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Design Project For Chemical

Engineers
Paracetamol (Acetaminophen)


By-

Abhijit Das (11BCH0047)
Krishna Agrawal (11BCH0033)
Utsav Saxena (11BCH0012)



Introduction
Paracetamol or acetaminophen or APAP, is a widely
used antipyretic and analgesic agent with weak anti-
inflammatory effects.
IUPAC name -> N-acetyl-p-aminophenol
It has been around as a drug for more than thirty years.
Paracetamol, being a safe and low priced analgesic, is a quite
popular world-wide.
Medical opinion favours Paracetamol, over the established
drug Aspirin, due to its lower side effects.
Paracetamol is the active metabolite of phenacetin which is an
analgesic.
Unlike phenacetin and its combinations, paracetamol is not
considered carcinogenic at therapeutic doses.
Structure:




3-D structure:


Physical Properties
Molecular formula- C
8
H
9
NO
2
Relative Molecular Mass- 151.17
Description- White crystalline powder
Melting point- 170
o
C
Density- 1.293 g/cm
3
at 21
o
C

Solubility-Insoluble in water (17.39 g/kg of water)
Soluble in ethanol ( 232.75 g/kg of ethanol)
Maximum solubility in diethylamine- 1316.9g/kg solvent

Octanol/water partition coefficient (P)- log P, 0.31

Conversion factor- mol/L = 6.62 x g/ml
Diffusivity coefficient (D
AB
)- 11.43x10
-6
m
2
/s

Specific Heat Capacity-C
p
=17.645+0.5226T (for temp up to
70
o
C)

Polymorphism- Acetaminophen exists in two meta stable
forms; Orthorhombic and Monoclinic.
Orthorhombic is suitable for direct compression tableting and
also be slightly more soluble.
Monoclinic is the commercially available crystalline form and
is thermodynamically more stable.

Not known to occur naturally.

Chemical Properties
pKa- The pKa of acetaminophen is 9.51 at 25C.
Stability- Acetaminophen is stable to temperature, light, and
moisture.
pH range- Acetaminophen oral solution (ie, elixir, adult
liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie,
infants' drops, children's suspension) has a pH of 5.4 to 6.9.
Oxidizing nature-
Acetaminophen reacts with CH
2
CH
3
I to give
Phenacetin-




Reaction with Nitrous Acid-

Sulfation And Glucuronidation of
Acetaphinomen
Applications
It has analgesic properties comparable to those of aspirin,
while its anti-inflammatory effects are weaker
Fever- Paracetamol is approved for reducing fever in people
of all ages.
Pain- Paracetamol is used for the relief of pains associated
with many parts of the body such as :-.
o Headaches
o Toothaches
o Backaches
o Osteoarthritis



Market Demand and Sales


Global Status
There was a 28% growth in acetaminophen market between
year 2004 and 2008.

Over 370 million bottles and packets, or 24.6 billion doses
were sold in year 2008.

Nearly 80% of entire market is OTC products (nearly $1.15 in
sales).

Proportion of prescripted acetaminophen market steady at
nearly 20% of overall market(nearly $1.4 billion in sales).
Production
165
170
175
180
185
190
195
200
205
210
215
2008 2009 2010
Total production of paracetamol in india
(thousands)
(packets)
(Years)
Indian Status
Indian analgesic and anti-pyretic market is a huge one, growing
at 9.5%.

Acetaminophen comes under the category of OTC drugs.

Indias Acetaminophen sale has grown around 10%in the last
two years, leaving the U.S. and China, much behind, where the
drug sale is estimated at 4% to 5% respectively.

The share of sales of OTC traditional drugs in India has gone
up to 30%.

This market actually harbours 62 nationally distributed
analgesics and over hundred local brands.

Manufacturing Processes

Phenol Route
P-nitro chloro benzene route (PNCB Route)
Nitrophenol route
Para Hydroxyacetophenone Hydrazine Route

All the routes primarily lead to the manufacture of Para
Aminophenol (PAP) of which Acetaminophen (APAP) i.e.
Paracetamol is a derivative.
Why PNCB Route?
Manpower required is less than that of the Phenol route.
It has minimum economic plant size of 20-25TPM as compared
to other routes.
It has minimum level of investment for MES Plans of Rs.1 crore.
It has an easy acquisition of technology.
Unit cost of production is less than that of the Phenol route.
Other Advantages-
Ease of operation
Lower investment
Less operational skills required


PNCB Route
Currently, almost 100% of paracetamol production in chemical
industries is followed by PNCB route. So, this route of
production can be considered as the most popular process
route.

The entire process is divided intro 4 steps :-
Neutralization of p-nitrochlorobenzene using NaOH
Nitration to give p-nitro phenol
Reduction of p-nitro phenol to p-amino phenol
Acetylation of p-amino phenol to acetaminophen

Since all the routes lead to the formation of p-amino phenol, the
acetylation step gains importance to get the paracetamol of desired
pharmaceutical standards.

Process Chemistry



Process Description
Chlorobenzene with hydrolysis is carried out by the reaction of 9%
caustic soda solution with p- nitrochlorobenzene.
The reaction mass is filtered and with suitable process control and
proper design of the reactor, the yields could be optimized,
resulting into lower requirement of inputs and generation of lower
quantities of effluent.
The sodium salt of p-nitrophenol is then treated with concentrated
sulphuric acid at 35-45C.
p-Nitrophenol is filtered.
p-Nitrophenol is reduced with iron at 90-100C temperature in
wooden vat. The reaction temperature is raised by direct injection
of steam.
On completion of reduction, water is added to the reaction mass,
iron sludge is removed by filtration and the filtrate is cooled to
15C p-Aminophenol is filtered and the filtrate is collected.




The reaction takes place in an autoclave or suitable hydrogenating
equipment.

This filtrate, containing p-aminophenol could be re-used in the
reduction step 4-5 times before being discharged as effluent.The
iron sludge could be used for making iron oxide for red oxide
primers.

Pure p-aminophenol is reported to be prepared by adding more p-
nitrophenol to the reaction mixture (if the reaction has gone to
completion), adjusting the pH between 5.0 and 6.5 and separating
the p-nitrophenol phase and the p-aminophenol could be purified
by giving treatment with carbon in aqueous hydrochloric acid
solution and it could be stabilized by the addition of sodium
sulphite.

The acetylation of p-aminophenol to crude paracetamol is carried
out by the addition of acetic anhydride.


The temperature could increase to around 80C. After cooling,
crude paracetamol is filtered. The crude paracetamol is given
charcoal treatment and pure paracetamol is recrystallized in
water. The wet cake of paracetamol is centrifuged, dried
and packed.
A Second Stream arises from the centrifuge.

The filtrate, after filtration of crude paracetamol, is dilute
acetic acid solution containing unreacted p-aminophenol and
paracetamol. Secondary acetylation may ensure that the
conversion of p-aminophenol is complete. With solvent
extraction, paracetamol could be recovered and dilute acetic
acid could find some uses.

The filtrate obtained after filtration of pure paracetamol could
be re-used in the purification step 3-4 times before being
discharged as effluent.

Paracetamol could be recovered from this effluent by lowering its
temperature or by solvent extraction or by salting out. This would
improve the yields.

The precipitated paracetamol is separated by filtration through a
centrifuge

The slurry, still having some paracetamol , is then transferred to a
liquid-liquid extractor where 99% of the acetic acid and over 90 %
of the paracetamol is removed in the extract using a suitable solvent
like hexane or ethyl acetate

A vertical packed bed or centrifugal extractor maybe used for the
counter current extraction

The extract is subjected to distillation for recovery of the solvent
and acetic acid, leaving a residue containing paracetamol



The overhead stream in the distillation column is divided into two
parts- one for acetic acid and the other for the solvent

The residue consists primarily of paracetamol and may be sent to a
second crystallisation unit or recycled back to the primary
crystallisation unit

Where a second crop of crystals is desired, the bottom fraction is
mixed with water to depress paracetamol solubility and then
cooled to ambient temperature or somewhat below in order to
crystallize it

If the paracetamol color does not pertain to the standards of
pharmaceutical industry, adsorption by carbon particles may be
done in the step before crystallisation to make it completely white
Process Flow Sheet