Formation of low mass protostars and their circumstellar disks
Process intensification
1. Analytical Chemistry (CHY3022)
Process Intensification
Ethan Gayle 1803094
Dadrian Black 1600568
Shanice Stennett 1800453
Date: April 14, 2020
Lab Pool: Monday 3 - 6 pm
Presented to: Dr Min
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Abstract:
Process intensification (PI) provides great opportunities to drastically improve the performance
of chemical processes within many branches of the chemical industry including the
pharmaceutical industry. This paper provides a review on process intensification and its latest
trends in the pharmaceutical or chemical industries. The aim of this project is to provide
supplementary information on the operation, the application of this technique as well as its
applicability to the field of study, Pharmaceutical Technology. Through basic recommendations
as well as advantages and or disadvantages (limitations) of the techniques employed in process
intensification, students and researchers can make an informed choice of the techniques to
employ in future endeavors.
Keywords: Efficiency, Pharmaceutical Industry, Process Intensification
Introduction:
This project aims to inform persons about Process Intensification and its latest trends in
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the Pharmaceutical or Chemical Industries. It was also beneficial to the Pharmaceutical
Technology students that conducted this research as process intensification is applicable to the
course of study.
Process Intensification is one of the most significant trends in the Pharmaceutical or
Process Chemical Industries. A number of commercial-scale applications of the Process
Intensification principles have already taken place. The word, intensive, originated around the
fifteenth century according to the ‘Miriam-Webster’s Collegiate Dictionary’. At the peak of the
renaissance, ‘De Re Metallica’, a book published by Georgius Agricola, illustrated woodcuts
showing equipment and processing methods used and clearly elements of process-intensification
oriented thinking were found. For example, the technique employed in retrieving gold from gold
ore in the sixteenth century (see Figure 1). Almost 450 years later, Agricola’s contemporaries
had a striking resemblance to the equipment used in the chemical industry (see Figure 2). At the
beginning of the third millennium, stirred tanks remained as the most common chemical
processing system and later a technological leap was achieved by replacing the mechanical mixer
with a static mixer to mix fluids.
The term Process Intensification appeared mostly in Eastern Europe around the mid-
1960s and early 1970s but the birth of Process Intensification in Chemical Engineering came
several years later at the Imperial Chemical Industries (ICI) in the United Kingdom. The research
performed there paved the way for other companies developing and using processing
intensification techniques and equipment. Up until the early 1990s, Process Intensification was
mainly a British discipline that focused on four main areas: intensive mixing, compact heat
transfer, combined technologies and the use of centrifugal forces. However, Process
Intensification was already on the international scale. In Holland, for example, the initiatives of
the Delft Skyline Debate and the active research groups in China, France, The United States of
America and Germany paved the way for a long term and very important future for Processing
Intensification.
At the end of the 20th century and the beginning of the 21st century, the growth of Process
Intensification in the industry and academia was immeasurable. Bioprocessing, fermentation and
fine chemistry were added to the list of the traditional areas that were initially focused on. As a
result, the definition of Process Intensification changed overtime. According to the text, ‘Process
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Intensification For Green Chemistry’, a more recent definition for Process Intensification is “The
development of innovative apparatus and techniques that offer drastic improvements in chemical
manufacturing and processing, substantially decreasing equipment volume, energy consumption,
or waste formation, and ultimately leading to cheaper, safer and sustainable technologies.” Now,
Processing Intensification is not only applicable to the chemical industry but also the food and
pharmaceutical industries.
According to Stankiewicz and Moulijn (2000), Process Intensification can be divided into
two areas: Process Intensifying equipment and Process Intensifying methods. Process
Intensifying equipment are special designs that optimize critical parameters while Process
Intensifying methods describe multiple processing steps that are integrated into a single unit
operation or where alternative energy sources are used.
Reactive distillation, one of the oldest and most widely implemented equipment is a
combination of a chemical reactor and a distillation column (see Figure 3). The reactive
distillation leads to a 20-80% reduction in capital costs and or energy usage (Harmsen, 2010).
Another example would be a static mixer which was mentioned earlier. The static mixer, a
significant improvement over mechanical agitation lowers energy costs and uncomplicates the
design with no moving parts. Other examples include monolithic reactors, compact or
microchannel process units, divided wall column (DWC) distillation, ultrasonic and microwave
units, and reverse flow reactors (see Figure 4). These designs may lead to significant
improvements in capital costs, energy usage, and process footprint. Though beneficial, like most
instrumental methods, this is expensive.
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Figure 1 showing the technique employed in retrieving gold from gold ore in the sixteenth
century. The arrows indicate the vessels (O) and mechanical mixer (RS).
Figure 2 showing the striking resemblance to the equipment used almost 450 years later.
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Figure 3 showing the reactive distillation equipment.
Figure 4 showing the Process Intensification toolbox.
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Application:
The pharmaceutical industry aims to ensure patient safety by producing a safe product
that is tested by the manufacturers and pharmaceutical scientists who utilizes world accepted
standard current scientific knowledge when testing the product. The product consists of the
active pharmaceutical ingredient as well as non-active compounds (excipients) that aid in
producing a therapeutic effect for the patient. In the Pharmaceutical Industry, the manufacturing
of the API’s are done in batch reactors. When done this way, despite being well planned and
implemented, it possesses many limitations. These limitations can lead to safety issues as well as
a reduction in yield obtained and product quality (Laurent, 2017). In addition to this, the
traditional operations and manufacturing set up of machines for drug extraction and development
has resulted in an increase in expenditure, production costs, environmental footprint from the
manufacturing processes, energy etc. Furthermore, with an increase in global competition from
generic manufacturers, pharmaceutical scientists require more efficient and robust manufacturing
strategies to remain competitive within the market to see increased revenue. Therefore process
intensification techniques and methods were researched and tested to determine how these issues
could be overcomed.
Process Intensification is a chemical engineering development that leads to a substantially
smaller, cleaner and more energy efficient technology process (Stankiewicz & Moulijin, 2000).
The pharmaceutical field did not broadly embrace the innovation of the process intensification
methods developed in the 1970s to maximize process and plant design, production, and
execution. P.I. was originally designed for the bulk chemistry industry and has now entered the
active pharmaceutical ingredient market. For example replacing costly production facilities,
including all-in-one glass reactors (Neil, D. 2016). This was beneficial as conventional batch
times could take as much as 15 - 20 hours to ensure that all ingredients were given enough time
to be in contact and react with one another. In the case of all-in-one glass reactors, more efficient
solutions were found such as custom-built agitation systems that when used, it saves up to 14
KW; which is a 78% energy reduction.
Another example of an efficient solution is the usage of multifunctional reactors.
Multifunctional processing equipment are reinforced pressure vessels with stainless, glass or
metal alloy linings. Multi-purpose reactors have external shells and internal coils which are filled
with cooling water, steam or chemicals with special heat-transfer properties. According to (Tait,
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n.d.), Multi-purpose reactors have agitators, baffles and many inlets and outlets connecting them
to other process vessels, equipment and bulk chemical supplies. Multifunctional reactor systems
have been developed to intensify chemical processes by synergistically combining chemical
reaction with momentum, heat and mass transport in a single vessel. This reactor system allows
for a continuous manufacturing process that is void of intermediate steps that could result in an
increase in energy needed for the process.
There is a growing need for reliable, safe, and inexpensive human and animal vaccines;
process intensification in the development of cell culture-viral vaccines requires innovative
process techniques to address the limitations of traditional batch cultivations. Fed-batch and
Perfusion Strategies may result in ten to a hundred times higher product yields as opposed to
traditional batch processes. In fact, all cultivation techniques may be applied to hit
concentrations of cells greater than 107 cells / mL or even 108 cells / mL (Tapia, F. 2013). Fed-
batch is Defined as an operating technique in which biotechnological processes where, during
processing, one or more nutrients are fed to the bioreactor and the substance remains in the
bioreactor until the end of the cycle. Process intensification strategies such as these are the
solution to reducing the cost of vaccines by reducing the resources needed to produce larger
quantities.
In the journal article ‘Modeling and Optimization of the Drug Extraction
Production Process’ several attempts are made at optimizing the extraction of the effective
constituents needed to prepare medicines from crude plant material. These technologies aim to
reduce the cost and increase yield by utilizing clever methodologies perfected over the years.
These include the use of mechanistic, mathematical modeling (He, D. 2016). The mechanistic
modeling of drug extraction consists mainly of modeling the following components: extraction
tank, EC mass transfer process, volatile oil recycling and oil-water separator efficiency. Provided
these systems can be copied to work as efficiently as designs based on known criteria such as
particle size and solubility in solvents etc. the overall process speed and efficiency can be
increased (He, D. 2016). Mechanistic modeling can be used to predict system responses through
the use of deterministic ordinary differential equations along with literature of real time
observations of industry operations. With this combination, best and worst case scenarios can be
addressed, drug repositioning can be guided, pre-clinical research can be prioritized etc
(Schmidt, Papin, & Musante, 2013).
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Process Intensification strategies can be predicted using complex algorithms; For this
optimization, a predictive model is also needed. The established mechanism is simplified in this
work to deliver as a predictive model. This is beneficial as the financial benefit per unit time is
perceived to be the optimization objective. In the pharmaceutical industry, researchers face
issues such as the length and overall cost of the discovery and development of a new drug. This
process needs to be shortened to reduce the costs and increase the success rate of the potential
drug. In addition to this, with an increase in drugs within the market, there is greater pressure on
pharmaceutical companies to produce effective drugs for potential patients. These issues can be
fixed using predictive modeling within the clinical stages of development for that potential drug.
This will indicate the chances of that drug having a high success rate in treating the specified
target group to demonstrate efficacy and cost-effectiveness (Archer, 2007). Through this method,
solutions are found for more difficult cases when researching new drugs.
Issues within the pharmaceutical industry can also be solved using mathematical
modeling. Fortunately, mathematical‐ based models can be applied at all stages of development,
starting with formulation design, continuing through process development and scale‐ up, and
extending into process monitoring and control of the commercial process. As a result, the
absorption, distribution, metabolism, excretion and toxicity (ADMET) attributes of molecular
structures involved in the process can be predicted (Chatterjee, Moore, & Nasr, 2017).
Mathematical models help to depict explicit relationships and interrelationships among the
vari-ables and other factors deemed important in solving issues.
Critical Review:
In the pharmaceutical industry, issues such as reduction in yields, reduction in product
quality, expenditure, production costs, environmental footprint from the manufacturing
processes, energy wastage, competitive markets etc arise during the stages of development as
well in the manufacturing of a possible drug. Through the use of models such as predictive
modeling, mechanistic modeling, mathematical modeling as well process intensifying methods
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such as multifunctional reactors; they thelp to implement process intensifying principles to
various industry based situations, which in turn alleviate these issues.
With every possible strategy, there are advantages and disadvantages that could either
benefit or hinder the process when utilized. Firstly, the strategy of predictive modeling can help
to improve pharmaceutical companies’ ability to produce effective drugs to be sold on the market
at a quicker pace and at a lower cost. Predictive modeling helps to cut development time, costs
without compromising safety, target spending on the project, and deliver an increased
understanding of the drug-drug interactions outside of clinical trials; while also helping to predict
potential side effects. Despite this, extensive amounts of current relevant data is needed to
predict the outcomes of the situation, special software is needed to compute the data as well as
trained professionals who are versed in statistical modeling are needed to analyze the results to
then implement the solution. In addition to this, the possible outcomes of a solution may only be
applicable within a certain window of time. As with time, the variables and data obtained may
change which then calls for an updated model, ie; constant analysis is needed.
Secondly, in using mechanistic modeling, there is an allowance for a high degree of
productivity, economy and efficiency. However, this model requires direct observation,
measurement and extensive data records as well as a thorough understanding of the behavior of a
system's components. Furthermore, mechanistic models are often rigid and resist change, making
them unsuitable for innovativeness and taking quick action (University of Minnesota Libraries
Publishing, 2015).
Mathematical modeling can help situations within the industry as the discovery and
experimentation costs can be reduced, the development cycle trial times can be shortened as well
as there can be an improvement in productivity as well as in product quality. In addition, results
from this model are quick and easy to produce and help to improve our understanding of the
possible outcomes as the variables can readily be changed. However, the execution of this model
requires professionals who are able to employ the equations needed and interpret its results.
Also, this method is a simplification of the issue as it does not include all aspects of the problem
and the results may only work in certain situations.
The use of multifunctional reactors are the last of the strategies spoken about. In using
multifunctional reactors, there is a reduction in investment costs and significant energy savings.
Also, these reactors enhance the performance of chemical reaction or/and physical effect. There
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can also be higher productivity, higher selectivity, improved operational safety, and improved
ecological harmlessness. Furthermore, through their use, there has been improved product
selectivity which leads to a reduction in raw material consumption and, hence, operating costs
(Dautzenberg & Mukherjee, 2001). Despite this, in using this equipment, there is increased
operational complexity, a limited application window, expensive development costs as well as
scale-up risks (Sundmacher & Qi, 2010).
Fortunately for pharmaceutical scientists, there are a multitude of ways to solve these issues
with help of Process Intensification. Other methods such as ultrasound assisted based
technologies, supercritical fluid technology and microchannel reactors are a few of the
recommended methods that could also be used.
Ultrasonic Sonochemistry is an emerging next generation technology which has the potential to
significantly improve the feasibility and economic performance of reactive systems. It is the
formation of acoustic cavitation in liquids, resulting in the enhancement of the chemical activity
in the solution. According to (Kiss, et al., 2018), it can be used in homogenous and heterogenous
systems such as liquid-liquid, liquid-solid and liquid-gas. Ultrasound assisted based technologies
such as this offer operational flexibility, fast response times to inlet variations as well as low
operating costs.
Another method that could be employed is supercritical fluid technology. This is a form of
extraction in which a component is separated from another through the use of a supercritical
fluid as the extracting solvent. It is a diffusion based extraction that offers products free of
residual solvent that are commonly of high quality (Majumer n.d.) . This is made possible by the
separation of fluids at high pressures. In using this technology, there is an opportunity for faster
and more complete extractions of materials such as lipids, waxes, resins etc of high molecular
weight that could be a desirable API used in the manufacturing of a product.
Microchannel reactors are used as a cost effective tool during drug development. These
reactors have a high surface to volume ratio, efficient heat and mass transfer characteristics,
improved fluid mixing etc. These reactors allow for precise control of reactions with improved
selectivity and yields of the desired ingredients (Gokhale, Tayal, Jayaraman, & Kulkarni, 2005).
Reaction times are shorter in these reactors when compared to conventional reactors, in addition;
there is less degradation and side products produced at the end of the process.
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Conclusion:
The Pharmaceutical and Process Chemical Industries have become more productive, energy
efficient and in the process achieved higher yields with less resources through the use of process
intensification strategies as a solution to the need to do less with more. Process Intensification
will continue to be the aim and moving target that can never be achieved but must be sought
after.
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