low-boiling compo-
nents at the start of the front-cut distillation (solids curves in Fig. 10
with additional samples taken at 0 h after total reflux), yielding a
much shorter distillation time to achieve the In-Process specifica-
tion of ≤0.6% of low-boiling impurities for switching to product-cut.
It should be noted that the areas under the low-boiling impurity
curves prior to and after the process improvement are essentially
the same, representing that the total amount of low-boiling impuri-
ties removed are similar for these five production runs. This process
improvement not only reduces the cycle time of front-cut distil-
lation, but also results in a lesser amount of front-cut material
collected as waste, thus, increases the yield.
4. Other improvements to reduce cycle time
4.1. Increase of jacket temperature for faster boiling-up rate
The jacket temperature during distillation was originally set at
130 ◦ C in production. Since the boiling temperature of the crude
mixture under the given vacuum is about 118 ◦ C, the temperature
 Y. Yang, R. Tjia / Computers and Chemical Engineering 34 (2010) 1030–1035
difference in the reboiler was only 12 ◦ C. Stability studies indicated
that the jacket temperature could be increased to 150 ◦ C without
impacting the product quality. Since it is desired to reduce the cycle
time, the jacket temperature was gradually increased to 140 ◦ C
during distillation. The differential pressure along the distillation
column only increased slightly from 1.6 kPa to 2.2 kPa when the
jacket temperature was increased to 140 ◦ C, indicating a good col-
umn performance with an increased boiling-up/distillation rate.
The product-cut distillation normally took 3–4 days (72–96 h) in
the original process with the jacket temperature at 130 ◦ C. After
the jacket temperature is increased to 140 ◦ C, the average time for
the product-cut has been reduced to 36–53 h.
4.2. Decrease in condenser temperature
The condenser temperature was set at 28 ◦ C during the product-
cut in the original process, resulting in loss of some product to
the vacuum. When the condenser temperature was set to 22 ◦ C,
the condenser was frozen with solids. Investigation on the issues
revealed that the frozen material(s) was due to low-boiling impu-
rities. The condenser temperature is then gradually decreased to
24 ◦ C for the front-cut and 22 ◦ C during the product-cut. It is mea-
sured that the loss of product to the vacuum is decreased by about
3% due to the lower condenser temperature.
4.3. Better vacuum
The calculated VLE using UNIFAC and group contribution
method in the built-in property estimator of AspenPlus® (Aspen
Tech, 2004) indicates that the relative volatility of Impurity A and
product slight increases at a higher vacuum (low pressure). Because
of the slight increase in separation efficiency, the vacuum at the top
of the column is reduced to less than 0.66 mbar from 2.63 mbar.
This has resulted in smoother and lower temperatures at top of the
column, made the separation more efficient, and slightly increased
the boiling-up rate. Due to better vacuum the distillation rate is
increased and the cycle time is slightly shortened.
4.4. Better control of reflux ratio
Careful evaluation of the reflux ratio in the front-cut indi-
cated that with a reflux ratio setting at 135:3 s (45:1 ratio), the
splitter valve actually closed and opened for 138.83 s and 3.50 s,
respectively, resulting in an effective reflux ratio of approxi-
mately 40:1 (due to the limit of control system and the physical
movement of the valve). Lower reflux ratio would reduce the sep-
aration efficiency of low-boiling impurities in the front-cut. This is
modified and compensated by changing the splitter setting from
135:3 s to 180:4 s in the front-cut. This produces a better reflux
ratio close to the setting that slightly increases the separation
efficiency.
After these process improvements and optimization, the overall
cycle time per batch has been gradually decreased from approxi-
mately 7 days to about 2.5 days as illustrated in Fig. 11, and the yield
has been increased from original 82% to an average of 88% while still
producing the same high quality of product. These improvements
are achieved with the original equipment and with a minimal cost.
Since these changes are within the regulatory filings for the pro-
cess, they are implemented quickly in commercial production to
improve the throughput.
1035
Fig. 11. Reduction of process cycle time after process optimization.
5. Summary
Process understanding and improvements were required to
decrease the cycle time for a batch distillation process. Based on
process understanding and modeling of the batch distillation, four
process improvements have been made to reduce the cycle time
and to increase the manufacturing throughput: (1) increasing the
equilibrium time prior to the front-cut to achieve better equilib-
rium for a more efficient separation of low-boiling impurities, (2)
increasing the jacket temperature of reboiler for faster boiling-
up/distillation rate, (3) reducing the condenser temperature to
minimize the product loss to vacuum, and (4) optimizing the vac-
uum and splitter system.
Through the process modeling and improvements, the average
cycle time was dramatically decreased to 4.2 days first and then to
an average of 2.5 days, which represents 64% reduction in cycle
time from an average of 7 days process originally, or increases
the throughput by a factor of 2.8. Furthermore, the yield is also
increased and the strict specifications are met. This is achieved
with the original equipment and without capital investment. These
changes have been implemented in commercial production to man-
ufacture the increased demands on the drug substance.
In conclusion, fundamental understanding and process model-
ing of the batch distillation process allow us to quickly improve the
existing commercial process to increase the throughput by a factor
of 2.8 using the approach of quality by design (QbD), and to produce
the quality product consistently.
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