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[51] Stephanopoulos, G. Chemical Process Control: An Introduction to Theory and Practice,
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[55] Dimethyl Fumarate Selling price https://www.reuters.com/article/us-health-ms/u-s-prices-
for-multiple-sclerosis-drugs-are-on-the-rise-idUSKCN1VH2I5 May 28, 2020.
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[59] Malhotra, G.: Comparison of Drugs Prices: US vs. India; Their Manufacturing Costs &
Opportunities to Improve Affordability, https://pharmachemicalscoatings.blogspot.com/
2018/01/comparison-of-drugs-prices-us-vs-india_89.html, January 18, 2018, Accessed
May 20, 2020.
[60] Malhotra, G.: Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs)
on Drug Shortages and Affordability Part 2, https://pharmachemicalscoatings.blogspot.com/
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[61] Malhotra, G.: Systematic Demystification of Drug Price Mystique and the Needed Creative
Destruction, https://pharmachemicalscoatings.blogspot.com/2019/10/systematic-
demystification-of-drug.html, October 2, 2019, Accessed July 7, 2020.
[62] Malhotra, G.: Chemical Process Simplification: Improving Productivity and Sustainability John
Wiley & Sons, February 2011,.
[63] Malhotra, G.: Alphabet Shuffle – Moving from QbA to QbD, Pharmaceutical Processing World,
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February 23, 2009, Accessed June 10, 2020.
[64] Malhotra, G.: Process of Continuous Improvement and Pharmaceuticals, https://pharmache
micalscoatings.blogspot.com/2009/06/process-of-continuous-improvement-and.html,
June 1, 2009, Accessed June 3, 2020.
[65] Malhotra, G.: Calling for Change, https://pharmachemicalscoatings.blogspot.com/2015/11/
calling-for-change.html, November 17, 2015, Accessed June 3, 2020.
[66] An alternate look at pharmaceutical world revenues and drug affordability, https://www.man
ufacturingchemist.com/news/article_page/An_alternate_look_at_pharmaceutical_world_rev
enues_and_drug_affordability/135165, October 23, 2017, Accessed June 8, 2020.
[67] Malhotra, G.: Drug Prices: Food vs. Medicine – A Difficult Choice for Some https://pharmache
micalscoatings.blogspot.com/2011/06/drug-prices-food-vs-medicine-difficult.html, June 16,
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[68] Patel, N.: Why Don’t Patients Take Their Medications? https://www.usciences.edu/blog/note
worthy/posts/why-dont-patients-take-their-medications.html, October, 24, 2018, Accessed
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[69] Malhotra, G.: Batch or A Continuous Process: A Choice; Pharmaceutical Processing,
March 2005, Page 16.
66 Chapter 2 Business model: brand versus generics, product
[70] Malhotra, G.: Hesitation in the Drive to A Continuous Pharmaceutical Manufacturing Process:
Real or Imaginary? Pharmaceutical Processing, July 2009 pgs.- 12–15.
[71] Malhotra, G.: A Radical Approach to Fine/Specialty API Manufacturing, Profitability through
Simplicity, https://pharmachemicalscoatings.blogspot.com/2010/01/radical-approach-to-
finespecialty-api.html, January 20, 2010, Accessed June 29, 2020.
[72] Malhotra, G.: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My
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[84] Malhotra, G.: Are US FDA 483 Citations a “Medal of Honor” or “Rite of Passage” to Disgrace
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[85] Malhotra, G: Climate Change and Greening of Pharmaceutical Manufacturing, https://pharma
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References 67
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Chapter 3
Physical and chemical properties
Every raw material used in the manufacture of chemicals, pharmaceuticals, and
their formulations come in three forms. Each of these forms has their own charac-
teristics and nuances. It is best to review characteristics of each chemical’s physical
forms and how their mutual behavior can be exploited and used in reactive and
blending processes:
1. Liquid
2. Solid
3. Gas
Some are compatible with each other and others are not. Compatibility can be the
degree of miscibility (solubility) that can vary from none to completely soluble. Safe
handling of chemicals is necessary. Flammability is a characteristic of the chemi-
cals. This has to be extremely carefully addressed as most organic chemicals have
varying degrees of flammability. It is determined by the flash point of a material.
Flash point is the minimum temperature at which a liquid forms a vapor above its
surface in sufficient concentration that it can be ignited. Flammable liquids have a
flash point of less than 100 °F. Liquids with lower flash points ignite easier [1]. Each
chemical has certain toxicity and is discussed later in this chapter.
Process developers and designers have to know everything about the chemicals
used and produced in every reaction. Some of the n eeded physical properties are
listed in Tab. 3.1 [2]. Additional properties for specific need might also be needed. If
they are not readily available, they will have to be generated.
Properties [2] listed in Tab. 3.1 are of high value, and when used result in process
design that will produce quality products. It is not necessary that each of the property
mentioned may be needed or used in the design. Properties of raw materials used in
production of active pharmaceutical ingredients (APIs), produced intermediates and
Tab. 3.1: Chemical and physical properties of chemicals [2].
Physical properties Chemical properties
– Mass
– Density
– Melting/freezing point
– Boiling point
– Viscosity
– Solubility
– Azeotrope
– Heat of formation
– Heat of reaction
– pH
– Surface tension
– Flammability
– Toxicity
– Hygroscopic
https://doi.org/10.1515/9783110702842-003
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formulations that may not be commonly available. Their physical property data might
have to be generated theoretically and checked experimentally.
Before internet, many trade publications and companies published physical and
chemical property data. In 1960s and 1970s, chemical engineering [3] and hydrocarbon
processing [4] magazines published 24 and 44 articles, respectively, about physical and
thermodynamic properties of hydrocarbons. Other publications [5] detailing physical
properties are also available. Companies do provide physical properties and safe han-
dling procedures [6]. Most of this information is available to potential customers only.
With the advent of internet, physical and chemical property data can be accessed
from these sources [7–10]. Sometimes data needed for specific needs has to be gener-
ated by the user in the laboratory.
Most companies provide material safety data sheets (MSDS) that meet the regu-
latory requirements but do not have detailed properties which are needed and used
for meaningful and safe process design. If additional information is needed, it
might be available if one is a customer. Figure 3.1 shows parts of a typical safety
data sheet (SDS) [11]. Each supplier has to provide SDS.
There are companies that will provide excellent physical property, safety, and
handling data, for example, data for sodium hydroxide [6].
They can also be generated mathematically as has been illustrated in different jour-
nals of American Chemical Society [12–14] and Chemical Engineering Thermodynamics
book [15].
The need for all of physical and chemical properties might seem redundant or un-
necessary at the initial stages of chemistry development and process considerations.
However, as explained later and in different chapters, such information is necessary
for the process development and design and lets the process designers be creative and
imaginative in product development. It also lets the process engineers, operating per-
sonnel, and raw material buyers have total understanding and command of the pro-
cesses. This can be beneficial in troubleshooting process that needs attention. If data
such as solubility and viscosity are not available, it has to be internally generated.
3.1 Molecular weight
Molecular weight is not included in the property table as it is expected that each de-
veloper (chemist/chemical engineer) has to know the molecular formula and the mo-
lecular weight of each chemical that is used and/or produced in every reaction or the
blending process. They tell us everything about each chemical that will be produced
on our route to the final desired product and how they will be handled. Chemical
formula is a fingerprint of each chemical. They have their distinct numerical number,
and CAS number [16] can be used to know almost everything about the chemical.
Molecular weights are also used to mass balance the chemical reaction equations.
These in turn are used to calculate each reaction step yield. Reaction parameters
70 Chapter 3 Physical and chemical properties
Fig. 3.1: Parts of a typical MSDS.
3.1 Molecular weight 71
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can be optimized to improve the proc ess yield. Better yield means lower cost and
higher profits.
3.2 Physical state
Each chemical at room temperature has either of the three natural physical forms.
Each form has its value and they are reviewed:
Fig. 3.1 (continued)
72 Chapter 3 Physical and chemical properties
1. Liquid
2. Solid
3. Gas
If we understand and capitalize on mutual behavior of chemicals, we will have an
improved design. Learning and understanding physical and chemical properties of
chemicals that are used and produced (intermediates and final) in the process influ-
ence process unit processes and unit operations [17–20].
3.3 Liquid
Of the three forms, liquids are process developer’s best friend. Chemicals that flow
facilitate processing. Liquids also assist in the creation of other dispensable forms
such as tablets, ointments, drops, and injections. Flow of liquids can be precisely
controlled, a must for creating an excellent economic process. If need be, they can be
solidified and gasified. However, this transformation is rarely needed. Reaction inter-
mediates or final product creates processing opportunities. Generally, intermediates
will not be purified. However, the final liquid product will be purified using single or
combination of different unit operations [18]. Each has to be dealt accordingly.
3.4 Solid
Chemicals that are solid at room temperature can be handled in their natural state
but compared to liquids, they present handling challenges. Solids are easier to han-
dle in solutions. Solubility of the solid in different solvents at different temperatures
is extremely useful information. Most of the time, solubility information is not avail-
able. It would have to be generated in the laboratory. Solids can be charged to the
reactors and would necessitate proper solid handling measures. These depend on the
process. Economics and solid toxicity dictate the method of handling and respective
investment. Other alternate to handle solid is the molten form, but as discussed later,
melting point, product demand, supply, logistics, equipment design, and economics
are major considerations for this route.
Solids that are formed during the reaction could be filtered, if they are a prod-
uct and purified. If further processing to a product is needed, proper unit operations
and processes have to be used to convert to the desired product. Physical properties
such as melting point and solubility come into play. Since most of the reactions are
at elevated temperatures and solvents are present, viscosity of the mixture seldom
interferes the reaction progress.
3.4 Solid 73
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3.5 Gas
Gases are best handled in their compressed liquid form. They ca n be handled as
solution but, discussed later, they have their own challenges.
3.6 Material handling
Melting, boiling, and freezing points determine the physical state of each chemical.
At room temperature, each chemical comes in either of the three states: solid, liq-
uid, or gas. This sets how each material will be handled for batch and continuous
processes. Irrespective of the state of the chemical and quantity used, it is abso-
lutely necessary that each chemical, intermediate and by-product be handled with
respect. Toxicity of many chemicals is documented [21–24].
It is still possible that long-term toxicity impact of many chemicals or their mix-
tures on aquatic, human, and bird life may not be known for an extended time. Toxic-
ity of chemicals can have significant ecotoxicological and environmental impact [25,
26]. It is necessary that an effort to improve the process yields be part of the continuous
process improvement regimen.Inaddition,adequatecarebetakentoproperlydesign
and care for waste disposal and treatment. It is most important that the products and
by-products of API, solvents, and their formulated mixtures be respected [27].
The method of handling materials in small quantities in the laboratory is signifi-
cantly different from the ways for larger quantities for a batch or a continuous pro-
cess. Raw materials that are liquid at room temperature can be pumped and metered
precisely in scale-up and for a commercial process. They are the easiest to handle.
Raw materials that are solid at room temperature in the laboratory are handled
in the laboratory hood or a similar enclosure following the suggested safety guide-
lines. They can be slurried or dissolved in a liquid and added to the reaction vessel.
Since solids in the laboratory are dissolved or directly added to the reactor, develop-
ers generally do not consider how they would be added to the reactors on a commer-
cial scale. Their addition methods change for scale-up experiments to commercial
operations. Scale-up methods, if commercial operation emulates, can be extremely
beneficial as they can be used as a proving ground.
Figure 3.2 reviews considerations for handling gas, liquid, and solid raw materi-
als on a commercial scale. Each raw material state besides presentin g chall enges
also have value if handled properly.
74 Chapter 3 Physical and chemical properties
3.6.1 Gas as a raw material
In every commercial reaction, if a gas is used as a raw material, it will be generally
fed as a liquid. Its flow rate can be precisely controlled and managed. Gas, fed as
aliquid,isalsoanassetasitabsorbstheheatofreaction/exothermthatisgener-
ated during reaction and essentially speeds the reaction rate. Reduced reaction
time can reduce the size of the equipment, that is, capital investment. In labora-
tory, ammonia can be use d as ammonium hydroxide but on a commercial scale, it
is best used as 100% liquid. Reaction productivity loss is significant if it is used as
Fig. 3.2: Gas, liquid, and solid raw material handling options.
3.6 Material handling 75
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