ASPEN PLUS

SOFTWARE
Aspen Plus is a process modeling tool used
for process monitoring, optimization and
conceptual design, especially by chemical
process industries. It is founded in 1981,
AspenTech was born out a joint research
project between the Massachusetts Institute
of Technology (MIT) and US Department of
Energy—called the Advanced System for
Process Engineering (ASPEN) Project.
 What is Aspen Plus?

 Aspen Plus (AP for short) is the leading Chemical

Process Simulator in the market (or at least in the
Chemical Engineering World)
 AP is a software that will allow the user to build a
process model and then simulate it using complex
calculations (models, equations, math calculations,
regressions, etc)
 There are many perks in AP, from designing new
processes to improving existing ones. That is so, that
even AP ensures so in its website:
 (it will) Maximize profits using a plant-wide simulation
solution that combines unparalleled accuracy and
engineering collaboration with time-saving workflows.
Lets get more technical:
 Given a process design and an appropriate
selection of thermodynamic models, AP uses
mathematical models to predict the performance
of the process.
 Engineers will typically simulate this using the
software in order to optimize the design and
improve existing ones.
 This accurate modeling of thermodynamic
properties is particularly important in the
separation of non-ideal mixtures.
 One of the best advantages is that Aspen Plus has
already an existing data base of of species and
their pure/binary regressed parameters.
 It can also handle very complex processes, such
as:
 Multiple-column separation systems
 Chemical reactors
 Distillation of chemically reactive
compounds
 Electrolyte solutions such as in Chlor-
Alkali Industry
 Complex Recycle – Bypass Stream in
Processes
 What is Process
 Simulation?
Lets get something clear about Process Simulation, specially in the
chemical Process Industry, is NOT drawing and modeling Equipment
alone… It is mostly focused on the physical and chemical
characteristic on how unit operations will work!
 Process Simulation is the Art of Modeling Chemical and Physical
Processes in Computer. I’m sure you have heard about the so-called
“computer aided design” or CADS.
 As you can imagine, long time ago there were no CADs and most
calculations were done on computer or even by hand! So it is now a
delight to have a CAD available for Process Simulation… If you don’t
think so, I dare you to calculate the viscosity, temperature, pressure
and concentration profile on ternary mix of non-ideal substances
going through a Distillation Column! Case A – for 10 stages; Case B,
for 20 Stages! (good luck!)
 A little of AspenTech History
 Aspen Plus is actually a product from the
american company Aspen Technologies
 AspenTech wasFounded in 1981. It was
born out a joint research project between
the Massachusetts Institute of Technology
(MIT) and US Department of Energy—an
Advanced System for Process Engineering
.
 Since then, AspenTech has been creating a lot
of products, mostly in the following branches:
 • Process Simulation for Energy
 • Process Simulation for Chemicals
 • Advanced Process Control,
 • Manufacturing Execution Systems,
 • Petroleum Supply Chain
 • Supply Chain Management
 • and much more…
 Of these, the most relevant software that we
are going to talk about are
 • Aspen Plus
 • Aspen HYSYS
 Both of them are Process Simulation
Software.
Who uses this tool?
 By now you should know the importance of the
software and why it is so powerful… But which
companies use this software? Is your industry of
interest here? Or maybe you know that at X company
they use Aspen Plus…

Well, the most common industries are:

Oil & Gas (upstream and downstream)
Petroleum Refining
• Natural Gas
• Petrochemicals
• Chemical Industry
• Polymers
• Pharmaceuticals
• Painting & Coatings
• Food & Bevereages
 Advantages of aspen plus in
process simulation:
One of the best advantages is that aspen has
already an existing data base of species and
there pure regressed parameters. It can also
handle very complex processes such as
 Multiple column seperation systems
 Chemical reactors
 Distillation of chemically reactive compounds
 Electrolyte solutions such as in Chlor-Alkali
industry
 Complex recycle-Bypass stream in processes.
 Disadvantages
 It takes an existing design that the user adds or
inputs via new flow sheet or existing templates
in order to simulate and improve its
performance.
 A good process engineer will be required,as
real life application must be used while using
the software.
 The chemical engineering principles are still
required.
 You are mostly on your own. Might be
expensive. Typically, will not cover very specific
type of simulations. Hard to find extensive
offering specially in advanced topics (polymers,
biotech, electrolytes, etc.)
 Commands of Aspen plus software using biotechnology

BIOCHEM: This command is used to define the biochemistry model for the process.
It allows the user to specify the reactions, stoichiometry, and kinetics of the
biological system.


BIO-MOD: This command is used to specify the biological modules that are used in
the process. These modules can include enzymes, microbes, and other biological
components.


BIO-REACTION: This command is used to define the reactions that occur in the
biological system. The user can specify the reactants, products, stoichiometry, and
kinetics of each reaction.


BIO-FEED: This command is used to specify the feed stream for the biological
system. The user can specify the composition, temperature, and flow rate of the
feed.
BIO-PRODUCT: This command is used to specify the product stream for the
biological system. The user can specify the composition, temperature, and flow
rate of the product.


BIO-PARAM: This command is used to specify the parameters for the biological
system. The user can specify the reaction rates, activation energies, and other
parameters that affect the behavior of the system.


BIO-REPORT: This command is used to generate reports of the results of the

simulation. The user can specify the variables to be reported, such as the
concentrations of the reactants and products, and the rates of reaction.


BIOCHEMICAL REACTION: This command allows the user to define

biochemical reactions in the model. The user can specify the stoichiometry of
the reaction, the kinetic parameters, and the thermodynamic properties.
BIOCHEMICAL REACTOR: This command models the behavior of a bioreactor.
The user can specify the reactor type, the operating conditions, and the mass
transfer coefficients.
FERMENTATION: This command simulates the fermentation process. The user
can specify the microorganisms used, the substrate, and the operating conditions.


ENZYME KINETICS: This command models the behavior of enzymes in a

bioreactor. The user can specify the kinetic parameters and the thermodynamic
properties.


CELL CULTURE: This command simulates the growth of cells in a bioreactor. The
user can specify the cell type, the nutrient medium, and the operating conditions.


BIOMASS PRODUCTION: This command models the production of biomass in a

bioreactor. The user can specify the microorganisms used, the substrate, and the
operating conditions.


PROTEIN PRODUCTION: This command simulates the production of proteins in

a bioreactor. The user can specify the microorganisms used, the substrate, and
the operating conditions.
OPTIMIZATION OF DRUG SOLUBILITY USING ASPEN PLUS: ACETYLSALICYLIC
ACID (ASPIRIN) SOLUBILITY – A SECOND CASE STUDY

 ABSTRACT


 Objective: The objective of the study is to optimize the solubility of a drug or

a drug-like molecule using Aspen Plus simulation platform. Aspirin (solute)
was taken as the second case study. The following solvents were used in our
dry (virtual) laboratory experiment: Water, acetone, ethanol, and ethylene-
glycol-mono-propyl-ether (PROPGLYC).

 Methods: A simplified process flow sheet made of a single mixing tank

where it has five feed streams, representing the solute, the water, and the set
of three organic solvents, and one product stream where aspirin is either
solubilized (liquid solution) or remains as solid crystal. Minimization of the
molar Gibbs free energy of mixing, ΔGmix, was used as an objective function
from an optimization point of view. The Non-random Two-liquid property
method was used to analyze the solution properties.
 Results: Using the molar Gibbs free energy of mixing, ΔGmix, as a
criterion of solution thermodynamic stability, it was found that the most
stable solution is the quinary mixture made of 24.42% aspirin, 10.22%
water, 21.08% acetone, 19.51% ethanol, and 24.77 mole % PROPGLYC.

 Conclusions: Exploiting Aspen Plus can be extended to handle the

solubility of a new drug-like molecule once it is defined within its
molecular editor with a little knowledge such as density and/or melting
point.

 Keywords: Solubility, Acetylsalicylic acid, Aspen plus, Optimization,

Aspirin, Gibbs free energy.
 INTRODUCTION

 O-Acetylsalicylic acid, 2-Acetoxybenzoic acid, or aspirin, with the linear formula

(2-(CH3CO2)-C6H4-CO2H), belongs to the family of medications called analgesics
(pain relievers), antipyretics (fever reducers), anti-inflammatories (inflammation
reducers), and platelet aggregation inhibitors (anti-clotting agents). It has a
limited solubility in water, which amounts to 2–4 mg/mL and its solubility varies
significantly with temperature . Aspirin is more soluble in ethanol, ethyl ether,
chloroform, sodium hydroxide solution, and sodium carbonate solution than in
water.
 Maia and Giulietti examined the solubility of acetylsalicylic acid in ethanol,
acetone, propylene glycol, and 2-propanol, in addition to comparing their
solubility values with the expected from an ideal solution. The solubility of
acetylsalicylic acid was found to be highest in acetone in all studied temperature
ranges until T=326.3 K. Propylene glycol was found to have lower solubility data
in all studied temperature ranges. The solvent that presented the lowest average
percentage logarithmic deviation, concerning the ideality of the system, was
ethanol, and the highest value of average percentage logarithmic deviation was
found in propylene glycol solutions. They also contrasted their experimental
solubility data versus those predicted by the Nývlt model and found that the
Nývlt model was capable of properly representing the experimental data.
 Huang et al. examined the introduction of polar cosolvents to dramatically
increase solubilities of polar organic solids in supercritical CO2. In their study,
they have measured the solubility of aspirin in methanol-modified and
ethanol-modified supercritical CO2 by means of a dynamic saturation method.
Experimental results showed that the aspirin solubility could be greatly
enhanced up to 14 times by introducing 3.0 mole % methanol or ethanol. In
their opinion, the enhancement was mainly attributed to the strong attractive
molecular interactions between the polar cosolvent and the polar solute. The
aspirin ternary solubility data were fairly well described using the Peng–
Robinson equation of state (EoS) model with an absolute average relative
deviation ranging from 14 to 23%.
 Mota et al. examined the solubility of drug-like molecules in pure organic
solvents using the cubic-plus-association EoS that combines the simplicity and
robustness of a cubic EoS with the Wertheim’s association contribution. In
their work, such an EoS was proposed for the 1st time to model organic phase
solubilities of drug-like molecules in a wide range of temperatures. They
estimated solubilities of acetanilide, acetylsalicylic acid, adipic acid, ascorbic
acid, hydroquinone, ibuprofen, paracetamol, and stearic acid in alcohols,
ketones, alkanes, esters, acids, aromatics, chlorinated solvents, as well as in
other common solvents. They accounted for hydrogen-bonding behavior for
each associating group being treated individually as well as multiple group
substitutions. Accurate correlations were obtained using a single binary
interaction parameter with an average absolute deviation of 24.2%.
 In the previous works, the aqueous solubility of simple inorganic and that of
simple (single carbon) organic molecules were examined and expressed in
terms of important molecular properties. Moreover, the aqueous solubility of
some organic solvents was examined as a function of some selected
molecular descriptors which are thought to affect the solvation process. It
was found that to have an organic solvent with a high aqueous solubility, it
has to have a low value of both the log partition coefficient between octanol
and water, LogKow, and the molecular rugosity, R=V/S, accompanied by a
high value of polar to hydrophobic surface area ratio, PHSAR. Aspen Plus was
used to optimize acetaminophen (paracetamol) solubility in a set of solvents,
including water . Three objective functions were used to find the optimum
formulation in terms of molar and mass composition of paracetamol
solution.

 In this work, aspirin, also known as o-acetylsalicylic acid, 2-acetoxybenzoic

acid, is used as a solid solute to demonstrate how we can exploit Aspen Plus
simulator as a powerful tool to optimize the solubility of aspirin using
different organic solvents and water, as well. The minimization of molar
Gibbs free energy of mixing (ΔGmix), expressed in kJ/kmol, is used as the
objective function, from an optimization standpoint.
 METHODS

 The following paragraph describes what Aspen Plus simulator is all about:
“Aspen Plus, a flow sheet simulation, is a computer software that is used to
quantitatively model a chemical processing plant, which in addition to the
core reactor unit, it also includes pre-treatment and post-treatment steps, as
well. Thus, simulation of an entire chemical process, starting from the raw
material side down all the way to the final, finished product side, is
symbolically represented by different icons where each icon stands for a unit
operation, chemical process, input/output material stream, input/output
energy stream, or input/output electric/pneumatic signal. Given reliable
thermodynamic data, sensible operating conditions, and rigorous equipment
models, Aspen Plus enables us to run many tasks, like carrying out
optimization case studies” .
 I will show below in a chronological order the steps needed toward utilizing
Aspen Plus powerful capability in carrying out optimization case studies for
different pharmaceutical processes, in addition to traditional chemical
processes.
 The first step is to select the proper template. Since we deal with a drug, we
will select the pharmaceutical template, as shown in Fig. 1.
 The second step is to define the list of components to be used in our
optimization case study. Fig. 2 shows such a list. The components are,
acetylsalicylic acid (ASPIRIN), used as a solid solute, WATER, ACETONE,
ETHANOL, and ethylene-glycol-mono-propyl-ether (PROPGLYC). Notice that,
aspirin has been defined as “Conventional” not “Solid” type, with the
understanding that a conventional solid will be part of the aqueous medium
(i.e., participates in phase equilibrium) and it has a well-defined molecular
structure, according to Aspen Plus terminology. Organic solvents were
chosen in light of the cited literature [3-5].
 It is worth-mentioning here that Aspen Plus has some built-in databank
drugs, such as ibuprofen, aspirin, and acetaminophen (paracetamol);
nevertheless, if the drug is not defined as part of Aspen Plus databank, then
it can be defined within Aspen Plus platform through its skeletal molecular
editor and knowing some tiny little information about the drug itself, such as
the melting point, boiling point, or density.
 The third step is to define the property set which accounts for the outlet
mixture property; namely, the molar Gibbs free energy of mixing, ΔGmix, as
shown in Fig. 3. Such a property set will be utilized later in the optimization
case study.
 The fourth step is to select the property method, as shown in Fig. 4. In this
case, the method filter is “PHARMA,” which facilitates the selection of the
property method. “Non-random Two-liquid” method is chosen as it has the
capacity to deal with a very broad spectrum of components present in
solutions.
 After successfully carrying out the property analysis/setup step, we have to
move from “Properties” to “Simulation” environment within Aspen Plus
simulator.
 The fifth step is to create a process flow sheet for handling the mixing
process of paracetamol. Fig. 5 shows a simplified flow sheet for the aspirin
mixing where it has five feed streams: One accounts for the solute; three of
them for the set of organic solvents; and the last for water. Moreover, the
product stream mixture can have aspirin as solubilized (liquid solution),
undissolved (solid or crystal form), or both (S/L equilibrium phases). This
process of mixing simply says that we start with pure individual raw
materials and end up with a mixture or solution, which has, in general, molar
solution properties that are functions of pressure, temperature, and molar
composition of the constituting ingredients.
 The sixth step is to enter feed stream properties, as shown in Fig. 6. Such values of flow
rate are tentative and they are subject to change or modification by the optimizer as
shall be seen shortly. Notice that, Fig. 6 is a compilation of five separate feed folders.
 The platform is now ready for using Aspen Plus “Optimization” tool under “Model
Analysis Tools” feature.
 The seventh step is to create an optimization case study. We will create one case study
with the objective function named DGMIX, the molar Gibbs free energy of mixing for
the output mixture stream, as shown in Fig. 7.
 The eighth step is to define the attributes of the optimization case study. Fig. 8 shows
how we define the objective function and then decide whether to maximize or
minimize it on executing the optimization algorithm. In this case, DGMIX ( ΔGmix) is
defined, shown under “Define” tab, in light of the property set shown earlier in step #3.
The molar Gibbs free energy change on mixing will be minimized, shown under
“Objective and Constraints” tab.
 The ninth step is to pick up the manipulated variables which are thought to affect the
already defined objective function, shown in step #8. Fig. 9 shows the list of
manipulated variables which represent the molar flow rates of each solvent, including
water. The variation of each molar flow rate from 0 to 10 kmol/h will give the
optimization algorithm the chance to search for the best composition which will give
the minimum change in molar Gibbs free energy on mixing. Obviously, this will affect
the final composition of the exit stream mixture. Notice that, we did not include the
effect of temperature at this stage. Intuitively, the medium temperature affects both the
stability and maximum solubility of an organic solute dissolved in a set of solvents,
including water.
 RESULTS AND DISCUSSION

 Fig. 10 shows the summary of carrying out the optimization case study with
DGmix being the objective functions. The molar flow rate of each manipulated
variable (Fig. 9) is shown at the final stage where the optimization algorithm
stops at or converges to at least one local minimum (DGmix=‒3248.7 kJ/kmol) if
not an absolute global minimum as far as DGmix changes as a function of the
mole fractions: X1, X2,…, Xn–1. The theme here is that given a molar flow rate of
aspirin, the goal is to formulate the solution by varying the flow rate of each
solvent involved in the solvation process.
 Based on the minimization of ΔGmix, the most stable formulated solution is the
quinary mixture made of 24.42% aspirin, 10.22% water, 21.08% acetone,
19.51% ethanol, and 24.77 mole % PROPGLYC, as shown in Fig. 11. Alternatively,
the optimized mass fraction of the product (i.e. exit) stream is also shown in Fig.
11.
 In a previous work [8], it was found that the solid powder of paracetamol
mapped to the highest molar Gibbs free energy. Here, the minimization of molar
Gibbs free energy of the solution, GMX, and maximization of solubility of aspirin
in liquid solution both yielded to a pure solid of aspirin with zero molar flow
rates of feed solvents (results are not shown here for the sake of brevity).
 CONCLUSIONS
 In general, Aspen Plus platform can be exploited to predict the optimum
formulation of a given drug with different set of solvents and compositions.
If the drug is not built-in as a data bank member, then it can be defined by
Aspen Plus skeletal molecular editor with some little information about
physical properties, such as melting point, boiling point, or density. Using the
molar Gibbs free energy of mixing, ΔGmix, as a criterion of solution
thermodynamic stability, the most stable solution is the quinary mixture
made of 24.42% aspirin, 10.22% water, 21.08% acetone, 19.51% ethanol,
and 24.77 mole % PROPGLYC.