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Table of Contents

 Reagents used
 Reagent purpose
 Stages of manufacturing Paracetamol
 Acetylation
 Reactions
 Reaction mechanism
 Pneumatic Conveying System
 Purification
 Agitated Nutsch Filter
 Drying and Pulverizing
 Spin Flash Dryer
 Blending
 Packaging
 Paracetamol Effluent Treatment Process
 Flow chart of Paracetamol process
 Quality Control/Assurance
 Weight Variation Test
 Friability test
 Disintegration test
 Dissolution test
 Drug Assay
Manufacturing of Paracetamol

Reagents used:

 Para Amino Phenol

 p-Aminophenol is a building block compound. Prominently, it is the final
intermediate in the industrial synthesis of paracetamol. Treating p-
aminophenol with acetic anhydride gives paracetamol
 Acetic Anhydride
 is most widely used as an agent for acetylation, the addition of an acetyl group
to a compound, such as its reaction with ethanol to form ethyl acetate. Being a
carboxylic acid anhydride, acetic anhydride will slowly decay in contact with
water into acetic acid.
 Activated Carbon
 is used to treat poisoning and overdose.
 Soda Ash
 Neutralized the acidic water.







06 E.T.P.
1. In the Reactor, ML (Mother Liquor)/ Water of required quantity is taken from Storage Tank,
2. Para amino Phenol powder is charged into the Reactor indirectly through Pneumatic
conveying system from Dispensing Room in R.M Approved Store.
3. Then heating is applied to heat the mass up to 40 °C.
4. Acetic Anhydride is taken in Receiver from Storage Tank.
5. Acetic Anhydride charging is started at slow rate by monitoring temperature.
6. Apply Steam to the Jacket, the reaction will take place
7. After the reaction stop Steam heating and apply Cooling from Cooling Unit.
8. The total mass is allowed to cool up to 40 °C.
9. After cooling the Product, stop Cooling and apply Chilling from Chilling Unit till 15 °C.
10. Paracetamol will get crystallize. The by-product Acetic Acid is formed.

Reaction Mechanism:
A Pneumatic conveying system transfers
powders, granules, and other dry bulk
materials through an enclosed horizontal or
vertical conveying line.

How it works?
The air pressure in the conveying line is
changed by the system’s air mover, which
generates pressure or vacuum. Where the air
mover is located in the system determines whether it generates one or the other. When located
the system’s start, the air mover pushes air through the system and the system operates under
pressure. When located at the systems end, the air mover pulls air through the system and the
system runs under vacuum. By controlling the pressure or vacuum and airflow inside the system,
the system can successfully transfer materials.

1. The slurry is transferred to ANF by applying Air Pressure.
2. The slurry is filtered in ANF (Agitated Nutsch Filter) by applying Air Pressure.
3. The Liquid – ML (Dil. Acetic Acid) is transferred to Storage Tank in Distillation Plant for
4. After filtration the cake is washed with D.M Water.

5. Wash ML is collected separately in Storage Tank-20 KL in Distillation Plant. After Washing

the cake is transferred into another Reactor for Purification.

1. In the Reactor, ML (Mother Liquor)/ Water of required quantity is taken from Storage Tank,
2. Technical Grade Para is charged from ANF into the Reactor directly through hopper.
3. Activated Carbon is charged into the reactor directly from the Carbon Room in slurry form
through pipeline.
4. Apply Steam to heat the mass slowly till it dissolves completely.
5. Maintain the temperature the temperature for 30 min.

1. Filter the mass to Crystallizer through on-line Filter. Filtration is done by applying Air
1. In Crystallizer, the Reaction mass is allowed to cool slowly up to 40 °C.
2. After cooling the Product, stop Cooling.
3. Paracetamol will get crystallize out in Pure form.

1. The slurry is transferred to ANF by applying Air Pressure.
2. The slurry is filtered in ANF (Agitated Nutsch Filter) by applying Air Pressure.

3. The Liquid – ML is transferred to Storage Tank for Recycle.

4. After filtration the cake is washed with DM Water.
5. Wash Water is collected separately in Storage Tank- for recycle.
6. After Washing the cake is transferred into hopper for Drying and Pulverizing in Spin Flash

Agitated Nutsche filter (ANF)

 is a filtration technique used in applications such
as dye, paint, and pharmaceutical production and waste water


1. Filling/Charging

The first step involves the transferring of the product to be filtered,

usually an aqueous or solvent based solid/liquid slurry, from the
primary location (e.g. reactor) to the filter/dryer. The filter should
be sized appropriately to handle the solids volume that is being
charged. A general rule of thumb to follow is that the maximum solids height should be equal or
less than the agitator stroke, typically 12 - 20 inches.
2. Filtering
The second step involves the use of pressure and/or vacuum to force liquid through the solid bed
and filter media. The process is stopped when solids are visible, or can be continued until all the
liquid is pushed out. There are various types of filter media available in nutsche filters – cloth,
single layer metal screen, or multi-layer sintered metal. The media should be determined based
on the characteristics of the slurry including particle size and shape, cake porosity, and
compressibility (which are all factors that, when taken into account with the filter media
selected, will determine filtration rate).
3. Displacement Washing
Here, fresh wash liquid is sprayed on top of the solid cake taking care not to disturb the surface
of the cake. The liquid is forced through with pressure or vacuum. Displacement washing
serves several purposes – it removes the liquid and its impurities while keeping the cake intact
and it replaces the previous liquid with fresh liquid. There is also the opportunity prior to this
step to try and close cracks if the cake has any via smoothing.
4. Reslurry Washing
As an additional washing option, a re-slurry washing can be performedif additional extraction
or dissolving of impurities is necessary. This is executed by the addition of fresh wash liquid
that is mixed with the solids. The agitator is stopped and raised before filtering the wash
liquid. The re-slurry process is also used when a long contact time is needed between the wash
fluid and the solids or the displacement wash does not provide the required wash quality.
5. Smoothing
This next step may be used after any filtration or wash, especially after the final wash, when gas
is blown through the cake. The agitator is used to close cracks and compress the cake to reduce
residual moisture level. This function will help to achieve uniform flow of liquid or gas through
the filter cake, while helping to eliminate liquid and gas channelling that reduces the efficiency
of displacement washing and gas blow through.
6. Drying/Cooling
In most filter types, the solid must be evacuated into a second dryer to complete the drying and
subsequent cooling process. In nutsche filter/dryers, the two functions are combined and drying
can take place in the same vessel. To accomplish this, the vessel surfaces (including the wall,
base, and agitator) are heated. There are two types of drying that can be conducted – vacuum
drying and convection drying. The method used depends on the product behavior. Vacuum
drying, the most common method, involves a vacuum source, agitation, and dust filter. This type
of drying utilizes vacuum to reduce the temperature at which the solvent evaporates, reducing the
average drying temperature. During convection drying, hot, pressurized gas (usually nitrogen) is
blown down through solids and out of filtrate lines (and even recirculated as necessary); this will
eventually dry the solids. Convection drying is unique to filter/dryers due to their porous filter
plate. Unlike vacuum drying, it does not require agitation. Whether vacuum or blow-through
drying is selected, a filter/dryer can allow you to get completely dry material out from your
process, with less than 0.1% final product moisture. At this point the vessel and product may
need to be cooled to an ambient temperature prior to discharge.
7. Discharging
This final step is accomplished through the valve/port located on the vessel sidewall. The
agitator is slowly lowered as it rotates, effectively moving product to the side discharge
valve. There are certain applications where the desired product to be discharged is not a dry
solid. Nutsche filter/dryers are designed to facilitate flexible discharge, which allows for wet
solids, slurries, or even liquid to be discharged.
SFD – SPIN FLASH DRIER – 150 Kgs/hr.
1. Drying & Pulverizing is done in SFD (Spin Flash Drier)
2. In this Process the Pure Paracetamol Crystals (Wet crystals) are fed into the hopper directly
from ANF.
3. Heating source is Steam. Steam is applied at the inlet Point of Steam Heater in SFD.
4. Air Supply is given at the inlet Point of SFD for Bag Filter.
5. The Wet crystals are dried and pulverized simultaneously into dry Powder.
6. The powder is collected in Blender directly for blending.


• A spin flash dryer produces powder from feed, which is viscous or gelatinous in nature,
paste or filter cake. The two step process involves disintegration of the feed and drying of
the disintegrated feed.

• A product clarifier ensures desired size and the dried particles only leave the drying

The product is fed to the feed Agitator which is connected to a variable speed screw
conveyor and conveyed to the Spin flash chamber in a rated capacity. The air is heated by
passing over indirect fired hot air generator. The material come to the spin flash chamber
get disintegrated between the rotating spins and simultaneously dried within the hot air
media. Dried product is collected from the bottom of bag filter. A separate control panel
mounted with instruments is also provided. The process is displayed by MIMIC diagram
on control panel.

The material of construction of equipment depends on the product to be dried. The

advantage of the system is that it can be operated at high temperature for non-sensitive
1. The dried powder is collected in Blender from SFD.
2. The collected Powder is Blend and sample is collected and Tested in Quality control Dept. as
per specification.
3. After QC approval, the batch is taken for packing.
1. After blending, the Final Batch Quantity Is Packed in Bags in Primary
Packing Section.
2. Composite sample is collected from each bag and sent to QC for analysis.

1. The ML from Storage Tank is transferred to a Reactor for distillation.
2. In this Reactor, steam is injected into the Jacket as heating source to heat the ML to 120 °C
3. At this temperature Acetic acid along with water evaporates and Condensed in the Condenser
attached to this Reactor.
4. Acetic Acid Distilled is in dilute form (30 to 35%), which is collected in Storage Tanks for
5. The distilled, which contains Paracetamol is transferred to another reactor for cooling in
6. The cooled mass is filtered in Filter.
7. The solid product is sent for purification in Recovery Plant.
8. The liquid influent is stored in storage tank for Treatment.

1. In the Reactor, ML (Mother Liquor) of required quantity is taken from Storage Tank, Crude
Para is charged into the Reactor.
2. Activated Carbon is charged into the reactor directly from the Carbon Room in slurry form
through pipeline.
3. Apply Steam to heat the mass slowly till it dissolves completely.
4. Maintain the temperature the temperature for 30 min.
5. Filter the mass to Crystallizer through on-line Filter. Filtration is done by applying Air
6. In Crystallizer, the Reaction mass is allowed to cool slowly up to 40 °C.

7. After cooling the Product.

8. Paracetamol will get crystallize out.

1. The slurry is transferred to ANF by applying Air Pressure.
2. The slurry is filtered in ANF (Agitated Nutsch Filter) by applying Air Pressure.
3. The Liquid – ML is transferred to Storage Tank for Recycle.
4. After filtration the cake is collected sent to STAGE-2 for purification.

1. The Liquid influent is taken in an evaporator. If it is acidic, then it is neutralized with Soda
2. The neutral water is evaporated by forced evaporation to atmosphere.
3. The residue if any is collected in bags and disposed to Common Hazardous Waste Transportation
Storage and Disposal Facility (CHWTSDF).


Friability is the tested for a tablet to see whether the tablet is stable to abrasion or not, it is tested
by using Roche Friabilator and 1% maximum loss in the weight after friability test is allowed.
Weight variation test is performed to check that the manufactured tablets have a uniform
weight. As per USP following limit for the tablets (Table 1)


Average weight ( mg) Maximum percentage difference allowed

130 or less ±10

130-324 ±7.5

More than 324 ±5

Weight variation test: The purpose of this test is to verify the uniformity of each batch which
ultimately reflect the drug content uniformity in all the formulation batches. The test was
performed as per the official procedure, 20 tablets were randomly selected and weighed
individually and also average was calculated. The difference between average and individual was
calculated, further % weight variation was calculated and compare with the USP limits.

Friability test: This test is usually performed to check possible wear and tear loss in the tablet
during the transportation and this is closely related to tablet hardness. It is usually performed in
the Roche Friabilator. Randomly 10 tablets were selected and their initial weight ( W1) was
recorded and after that these weighed 10 tablets were placed in the friabilator and the friabilator
was operated for four minutes at 25 rpm speed and 100 revolutions, the tablets were weighed
again (W2) and the percent loss (Friability) was then calculated by using following formula
% Friability = (W1- W2)/W1 *100
The official permissible limit for friability is 1%.

Roche Friability
2. Connect power cord to an appropriate electrical outlet
3. Unscrew locking nut to release drum
4. Brush any loose dust from tablets
5. Accurately weigh tablets
6. Load tablets into drum
7. Place plastic cover over drum
8. Hold cover firmly in place and
9. slide drum onto the shaft
10. Place locking nut onto the end of the shaft
11. Tighten locking nut into position
12. Turn timer to the desired
13. number of rotations
14. Wait until drum returns to stationary position
15. Remove locking nut
16. Carefully remove drum from shaft
17. Remove tablets and brush away any loose powder
18. Any cracked, cleaved or broken tablets
19. Tablets sample has failed the friability test
20. Reweigh tablets
21. Calculate the percentage weight loss using the following formula:
% Weight Loss = (Initial weight – Final
weight) /

When a weighing scale is connected to EF-1W the weight of the sample before and after the test
can be recorded through the RS-232 interface. The weight should be manually fed in when the
weighing scale is not connected.
During the test, the actual RPM and the elapsed time or revolution count are displayed on the LCD

On completion of the friability test, the drum reverses automatically and discharges all its contents
into the tray. The friability is then calculated and displayed as percentage weight loss.

A test report can be printed at the end of the test which includes the friability in terms of percentage
weight loss, the test parameters, information about speed and accuracy during the test run and
actual time and date on which the test was performed. It also includes entry fields for user name
and product details.

The unit has got a unique power failure detection facility. If the power fails during the test run, the
remaining test can be completed when the power supply is resumed.

Disintegration test: Disintegration is the process of breaking the tablet in to the small granules
and it is prior step of drug dissolution so it is the part of In-vitro- In vivo correlation so the
disintegration test determine the time required to breaking the tablet and pass all the particle
from mesh size 10. USP disintegration apparatus (Electolab ED-2L) containing six glass tubes
was used for the purpose. The disintegration test was performed as USP and to determine the
disintegration time, one tablet of Paracetamol was placed in each tube and the basket rack is
positioned in a 1L beaker containing distilled at 37±2°C temperature. The instrument was
operated with a motor driven device with 28-32 cycle/min frequency. When all the particles from
all the six tubes passed from the tube mesh to the outer beaker that time was noted as
disintegration time after that the average time was noted and this process was repeated for all
four different brands of Paracetamol tablets. For the uncoated tablet the disintegration time limit
is 15 minutes.
 Electolab ED-2L

 Complies with USP, IP, Ph. Eur. specifications

 Snap-ClickTM loading and a swivel free basket movement
 Programmable Timer with alarm and temperature controller
 External probe for beaker temperature validation
 Illuminated bath for better visibility


No. of stroke 30 +1 stroke/minute

Stroke height 55 mm +2 mm
Motor DC stepper motor of 6V DC and 3.5 kg cm torque
No. of baskets 2 nos. (Each having 6 test tubes)
Water bath 6 mm thick transparent acrylic
Heater 400 watts, S.S. 304
Temperature range 20o C to 39.9o C
Temperature resolution 0.1o C
Temperature control accuracy +0.5o C
Timer Range 1- 1 sec. to 99 min. & 59 sec.
Range 2- 1 min. to 9 hrs & 59 min.
Timer resolution Range 1- 1 sec.
Range 2- 1 min
Power supply 220/230 VAC, 50/60 Hz, 500 VA
Dimensions (L x W x H) (350 x 390 x 510) mm (approx.)
Weight Net 23 kgs and Gross 28 kgs

Dissolution test: Dissolution test is close proximate to the bioavailability this is the reason it is
required to perform to confirm drug release pattern of the dosage form as well as efficacy of
dosage form. This test is the part of In-vitro-In-vivo correlation so all the parameters of this test
was set as per the In-vivo condition of human body. The dissolution test was performed by using
Dissolution Tester-USP (Electrolab EDT- 08Lx) of type 2. To determine drug release 900 ml of
phosphate buffer, pH 5.4 was used as dissolution medium. The 5, 10, 15, 30, 45, 60 minutes
were set as a sampling time. The dissolution medium was heated up to 37±0.5°C by an auto
heater. One tablet was put into all six baskets and stirred immediately at 50 revolutions per
minute (rpm). After specified time intervals the 5 ml solution was withdrawn, diluted it with
fresh solvent and the amount of dissolved Paracetamol was determined from UV-Visible
Spectrophotomter (Agilant 8453)by taking absorbance at the wavelength of maximum
absorbance at about 243 nm in comparison with a standard Paracetamol solution in the same
medium ( Phosphate buffer pH 5.8). By measuring the absorbance, the percentage (%) of drug
release was calculated.
Electrolab 8 Station Dissolution Tester (Model: EDT-
08Lx) (Body made of M.S. galvanized & powder
coated) Features: • New Larger LCD display of 40
characters and 4 lines for user friendly operation. • LAN
connectivity allows central printing, storing and sharing of
data. • Multilevel security with password. • Alphanumeric
data entry of product and user details. • Online OQ menu
• Unique Time Action™ function which allows media
changeover and infinity test run, ideal for sustained and
controlled release products. • Complies with USP, IP, Ph.
Eur. and JP specifications • Automatic stirrer height
positioning for USP 1, 2, 5, 6, intrinsic test methods and
also allows user specified height • Easy Snap-FitTM shaft
locking mechanism for positive engagement and wobble free operation • Clear water bath with
composite top-plate • Precise individual vessel centering system • Adjustable leveling of instrument •
Vibration free smooth motorized lift movement • Isolated water circulating pump for precise
temperature control of the water bath • 20 programmable protocols • 24 programmable sampling
intervals • Easy to empty and clean water bath with bottom drainage • Instrument accessories like
paddles, baskets, vessels etc. are • laser marked with serial numbers • Designed to minimize routine
validation • Report for online validation of test, monograph, error log • during the test and physical
validation • Programmable wake-up for temperature control • Programmable sample volume from 1
ml to 99 ml • Audio-visual indicators for system status • Power failure detection facility Specifications:
• Speed range: Variable speed from 20 to 250 RPM • Speed accuracy: +0.5 RPM • Temperature
range: 20o C to 40o C • Temperature accuracy: +0.1o C • Display: 40 x 4 character backlighted LCD
• No. of protocol: 20 maximum • Sample interval: Maximum 12 of 1 min to 999 hrs, 59 min • Printer
interface: RS 232 Connectivity • Printer supported: 80 column Dot Matrix printer • Bath: Clear acrylic
moulded water bath • Bath size (L x W x H): (705 x 374 x 200) mm • Heater: 1 kW/230 VAC, material
S.S. 304 with sensor • Pump supply: 230 VAC, 50 Hz • Pump type: Magnetic coupling • Pump flow
rate: 10 liters/minute maximum • Power supply: 220/ 230 VAC, 50/60 Hz, 1.3 kW/6 Amp • •
Dimensions (L x W x H): (705 x 505 x 645) mm • 1 B Standard accessories supplied in Electrolab 8
Station Standard accessories supplied in Electrolab 8 Station Dissolution Tester (Model: EDT-08Lx)
• Laser marked Basket with rod (USP I) QTY 8 • Laser marked Paddle (USP II) QTY 8 • Laser
marked glass Vessels with lids. QTY 8 • Water circulating Pump QTY 1 • Moulded Perspex water
bath QTY 1 • External temperature probe QTY 1.

 UV-Visible Spectrophotomter (Agilant 8453)

This Agilent 8453 UV-Vis Spectrophotometer ( Spectroscopy System ) with G1120A Multicell
transport and Computer with ChemStation ( Ultra Violet Visible G 1120 A ) is in excellent
condition. The Agilent 8453 spectrophotometer is a single-beam, microprocessor-controlled, UV-
visible spectrophotometer with collimating optics. With its diode-array technology, the
spectrophotometer is much faster than comparable conventional instruments—with more precision,
more sensitivity and more reproducible results. Accessories include special cell holders, peristaltic
pumps, autosampler, a multicell transport, a Peltier temperature control accessory, and valve unit
and valve-pump controller. The spectrophotometer can be either controlled from HP and non-HP
personal computers equipped with Agilent ChemStation software for UV-Visible spectroscopy
(personal computers used should be certified by UL1950), or from the dedicated handheld controller
that comes with the Agilent 8453E UV-Vis spectroscopy system.

 Easy to use - direct access to the cell holder and cells, built-in buttons at the front for triggering

 Stable optics - excellent wavelength reproducibility due to the ceramic spectrograph manufactured under
license from Carl Zeiss and high photometric accuracy due to the low noise electronics.
 Flexible accessories - Built-in interfaces for interconnectivity with accessories. Agilent's multicell transport,
Peltier thermostatted cell holder, sipper system, or autosampler. Gilson autosamplers, Labsphere diffuse
reflectance accessories, or fiber optics couplers from Custom Sensors & Technology.
 GLP built-in - Serial and firmware revision number held in firmware. Extensive self-test procedures for lamp
intensity, wavelength accuracy and noise to ensure consistent performance. Built-in log book carries the
results of self-tests, notes on instrument maintenance and lamp timers.
 Easy to exchange pre-aligned deuterium and tungsten lamp light sources.
 Firmware upgrades supported via built-in communication interfaces.

Drug Assay:
This is required to confirm that the labelled amount of drug is available in the given dosage form.
To perform this test twenty Paracetamol tablets were selected randomly and crushed them in the
mortar and powder was made. The equivalent powder containing about 0.15 g drug was taken in
the beaker and dissolved in 100 mL of water. The mixture was made uniform by the help of
Maxi Mix-II instrument. About 0.1 mL solution was taken, diluted it up to 10 mL and
absorbance at the wavelength of maximum absorbance at about 243 nm by measured by the help
of UV-Visible spectrophotometer. The available amount was calculated by using the standard
calibration curve.

Maxi Mix-II instrument

This Thermo Scientific® ELED Maximix II vortex mixer requires

120V, 0.30A. Excellent for mixing media in test tubes, mixing
cytogenetic suspensions in centrifuge tubes, vortexing cell suspensions
and vortexing drug extractions. Ideal for enzymatic and RIA assay
applications, atomic absorption sample preparation and Nelson's assay
for reducing sugars. Continuous-run or touch-activated run modes.
Simultaneously mixes contents of up to four test tubes or small flasks
with closed tops. White, durable plastic housing resists acids and
alkalines. Heavy-duty cast metal base with rubber feet assures stability
and eliminates creep during use. With two mixing devices, a rubber
single-cup tube holder and foam pad for mixing flasks or multiple
tubes simultaneously. Shipping Weight: 8lbs. Speed Range: 100 to
3000rpm. Platform, Foam Pad/Cup: Pad: 3.5in, Cup: 1-Inch. Exterior Dimensions (L x W x H): 7
x 4.5 x 6-Inch. Voltage Rating: 120V. Frequency: 50Hz. Current Rating: 0.30A.
Power Switch:
The power switch is a combination ON/OFF and mode switch to enable TOUCH operation.
Move the power switch to either the “FULL” position or the “TOUCH” position. In the “FULL”
position, the mixing head will begin oscillating automatically. In the “TOUCH” position, the
mixing head will oscillate when it is depressed.
Speed Control:
The speed control is a nonlinear type control. The oscillating speed will increase at a non-
uniform rate as the control is turned clockwise.
To operate Maxi-Mix, move power switch to either the “FULL” position or the “TOUCH”
position. Turn speed control to the desired setting. Touching the vessel to the disc will initiate the
vortex action. Mixing action will intensify as greater pressure is exerted against the mixing
surface. To stop the mixing action, remove vessel from disc or move the power switch to the
“OFF” position. (See Maintenance and Servicing for installation of the single cup mixing head
and the mixing surface disc