Mini-Project Pracetemol

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Aim
The aim of this project is to synthesize paracetemol from 4-aminphenol and acetic anhydride.
Objective
The objective of this project is to synthesize paracetemol from 4-aminphenol and acetic
anhydride by testing it under the following headings; Ultra- Violet Absorption, Infrared
Absorption, High Performance Liquid Chromatography, Graphite Furnace Atomic Absorption.
Flame Atomic Absorption, Colorimetric Identification and an Assay Test.
Introduction
Background of Paracetemol
Over 100 years ago the properties of Paracetemol were revealed by mistake when a related
molecule called acetanilide was supplemented to a person’s prescription. As a result of this
discovery chemists looked deeper into the effects of acetanilide and noticed that is was toxic in
small doses. They altered its structure and tried to develop a compound that was less detrimental
to a person’s health but at the same time still retained the analgesic properties that acetanilide
still possessed. One of these compounds is N-acetyl- para-aminophenol, which is known today as
paracetemol in the UK and acetaminophen in the United States.
Acetanilide Paracetemol Aniline
In the body itself acetanilide is to some extent changed into a mixture of paracetemol and
analine. As we already know the Paracetemol provides the painkilling effect but the analine
compound is toxic. The enzyme which recognises paracetemol also recognises aspirin due to
similarity in structure. Also this enzyme called cyclo-oxygenase (COX) which recognises both

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Paracetemol and aspirin is accountable for the biosynthesis of prostaglandins which is involved
in the dilation of blood vessels that cause pain experienced in a headache. The enzyme which
recognises paracetemol can reduce the amount of prostaglandin and as a result help prevent
headaches and any other pains.
Paracetemol popularity has grown worldwide due to its effectiveness firstly as a painkiller and
secondly due to its safeness and how easy it is on peoples stomachs. Paracetemol was originally
discovered due to its painkilling properties and fever reducing effects in the late nineteenth
century. Before paracetemol was discovered a tree which produced the cinchona bark which was
used to make the anti malaria drug quinine had been constantly used to treat fevers. Due to the
overuse of cinchona it became scarce so people began searching for other easier and cheaper
synthetic alternatives. Two such alternatives which were found were acetanilide and phenacetin
developed in 1886 and 1887 correspondingly. Harmon Northrop Morse had already synthesized
acetaminophen in 1878 through the reduction of p-nitrophenol with tin in glacial acetic acid.
The white, odourless, crystalline compound that we know today as paracetemol was properly
discovered in 1893. At the beginning patients who had been taking phenacetin, Paracetemol was
found in their urine. As time progressed, it was established in 1889 that paracetemol was a
urinary metabolite of acetanilide. Although new information about paracetemol was constantly
being discovered, it was for a long time ignored and was mostly unsuccessful in attracting any
concrete attention.
Fifthly years after Paracetemol was first discovered two people called Brodie and Axelrod in
1948 recognized that paracetemol was the chief metabolite in both acetanilide and phenacetin.
After this information was highlighted, it was not till then that paracetemol experienced a revival
in science circles. Paracetemol corresponds to the active principal metabolite phenacetin which is
a derivative of p-aminophenol. During this period it was understood that their rapid conversion
by the body into paracetemol was actually responsible for the therapeutic effects of both of these
medicines. After more and more study into phenacetin and paracetemol it was exposed that
phenacetin had its own pharmacological action and was not dependent on paracetemol for its
pain relieving effects. A high proportion of phenacetin is converted to paracetemol in the liver
because of this fact a large dosage of phenacetin is required to have any desired analgesic effect.
As time progressed Paracetemol became more developed and eventually in 1956 went on sale in
the United Kingdom in 500mg tablets. It was not long before its attractiveness as an over the
counter pain relieving drug grew. This reputation to some extent was due to the fact that
Parcaetemol was much gentler on the stomach than some other analgesics drugs which were on

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the market at the time and would eventually come onto the market (e.g. aspirin & ibuprofen).
Parcaetemol bit by bit was developed with both analgesics and oral decongestants.
A prostaglandin inhibitor such as Parcaetemol is quite weak. The mechanism by which this
occurs is attained by blocking the production of prostaglandins, which are chemicals involved in
the transmission of the pain message to the brain. Due to this Parcaetemol blocks the pain
message at the brain in contrast to other drugs such as aspirin and NSAIDs (non-steroidal anti-
inflammatory drugs) which block the pain message at the source of the brain.
As we have acknowledged Paracetemol has a similar structure as aspirin as they are both
recognized by the same enzyme cyclo-oxygenase (COX). Cyclo-oxygenase serves as a pain
activator, amplifying the degree of pain experienced in order to let the body know that there is a
problem. The biosynthesis of prostaglandins depends on the enzyme cyclo-oxygenase to work.
By decreasing the amount of prostaglandin obtainable for synthesis, Parcaetemol can act as an
analgesic and help relieve headache pain by reducing the dilation of the blood vessels that cause
the pain i.e. cyclo-oxygenase (pain activator). Paracetemol has little or no impact on peripheral
tissues in the body but it does have an effect on the central nervous system (CNS) as it inhibits
prostaglandin biosynthesis.
Paracetemol is used to relieve mild to moderate pain, including instances of tension headache,
migraine headache, muscular aches, neuralgia, backache, joint pain, rheumatic pain, general
pain, toothache, teething pain, and period pain. The numerous advantages for the use of
Paracetemol which have been highlighted above make it quite suitable for young and elderly
people alike as it contains very few side effects. The pain which comes with osteoarthritis, a type
of non-inflammatory arthritis due to the "wear and tear" of the joints can be relieved by taking
Paracetemol. The reason for this being that as we already know Paracetemol possesses analgesic
properties but also due to its lack of gastrointestinal side effects. In addition sufferers of arthritis
can take Paracetemol to relieve pain.
Paracetemol is an antipyretic. This means that it can reduce the fever of a person by targeting the
part of the brain known as the hypothalamus that regulates the temperature of the body. This is
why Paracetemol is incorporated into many patients’ cough, cold and flu prescriptions. Children
who have had vaccinations have also been given Paracetemol afterwards in order to prevent them
developing post-immunization pyrexia, or fever.
Patients who also suffer from asthma and peptic ulcers that can’t use NSAIDs use Paracetemol.
What we can see from the previous few paragraphs is the wide range of use Paracetemol has in
worldwide medicine. People who are sensitive to aspirin can take Paracetemol because of its

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limited interactions with other medicines. Cholestyramine, which lowers high cholesterol, may
reduce the rate at which paracetemol is absorbed by the gut, while Metoclopramide and
Domperidone, which are used to relieve the symptoms of stomach disorders, may have the
opposite effect and should be used with caution. Frequent use of Paracetemol by people has
shown no tendency to addictive although repeated use of Paracetemol may increase the chance to
stop blood from clotting (anticoagulation) of warfarin or similar anticoagulant medicines so
vigilance may be needed in these circumstances.
Within certain circles, some researchers believe that the day to day use of Paracetemol can
protect the arteries from hardening which if occurs can lead to strokes, heart attacks or
cardiovascular disease. The oxidation of some of the low density lipoproteins that bear ‘bad
cholesterol’ can be inhibited by the intake of Paracetemol counteracting the progression that
causes the formation of arterial plaque. There is also some evidence to suggest that paracetemol
may offer some protection against ovarian cancer. Although Paracetemol as I have learned can
reduce the risk of a cardiovascular disease and potentially protect against ovarian cancer is has
little or no influence in reducing the inflammation or the swelling of any skin or joint injuries.
This is because paracetemol has no clinically useful anti-inflammatory properties.
As more and more people use Paracetemol, some people believe that taking a large dose of
Paracetemol can damage the liver and because of this some people believe that taking a small
dose of Paracetemol must consequently cause minor damage to one’s liver. Proper therapeutic
dosages of Paracetemol should not cause any long term damage to the liver or any other organs.
Chemistry of Paracetemol
How it's made?
Since it was first released in the UK in 1956 Paracetemol has developed into one of the most
common drugs used in the world and the manufacture of Paracetemol is also developed in huge
quantities. The starting material for the commercial manufacture of Paracetemol is phenol, which
is nitrated to give a mixture of the ortho and para-nitrotoluene. The o-isomer is removed by
steam distillation, and the p-nitro group reduced to a p-amino group. When all of this is
completed it is then acetylated to give Paracetemol.

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Paracetemol or acetaminophen depending on where in the world the drug is being marketed is as
we know used as an over the counter analgesic (pain reliever) and antipyretic (fever reducer).
The terms acetaminophen and Paracetemol come from the chemical name for the compound
para-acetylaminophenol. In the United States Paracetemol is known as acetaminophen and
commonly trades by the brand name called Tylenol. While the terminology for Paracetemol may
differ between the UK and the United States the sole purpose and medication for Paracetemol
remains the same. As I have already discussed the possible side effects of taking too much
Paracetemol on a regular basis. The risk of these side effects (i.e. liver damage) can be increased
by the consumption of alcohol at any time while taking Paracetemol. Paracetemol toxicity is the
primary cause of acute liver failure in the Western world, and responsible for most drug
overdoses in the United States, the United Kingdom, Australia and New Zealand.
How does Paracetemol work?
The mechanism by which Paracetemol works has never being completely known and as a result
of this the usefulness Paracetemol was invented without knowing how it worked in the
metabolism. The mechanism of other pain relievers differs from Paracetemol. However it is
believed that the pain relief works in the brain and throughout the body. As I have mentioned the
exact mechanism of Paracetemol is not clear. Nonetheless the prostaglandin inhibitor in the brain
is known to create the temperature lowering effects. The prostaglandin inhibitor works by
blocking the production of prostaglandins which are chemicals involved in the transmission of

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the pain message to the brain. On-going research has shown that there is a presence of a new
previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which
is selectively inhibited by Paracetemol. This is different from the two already known
cyclooxygenase enzymes COX-1 and COX-2. With this current research into this new enzyme
cyclooxygenase enzyme COX-3 it is believed that the selective inhibition of this new enzyme in
the brain and spinal cord is responsible for the success of Paracetemol with regards to its
analgesic (pain relieving) and antipyretic (fever reducing) properties without having unwanted
gastrointestinal side effects.
Metabolism of Paracetemol
Paracetemol at recommended doses is a safe and effective medicine for the relief of mild pain
and fever. Paracetemol is available in soluble forms and in a variety of combinations but it is
most commonly available in 500mg tablets. With Paracetemol becoming so popular over the
years a liquid preparation is also available for young children.
Paracetemol is rapidly absorbed by the body, with the solid tablet form being absorbed much
slower than the quicker soluble form. As the Paracetemol is metabolized, the peak blood level
remains less than 20mg/litter after a standard adult 1000mg dose. After ingestion blood serum
levels will normally peak for between half an hour to two hours. The pain relieving effects of
Paracetemol will last for approximately four hours. Paracetemol has a half-life of about two
hours, after which it will rapidly be expelled from the body.
Paracetemol is largely metabolised in the liver. Paracetemol and its two primary metabolites (e.g.
acetanilide & aniline) are surprisingly safe compounds. Glucuronide and sulphate will be
combined with about 90% of the dose of Paracetemol before being excreted. Of the remaining
10%, about 5% will leave the body unchanged and the other 5% will be oxidized to
benzoquinoneimine. The benzoquinoneimine is then combined with glutathione and becomes
metabolized on to cysteine and mercapturate compounds before being safely excreted via the
kidneys.
Paracetemol and its two primary metabolites are remarkably safe compounds, and the
hepatotoxicity of Paracetemol arises only through the 5% that is oxidized. The immediate
oxidation metabolite, benzoquinoneimine, is a highly reactive substance that normally combines
with glutathione. The quantity of benzoquinoneimine produced increases as a result of the
increased dose of Paracetemol. There then comes a point where the glutathione stores in the liver
have been completely used up and the rate of production of new glutathione cannot keep up with
the rate of production of the benzoquinoneimine. It is at this point that the benzoquinoneimine
attaches to liver protein and causes liver injury.

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The time required for the liver to become depleted of glutathione, and for the benzoquinoneimine
to build up and cause fatal liver damage, is three to four days. At the beginning stages of this
process there may be some evident symptoms that may arise and it is extremely vital that in any
chance of a suspected overdose the patient does not wait for any symptoms to appear any to seek
medical attention straight away. Signs and symptoms of Paracetemol toxicity may initially be
absent or vague so it is essential if any bit unsure to pursue medical help. It is projected that liver
injury may begin to occur at a single dose of Paracetemol of 15g (30 standard tablets) or over.
If an overdose of Paracetemol occurs treatment should consist of hospital care. The common
treatment for an overdose is the administration of a remedy usually n-acetylcysteine. This form
of a remedy is given to the patient intravenously. N-acetylcysteine restores liver's capacity to
produce glutathione for combination with the benzoquinoneimine. Also this antidote provides
shielding effects for the liver.
The administration of an antidote within 12 hours of a suspected overdose is extremely beneficial
in removing the possible risk of liver damage. It has been shown that even taking an antidote
from 24 hours to even 48 hours is highly effective when dealing with an overdose. A
Paracetemol overdose can be successfully treated providing patients receive hospital treatment
straight away if they suspect that may have overdosed.
What is the recommended dosage of paracetemol?
 For adults the total quantity is 1 gram (1000mg) per dose and 4 grams (4000mg) per day.
This would mean taking only one tablet (i.e. 500mg tablet per dose) and taking no more
than 8 tablets in 24 hours. Taking above these recommended dosages could lead to
potential liver damage.
 For children different medicines are available in various concentrations depending on age
and the directions for use on the back of the packet should always be adhered to. Usually,
children's dosages are based on 10-15mg paracetemol per kilogram of body weight.
 Obviously anybody who is allergic to Paracetemol or acetaminophen should take this
drug.
 As mentioned already too high of a dosage of Paracetemol can cause liver damage so
anyone who has a liver disease or has suffered from alcoholism should seek advice from
their doctor before proceeding any further.
 Administering too high of a dosage of Paracetemol can lead to side effects such as
nausea, drowsiness and sometimes may result in renal failure.
 Paracetemol should only be taken for a lengthened period of time if recommended to do
so by your doctor.
 Women who are pregnant and women who are breast feeding their babies can also take
Paracetemol.
 The Paracetemol form for children comes in easy to take syrup form.

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What are the health benefits of paracetemol?
 Due to Paracetemols limited side effects, the health benefits of this drug are very good. It
is a good choice as a pain reliever and to reduce fevers. The beneficial side effects of
paracetemol can only be seen if taken in recommended dosages.
 As discussed earlier, due to constant research into Paracetemol it has been observed that
using Paracetemol could help prevent the build up of ‘bad cholesterol’ which leads to the
build up to arterial plaque. The build up of this arterial plaque is involved in causing
many cardiovascular diseases (i.e. strokes & heart attacks).
 Furthermore preliminary studies have shown that everyday use of Paracetemol offers a
major chance in the protection from ovarian cancer.
What are the drugs that may interact with paracetemol?
 There are a few drugs which should not be taken along with Paracetemol. These include
Cholestyramine, Metoclopramide and Domperidone.
 Firstly the drug Cholestyramine reduces the absorption of paracetemol from the gut.
Paracetemol should not be taken within 1 hour of taking Cholestyramine as the desired
effect of Paracetemol will be reduced.
 Metoclopramide and Domperidone drugs may increase the absorption of paracetemol
from the gut.
 Overuse of Paracetemol may enhance the risk of the anti blood-clotting effect of
warfarin. Increasing this risk may lead to a chance of bleeding.
 If Paracetemol is being used constantly with other medicines regular monitoring of blood
clotting times should be carried out but consultation with your doctor is paramount before
taking any other drugs with Paracetemol.
What are the side-effects of Paracetemol?
 From reading through this you will have learned that Paracetemol has very few side
effects. Although some people may experience skin rashes. How people respond to
Paracetemol varies from person to person and consequently the side effects
experienced vary also.
 Always consult your doctor before taking any medication as there may be side effects
of the drug unknown to the patient.
 The major side effect of Paracetemol is the administration of the drug with alcohol.
This should never happen as the consumption of alcohol with Paracetemol can cause
extreme liver damage.

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The reactions involved in paracetemol metabolism
Mechanism of Paracetemol
Since Paracetemol was first discovered over 100 years ago we are only learning now to an extent
how the mechanism of Paracetemol works in making it such an effective and useful drug. The
true mechanism of action of Paracetemol to this day is not completely known. It now appears
paracetemol has a highly targeted action in the brain, blocking an enzyme involved in the
transmission of pain. As with many other medicines the usefulness of Paracetemol was
discovered without properly knowing how it actually works in the body. With regards to other

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pain relievers Paracetemols mode of action was known to be different. Even though it produces
pain relief around the body the precise mechanism was not 100% clear.
Prostaglandin production is responsible in a person’s body to respond to inflammatory injury and
also the inhibition of prostaglandin production around the body. This occurs by blocking the
cyclooxygenase enzymes COX-1 and COX-2, these two enzymes for a long time have been
known to be the mechanism of action for aspirin and other non-steroidal anti-inflammatory drugs
(NSAIDs) e.g. ibuprofen. By blocking the action of the enzyme COX-1 this can be responsible
for the unwanted stomach side effects associated with these drugs.
The enzymes COX-1 and COX-2 have no significant effect on Paracetemol. This left the mode
of action unknown however it di explain its lack of efficiency in reducing anti-inflammatory
injuries. With Paracetemol having no real effect on COX-1 and COX-2 this information showed
us just why Paracetemol is free from such gastrointestinal side effects related to NSAIDs. Early
research had suggested that the fever reducing effect of Paracetemol occurred due to activity in
the brain whereas its deficiency in reducing anti-inflammatory injuries was consistent with its
low production of prostaglandin inhibition in the body.
As mentioned current research has demonstrated the existence of a new previously unknown
cyclooxygenase enzyme called COX-3. This enzyme is found in the brain and the spinal cord
and is selectively inhibited by Paracetemol. This new information may in the future lead to the
exact knowledge of the mode of action for Paracetemol. This selective inhibition of the COX-3
enzyme is understood to be the main reason for the effectiveness of Paracetemol in reducing
fever and relieving pain while maintaining its reasonably gentle effect on the stomach.
Regulation of Science
Food & Drug Administration
The Food and Drug Administration (FDA) protects and promotes the health and safety. It does
this so by improving the accessibility of medicines and food while constantly highlighting
medical and public health needs. The FDA also guards against the abuse of animals by protecting
the health and safety of animals by making available safe animal drug products and food. The
FDA is a science based regulatory agency which constantly monitors the nation’s general health
and the health care operations currently in place. The core responsibility of FDA is to protect
consumers by applying the best possible science to its regulatory activities—from pre-market
review of efficacy and safety to post-market product surveillance to review of product.

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Irish Medicines Board (IMB)
The purpose of the Irish Medicines Board is to ensure that present medical and scientific
knowledge is consistent with the quality and safety of all medicines available to people in
Ireland. Also the aim of the IMB is to comply with current systems in the European Union which
allow this. Prior to any medicinal product being given the authorisation to sell within Ireland
must be accompanied by all necessary documentation.
International Conference on Harmonization (ICH)
The ICH exists to promote harmonization in the area of the regulation of pharmaceuticals
 To help ensure timely registration of new products through harmonization of technical
content.
 To minimize duplication of work.
 To improve the process of electronic standards development and to ensure their
applicability in the ICH regions.
European Directorate for the Quality of Medicines (EDQM)
The role and remit of the EDQM is as follows:
 To establish and provide official standards which apply to the manufacture and quality
control of medicines.
 Ensure the application of official standards.
 Coordinate a network of official medicines control laboratories.
 Establish ethical and quality standards for the collection, storage and use of blood
components relevant to blood transfusion and for organ transplantation.
 Collaborate with national and international organisations in efforts to eliminate illegal
and counterfeit medicinal and medical products.
 Provide policies and model approaches for the safe use of medicines in Europe.
GMP/GLP
‘Draft requirements for good manufacturing practise in the manufacture and quality control of
drugs and pharmaceutical specialties’ World Health Assembly 1967.

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The definition for Good Manufacturing Process (GMP) is as follows ‘the part of quality
assurance which is aimed at ensuring that products are consistently manufactured to a quality
appropriate to their attended use’.
There are 10 basic rules essential to GMP:
 Production & Process controls
 Process equipment
 Buildings & facilities
 Personnel & organisation
 Control of raw materials
 Packaging & labelling controls
 Holding & distribution procedures
 Lab controls
 Records & reports
 Validation
GMP rules are directed primarily to diminish the risks inherent in any pharmaceutical production
that cannot be prevented completely thru the testing of products. E.g. cross contamination (in
particular by unexpected contaminants) and mix up (confusion) caused by false labels being put
on containers.
Good Laboratory Practice (GLP) is responsible for the constant monitoring, performance,
organisational procedures and the conditions within a laboratory as to how experiments are
recorded and reported. The values of GLP are intended for test facilities that are carrying out
studies on particular chemical substances where the results obtained from these studies are
submitted to the relevant Regulatory Authorities (national or international bodies i.e. Irish
Medicines Board or International Conference on Harmonisation).
Validation / Qualification
The qualification and validation process should establish and provide documentary evidence
that:
- The premises, the equipment and the processes have been designed in accordance with
the requirements of GMP.
 The premises, the equipment and the processes have been built and installed in
compliance with their design specifications.
 The premises, the equipment and the processes operate in accordance with their design
specifications.

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 A specific process will consistently produce a product meeting its predetermined
specifications and quality attributes.
What is the difference between Validation and Qualification?
Equipment is qualified. Systems, processes and method are validated. However the two are
closely related in that you can only correctly validate any system, process or method once the
equipment is correctly qualified.
Key Documentation for laboratory operations
Standard Operating Procedures SOPs
Test specification (Raw material, intermediate, finished product)
Test report
Certificate of analysis
Standard Operating Procedures SOPs
Within the pharmaceutical sector all operations have to be carried out in a specific manner to
ensure GMP is in operation at all times.
All operations on site are controlled by SOPs which detail exactly how each individual task is to
be conducted on site.
The SOPs details in clear unambiguous language step by step guidelines as to how to conduct the
operation you are doing.
This is to ensure that no matter who is carrying out the operation it will be completed in exactly
the same manner every time.
Test specification
Specifications describe in detail the requirements with which the products or materials used or
obtained during manufacture have to conform. They serve as a basis for quality evaluation.
Specifications should be there for:
 Starting and packaging material
 Intermediate and bulk products
 Finished products

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The final test specification details the entire tests that are conducted on the final product. It also
includes all the established limits as detailed in the relevant Pharmacopeia together with
reference to how these tests are going to be conducted.
It is a key document on any pharmaceutical site and will have its own specific documentation
number and format together with all the quality assurance checks.
It will be referenced on any Certificate of Analysis or Test report for finished products.
Test Report
The test report documents the results of each test carried out of the drug product and shows that
the results comply with the relevant limits stated in the Test Specification. Again it has a unique
number.
Certificate of Analysis
This is the final document to be written up. This document is signed off by the quality manager
and communicates with the receiver that the product they have obtained conforms to the
standards laid out by the manufacturing company and all other relevant standards.
Pharmacopeia
The pharmacopeia is the official document for testing pharmaceutical and medicinal products in
that region. All pharmaceutical and medicinal products must have a monograph logged in their
pharmacopeia.

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Test specification
The final test specification details the entire tests that are conducted on the final product. It also
includes all the established limits as detailed in the relevant Pharmacopeia. If the product fails
any of these tests it is out of specification.
Test Specification
Melting Point 168-172°C
Appearance White crystalline structure
Ultraviolet
Absorbance
Specifications λmax at 249nm is between 860-980nm
Infra- Red
Absorbance
Compared to spectrum
Colour Development of a violet colour that does not change red
4- aminophenol Blue colour produced in test solution is not more intense than the
standard solution
Loss on drying Not more than 0.5% loss on 1g by drying in a oven at 100°C
Sulphate ash Not more than 0.1% determined on 1.0g
TLC identification Sample and standard Rf values should be identical
HPLC No more than 1% of a difference between than sample and standard
retention times
Heavy Metals by
GFAAS
Results for cadmium should be less than 1ppb

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Prepared by: Lorraine Mellican Signature: ______________ Date: 18/10/11
Quality Control Analyst
Approved by: Ronan Mullane Signature: ______________ Date: 18/10/11
Quality Control Manager
Approved by: Tony O’Connor Signature: ______________ Date: 18/10/11
Quality Assurance Manager

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RLT PHARMACEUTICALS
Batch Book 1.0 Paracetemol
Batch number. 03.03.04
Revision number. N/A Supersedes: N/A
Author: _______________ Lorraine Mellican (QC Analyst)
Approved by: ___________ Ronan Mullane (QC Manager)
Approved by: ____________ Tony O’Connor (QA Manager)
Chemical Requisition:
Chemical Amount
p-aminophenol 1.5035g
Distilled water 25ml
Acetic Anhydride 2ml
Description: Paracetemol contains no less than 99% and no more than the equivalent of 101.0%
of N-(4-hydroxy-phenyl) acetemide, calculated with reference to the dried substance
Systematic Name: N-(4-hydroxy-phenyl) acetemide
Molecular formula: C8H9NO2
Molecular Weight: 151.17g/mol
Health and Safety:
Refer to the relevant risk assessments
1.0 Materials:
1.1 Reagents
 4-aminophenol
 Acetic Anhydride
 Deionised water
1.2 Equipment
 250ml round bottom flask
 Heating mantle
 Buchner flask
 Buchner funnel
 542 filter paper
 Analytical weighing balance
 Magnetic stirring chips
Diagram of Apparatus:

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Buchner Apparatus (figure 1.1)
2.0 Method
Step 1
A 400ml beaker was half filled with water. The beaker was placed on a hot plate and the water
was brought to the boil.
Step 2
1.5g ± 0.1g of p-aminophenol was weighed out and placed in a 250ml conical flask with 25mls ±
5mls of deionised water and stirred on a stirring mantle.
Actual weight: 1.5035g Actual Volume: 25mls
Signed: ______________ (QC Manager) Date: _____________
Signed: ______________ (QA Manager) Date: ______________
Method Continued
Step 3
5mls ± 1ml of phosphoric acid was added to the conical flask and was stirred using a glass rod
until all the amine was dissolved.
Step 4
The hot plate was turned off. The conical flask was placed in the hot water and 2mls ± 1ml of
acetic anhydride was carefully added to the flask. The conical flask was left in the warm water
for 10 minutes.
Step 5
An 800ml beaker was half filled with ice and water creating an ‘ice bath’.
Step 6
After the 10 minutes had expired, the conical flask was removed and placed the ice water bath

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for 30 minutes ± 5 minutes. The mixture was stirred to crystallize the acetaminophen.
Signed: _____________ (QC Manager) Date: ________________
Signed: _____________ (QA Manager) Date: ________________
Step 7
The contents of the 250ml conical flask were poured into the Buchner funnel and allowed filter
for 10 minutes ± 5minutes. The crystals were washed with three 10ml aliquots of cold water.
Weight of filter paper: 0.3846g
Step 8
A tiny amount of crude product was taken for the melting point analysis and IR analysis.
Expected Melting Point: 168-172°C Actual Melting Point: 169.4 -170°C
Signed: _____________ (QC Manager) Date: _____________
Signed: _____________ (QA Manager) Date: _____________
Step 9
The crude product was recrystallized by placing the crude product in 20mls of water and heating
on a hot plate until the crystals had dissolved.
Volume of water: 20mls
Signed: _____________ (QC Manager) Date: ______________
Signed: _____________ (QA Manager) Date: ______________
Step 10
The beaker was removed from the hot plate and allowed to cool.
Step 11
An 800ml beaker was half filled with ice and water creating an ‘ice bath’.
Step 12
The beaker was placed in an ice bath for 20minutes ± 5 minutes. The mixture was stirred to

Page | 22
crystallize the acetaminophen.
Step 13
The crystals and the filter paper were transferred to a pre weighted clock glass and placed in an
oven at 100°C ± 5°C until dry.
Weight of clock glass: 40.63g
Signed: _____________ (QA Manager) Date: ______________
Step 14
The weight of the empty clock glass and the filter paper were added together and subtracted from
the weight of the clock glass and the product (dry product) to find the actual yield of the product.
Weight of clock glass & filter paper: 41.01g Weight with product: 42.3g
Weight of product: 1.29g
Theoretical yield Calculation
1 mole of p-aminophenol reacts with 1 mole of acetic anhydride to give 1 mole of paracetemol.
Molecular weight of p-aminophenol is 109.13g, therefore
1.5035g is 0.01377 moles
Molecular weight of paracetemol is 151.17g, therefore
0.01377 x 151.17g = 2.082g
Theoretical yield: 2.082g
Percentage yield Calculation:
% yield = Actual yield x 100
Theoretical yield
% yield = 1.29g x 100
2.082g

Page | 23
% yield = 61.95%

Page | 24
RLT PHARMACEUTICALS
Batch Book 2.0 Paracetemol
Batch number. 03.03.05
Revision number. N/A Supersedes: N/A
Author: _______________ Loraine Mellican (QC Analyst)
Approved by: ___________ Ronan Mullane (QC Manager)
Approved by: ____________Tony O’Connor (QA Manager)
Chemical Requisition:
Chemical Amount
p-aminophenol 25.0023g
Distilled water 225ml
Acetic Anhydride 27.5ml
Description: Paracetemol contains no less than 99% and no more than the equivalent of 101.0%
of N-(4-hydroxy-phenyl) acetemide, calculated with reference to the dried substance
Systematic Name: N-(4-hydroxy-phenyl) acetemide
Molecular formula: C8H9NO2
Molecular Weight: 151.17g/mol
Health and Safety:
Refer to the relevant risk assessment
1.0 Materials:
1.1 Reagents
 4-aminophenol
 Acetic Anhydride
 Distilled water
1.2 Equipment
 250ml round bottom flask
 Buchner flask
 Buchner funnel
 542 filter paper
 Analytical weighing balance
 Stirring mantle
 Magnetic stirring chips

Page | 25
Diagram of Apparatus:
Buchner Apparatus (figure 1.1)
2.0 Method
Step 1
25g ± 0.1g of p-aminophenol was weighed out and placed in a 500ml conical flask.
Step 2
225mls of distilled water was added to the flask and was placed to stir on the stirring mantle at
room temperature.
Actual weight: 25.0023g Actual Volume: 225mls
Signed: ______________ (QC Manager) Date: ____________
Signed: ______________ (QA Manager) Date: ____________
Step 3
Then 27.5ml of acetic anhydride was added to the contents of the flask and stirred on the stirring
mantle until the precipitate had formed.
Step 4
After 10 minutes, the mixture was filtered using Buchner Filtration.
Step 5
The remaining contents in the flask were washed out with three 20ml aliquots of cold water.
Weight of filter paper: 0.3275g

Page | 26
Step 6
A tiny amount of crude product was taken for the melting point analysis and IR analysis.
Expected Melting Point: 168-172°C Actual Melting Point: 169.3-170°C
Step 7
The crystals and the filter paper were transferred to a pre weighted clock glass and placed in an
oven at 100°C ± 5°C until dry.
Weight of clock glass: 40.45g
Signed: _____________ (QA Manager) Date: _______________
Step 14
The weight of the empty clock glass and the filter paper were added together and subtracted from
the weight of the clock glass and the product (dry product) to find the actual yield of the product.
Weight of clock glass & filter paper: 40.77g Weight with product: 65.75
Weight of product: 24.98g
Theoretical yield Calculation
1 mole of p-aminophenol reacts with 1 mole of acetic anhydride to give 1 mole of paracetemol.
Molecular weight of p-aminophenol is 109.13g, therefore
25.0023g is 0.2291 moles
Molecular weight of paracetemol is 151.17g, therefore
0.2291 x 151.17g = 34.633g
Theoretical yield: 34.633g
Percentage yield Calculation:
% yield = Actual yield x 100

Page | 27
Theoretical yield
% yield = 24.98g x 100
34.633g
% yield = 72.13%
Signed: _____________ (QA Manager) Date:_____________

Page | 29
RLT Pharmaceuticals
SOP NO. QC120.470 Supersedes: N/A
Title: Preparation of mobile phase for High Performance Liquid Chromatography
Prepared by: Lorraine Mellican Signature:______________ Date: 17/10/11
QC Analyst
Approved by: Ronan Mullane Signature:______________ Date: 17/10/11
QC Manager
Approved by: Tony O’Connor Signature:______________ Date: 17/10/11
QA Manager
1. Purpose:
To describe the procedure for preparing mobile phase for HPLC.
2. Scope:
This SOP is applicable to all personnel carrying out quality control testing at RLT
Pharmaceuticals.
3. EHS Statement:
Refer to the relevant risks assessments.
4. Abbreviations:
Commonly used abbreviations in this SOP are documented in the respective sub sections.
Abbreviations
SOP Standard Operating Procedure
QC Quality Control
QA Quality Assurance
ml Millilitres
L Litre
µm Micrometre
HPLC High Performance Liquid Chromatography
N/A Not Applicable

Page | 30
5. RelatedDocuments
5.1 Impacted SOPs / Cross Referenced SOPs
QC 120.340 Analysis of Product by High Performance Liquid Chromatography
6. Responsibility:
6.1 It is the responsibility of the QC Specialist to revise this Sop and any associated
documents ensuring that they are an accurate up to date description of the current process.
The QC specialist also checks signs all completed testing to ensure that the tests are
completed and the paperwork is in order.
6.2 It is the responsibility of the QC Manager to approve QC SOPs and Specifications and
to assign the batch disposition on completion of testing.
6.3 It is the responsibility of the QA Manager to approve QC SOPs and Specifications
and to ensure that they are in accordance with relevant regulations, Quality Policies and
procedures.
7. Materials Required
Methanol R
Water R
8. Equipment
Mobile Phase Filtration Apparatus
Analytical Weighting Balance
500ml graduated cylinder
1L volumetric flask
Reagent bottles
9. Procedure:
Note. All standards and samples must be made up in mobile phase
Mobile Phase Preparation
70% methanol
30% water (distilled)

Page | 31
9.1 Wash a 1 litre volumetric Flask with distilled water and wash 250ml graduated
cylinder distilled water.
9.2 Measure out 300ml of distilled water using a 500ml graduated cylinder and place it
into the 1L volumetric flask.
9.3 Accurately measure of 500ml of methanol (instrument grade) using a clean 500ml
graduated cylinder and place it into the 1L volumetric flask.
9.4 Accurately measure of 200ml of methanol (instrument grade) using a clean 250ml
graduated cylinder and place it into the 1L volumetric flask up to the mark.
9.5 Set up the HPLC filtration apparatus and filter the mobile phase through a 0.45µm
filter paper.
9.6 When the mobile phase is completely filtered, pour the mobile phase into two 500ml
reagent bottles.
9.7 This is now a 70:30 Methanol: Water mobile phase.

Page | 32
RLT Pharmaceuticals
Title: Preparation of a 0.005g/100ml 4-aminophenol solution.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for preparing a 4-aminophenol solution.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
Refer to relevant risks assessments
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
g Grams
N/A Not Applicable
5. RelatedDocuments

Page | 33
5.1 Impacted SOPs / Cross ReferencedSOPs
QC 120.390 Analysis of sample using a 4-aminophenol test
6. Responsibility:
procedures.
Distilled Water R
Plastic pipette
4-aminophenol standard
8. Equipment
100ml Graduated cylinder
100ml volumetric flask
Analytical weighting balance
9. Procedure:
9.1 Weight out 0.005g of 4-aminophenol on an analytical weighting balance.
9.2 Measure out 20ml of distilled water using a 100ml graduated cylinder.
9.3 Dissolve the 0.5g of 4-aminophenol in a beaker containing 20ml of distilled water and
stir with a glass rod.
9.4 Transfer the contents of the beaker to a 100ml volumetric flask and make up to the
mark with distilled water.
9.5 This produces a 0.005g/100ml 4-aminophenol solution.

Page | 34
RLT Pharmaceuticals
Title: Preparation of 0.1M Hydrochloric acid
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for preparing 0.1M hydrochloric acid.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
M Molarity
N/A Not Applicable
5. RelatedDocuments

Page | 35
QC 120.300 Ultra-Violet Absorption Spectroscopy
6. Responsibility:
procedures.
Hydrochloric acid R
Distilled Water R
Plastic pipette
8. Equipment
Graduated cylinder
9. Procedure:
9.1 Put 60ml of distilled water R into a 100ml volumetric flask.
9.2 Use a pipette to add 1ml of hydrochloric acid R to the volumetric flask.
9.3 Stopper the flask and invert a number of times so that the solution is mixed uniformly.
9.4 Dilute the solution to 100ml with water R.
9.5 This produces a solution of 0.1M hydrochloric acid.

Page | 36
RLT Pharmaceuticals
Title: How to prepare a Sodium Nitroprusside and Anhydrous Sodium Carbonate Solution.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for preparing10g/l solution of Sodium Nitroprusside and a
10g/l of anhydrous carbonate solution.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
g Gram
g/L Gram per Litre
N/A Not Applicable

Page | 37
5. RelatedDocuments
6. Responsibility:
procedures.
Water R
Sodium Nitroprusside R
Anhydrous Sodium Carbonate R
Weighing boat
Glass rod
8. Equipment
Graduated cylinder
Instrumental Analytical Balance
9. Procedure:
9.1 Weight out 1g of Sodium Nitroprusside R on an analytical weighting balance.
9.2 Weight out 1g of Anhydrous Sodium Carbonate R on an analytical weighting
balance.
9.3 Put both the 1g of Sodium Nitroprusside R and the 1g of Anhydrous Sodium

Page | 38
Carbonate R into a 100ml beaker containing 50ml of distilled water.
9.4 Dissolve the contents of the beaker using a glass rod.
9.5 When dissolved, transfer the contents of the beaker into a 100ml volumetric
flask and make up to the mark with distilled water.
9.6 Stopper the flask was stoppered and inverted mix the solution.
9.7 This produces a 10g/L solution of Sodium Nitroprusside and a 10g/L of
anhydrous carbonate solution.

Page | 39
RLT Pharmaceuticals
Title: Preparation of Methanol and water Equal volumes.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for preparing equal volumes of methanol and water.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
Ml Millimetre
N/A Not Applicable
5. RelatedDocuments
5.1 Impacted SOPs / Cross Referenced SOPs

Page | 40
6. Responsibility:
procedures.
Methanol R
graduated cylinder
Distilled Water R
Plastic pipette
8. Equipment
100ml Graduated cylinder
9. Procedure:
9.1 Pour 50ml of methanol into a 100ml graduated cylinder.
9.2 Transfer the 50ml of methanol to the 100ml volumetric flask.
9.3 Pour 50ml of water into a clean separate 100ml graduated cylinder.
9.4 Transfer the 50ml of water into the 100ml volumetric flask already containing the
50ml of methanol.
9.5 The flask was stoppered and inverted to mix the solution.
9.6 This is now a 50:50 equal volume solution of methanol: water.

Page | 41
RLT Pharmaceuticals
Title: Analysis of Product by High Performance Liquid Chromatography.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for analysing the product by HPLC.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
µl Microliter
min Minutes
L Litres
HPLC High Performance Liquid Chromatography

Page | 42
Mins Minutes
N/A Not Applicable
5. RelatedDocuments
QC 120.470 Preparation of mobile phase for High Performance Liquid Chromatography
6. Responsibility:
procedures.
HPLC Grade Methanol: Water
Aceto-aminophenol standard
4-aminophenol standard
0.45µm filter paper
8. Equipment
Adjulant HPLC 1050
Mobile Phase Filtration Apparatus
1L volumetric flask
HPLC filtration apparatus
Reagent bottles
10ml glass pipette
Glass vials

Page | 43
9. Procedure:
Note. All standards and samples must be made up in mobile phase
Mobile Phase Preparation
70% methanol
30% water (distilled)
9.1 Wash a 1 litre volumetric Flask with distilled water and wash 250ml graduated
cylinder distilled water.
9.2 Measure 300ml of distilled water using a 500ml graduated cylinder and place it into
the 1L volumetric flask.
9.3 Accurately measure 500ml of methanol (instrument grade) using a clean 500ml
graduated cylinder and place it into the 1L volumetric flask.
9.4 Accurately measure 200ml of methanol (instrument grade) using a clean 250ml
graduated cylinder and place it into the 1L volumetric flask up to the mark.
9.5 Set up the HPLC filtration apparatus and filter the mobile phase through a 0.45µm
filter paper.
9.6 When the mobile phase is completely filtered, pour the mobile phase into two 500ml
reagent bottles.
9.7 This is now a 70:30 Methanol: Water mobile phase.
Preparation of Standard
9.8 Weight out 50mg of Aceto-aminophenol in a weighting boat on an analytical
weighting balance.
9.9 Transfer the 50mg of standard into a 100ml volumetric flask and make up to the mark
with mobile phase.
9.10 Shake the flask vigorously for a few mins so that the standard is completely
dissolved.
9.11 Stopper the flask and invert a couple of times so that the contents of the flask are
mixed uniformly.
9.12 This is now a 500ppm stock solution.
9.13 From this stock solution prepare a range of standards (10ppm, 20ppm, 30ppm,

Page | 44
40ppm, 50ppm).
9.14 From the 500ppm stock solution, pipette 2mls into 100ml volumetric flask and
make up to the mark with mobile phase.
9.15 This is now a 10ppm solution.
9.16 Form the 500ppm stock solution, pipette 4mls into a 100ml volumetric flask and
9.18 From the 500ppm stock solution, pipette 6mls into a 100ml volumetric flask and
9.20 From the stock solution, pipette 8mls into a 100ml volumetric flask and make up to
the mark with mobile phase.
9.22 From the stock solution, pipette 10mls into a 100ml volumetric flask and make up
to the mark with mobile phase.
9.24 Stopper all the flasks and invert them a couple of times so that the contents of the
flasks are mixed uniformly.
Preparation of Sample
9.25 Weight out 50mg of sample in a weighting boat on an analytical weighting
balance.
9.26 Transfer the 50mg of sample into a 100ml volumetric flask and make up to the
mark with mobile phase.
9.27 Shake the flask vigorously for a few mins so that the sample is completely
dissolved.
mixed uniformly.
9.29 From the 100ml volumetric flask, pipette 2mls into a clean 100ml volumetric flask

Page | 45
and make up to the mark with mobile phase. Mix well.
9.30 This gives a 10ppm solution of sample.
Sample Analysis / Instrument Preparation
9.31 Take seven vials. In the first vial fill with water. Fill the remaining vials as follows
10ppm, 20ppm, 30ppm, 40ppm, 50ppm and also the 10ppm sample.
9.32 Label each vial and place the vials in the following order in the carousel blank,
10ppm, 20ppm, 30ppm, 40ppm, 50ppm and 10ppm sample.
9.33 Place the carousel back into the instrument.
9.34 Click on method.
9.35 Click on edit entire method.
9.36 Set flow rate to 1.000ml/min.
9.37 In the solvents sub section B enter 70:30 and in description enter Methanol:
Water.
9.38 Set stop time to 10.00mins.
9.39 Set Posttime to off.
9.40 Click ok.
9.41 Injection section pops up. Set the following parameters
Injection volume: 20µl
Draw speed: 200µl/min
Eject speed: 200µl/min
Draw position: 0.0min
9.42 Click Ok.
9.43 Set detector wavelength to 245nm.
9.44 Click ok.
9.45 Signal details.
9.46 Click ok.

Page | 46
9.47 Enter the name of the method. (example Paracetemol)
9.48 Click on Sequence.
9.49 Go into Sequence table.
9.50 Set Sequence Table.
Line Location Sample name Method
1 Vial 1 blank Paracetemol
2 Vial 2 10ppm Paracetemol
7 Vial 7 Sample Paracetemol
9.51 Click on Instrument and go into More Pump  Control  click on for the
Pump.
9.52 Click on Instrument again and go into More VWD  Control  click on for the
light.
9.53 Go to Run Control.
9.54 Ensure all critical windows are green.
9.55 Click Run Sequence.

Page | 47
RLT Pharmaceuticals
Title: Infrared Absorption Spectroscopy
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for testing for the Infrared Absorbance of acetaminophen in the
sample.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
mg Milligrams
ml Millilitres
KBr Potassium Bromide
kg/cm2 Kilogram per Square Centimetre
IR Infrared

Page | 48
Mins Minutes
N/A Not Applicable
5. RelatedDocuments
N/A
6. Responsibility:
procedures.
Mortar and pestle
Potassium Bromide (KBr)
Sample
Weighting boats
8. Equipment
FT-IR Spectrometer
Hydraulic Bench Press
Analytical balance
Spatula
IR lamp
9. Procedure:
9.1 Prepare the sample in accordance to the European Pharmacopeia method. Weight out
20mg ± 10% of sample and about 2000mg (2g) ± 10% of KBr in separate weighting
boats.

Page | 49
9.2 Transfer the sample and KBr into a mortar and pestle and grind. Keep the sample and
KBr under the IR lamp during grinding.
9.3 Spread the mixture uniformly between two sintered alloy sample bases and mount in
the KBr die assembly.
9.4 Press the mixture into a disc and do this using a hydraulic bench press. Pump the
gauge to a pressure of 10,000kg/cm2.
9.5 Press the disc for 15mins.
9.6 Remove the KBr die assembly from the bench press after 15 mins and extract the disc
from the die. Place the disc into the disc holder.
9.7 On the computer desktop, open the Varian Resolutions 4.0 shortcut.
9.8 Click on File.
9.9 Click on New scan.
9.10 Click on Collect background. The background spectrum will be collected.
9.11 Click on Cancel on the save option when it pops up.
9.12 Load the sample disc into the collection chamber and close the lid.
9.13 Click on Collect sample. The sample spectrum will be collected.
9.14 Click on the icon Peaks and click on pick peak.
9.15 Click on File and click on print. Make sure the printer is connected to the computer.
9.16 Print the Sample spectrum was printed and compare to the Paracetemol reference
spectrum.

Page | 50
RLT Pharmaceuticals
Title: Analysis of sample using a 4-aminophenol test.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for testing the sample using a 4-aminophenol test.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
N/A
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
g Gram
N/A Not Applicable
5. RelatedDocuments

Page | 51
QC 120.410 How to prepare a Sodium Nitroprusside and Anhydrous Sodium Carbonate
Solution
QC 120.370 Preparation of a 0.005g/100ml 4-aminophenol solution
QC 120.400 Preparation of Methanol and water Equal volumes
6. Responsibility:
procedures.
Equal volumes of solution of methanol and water.
Sodium nitroprusside anhydrous.
Sodium carbonate solution.
4-aminophenol
Sample.
8. Equipment
250ml beakers (2).
Spatula.
Weighing boat.
5ml Pipette
Plastic Pipette
9. Procedure:
Sample preparation
9.1 Accurately weight out 0.5g of sample using an analytical Weighing Balance.

Page | 52
9.2 Dissolve sample in a beaker containing 20ml of equal volumes of methanol and water.
9.3 Add 0.2ml of Sodium Nitroprusside anhydrous and 0.2ml of anhydrous sodium
carbonate solution to the beaker.
9.4 Mix the solution using a glass rod and leave to stand for approximately 30 minutes.
Standard preparation
9.5 Accurately weight out 0.5g of acetaminophen R using an Analytical weighing
balance.
9.6 The Acetaminophen R standard was then dissolved in a beaker containing 30ml of
equal volumes of methanol and water.
9.7 Add 0.2 ml of sodium nitroprusside and 0.2mls of anhydrous carbonate solution to the
beaker.
9.8 Add 5ml of a 0.0005g/100ml solution of 4-aminophenol
9.9 Mix the solution using a glass rod and leave to stand for approximately 30 minutes.
Analysis of Sample
10.0 The physical appearance of the sample and standard solution was compared to each
other.
10.1 The blue colour present in the sample solution should not more intense than the blue
colour present in the standard solution.

Page | 53
RLT Pharmaceuticals
Title: Colourimetric Test
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for testing for the presence of a violet colour in the sample.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
g Gram
ml Millilitres
N/A Not Applicable
4.RelatedDocuments

Page | 54
N/A
5. Responsibility:
5.1 It is the responsibility of the QC Specialist to revise this SOP and any associated
procedures.
Weight boat
Hydrochloric Acid R
Distilled Water
Ice bath
Hotplate
Analytical balance
Beaker
1ml Glass pipette
Dichromate R
7. Equipment
Spatula
Hotplate
Analytical balance
50ml Beaker
8. Procedure
8.1 Prepare the sample in accordance to the European Pharmacopeia Method. 0.1g ± 10%
of sample was weighted out in a weighting boat.
8.2 Transfer this to a 50ml beaker.
8.3 Transfer the beaker to a fumehood and add 1ml of hydrochloric acid R.
8.4 Place the beaker on a hot plate and heat for 3 minutes.
8.5 Add 0.05ml of potassium dichromate R to the solution using a 1ml pipette.

Page | 55
8.6 A violet colour develops which does not change to red.

Page | 56
RLT Pharmaceuticals
Title: Loss on drying
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure loss on drying
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
g Gram
°C Degrees Celsius
N/A Not Applicable
5. RelatedDocuments

Page | 57
N/A
6. Responsibility:
procedures.
Sample
Spatula
8. Equipment
Clock glass
Oven
9. Procedure:
9.1 Place a clean Clock glass in an oven at 80°C.
9.2 Remove the clock glass from the oven and allow to cool.
9.3 Weight the Clock glass on an Analytical weighting Balance and record the weight.
9.4 Accurately weight out 1g of sample on the same clock glass.
9.5 Transfer the clock glass to the oven and set the temperature to 100°C and leave in the
oven for 1 hour.
9.6 Remove the clock glass from the oven and allow to cool.
9.7 Then place on the Analytical weighing balance and record the weight.
9.8 Record the weight of the dry sample.

Page | 58
RLT Pharmaceuticals
Title: Thin layer Chromatography (TLC)
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for TLC.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
TLC Thin Layer Chromatography
N/A Not Applicable
5. RelatedDocuments

Page | 59
N/A
6. Responsibility:
procedures.
Paracetamol Sample
Paracetamol Standard ( Aceto-aminophenol)
4- Aminophenol Standard
Methanol R
Dichloromethane R
TLC Plate
8. Equipment
Glass capillary Tubes
1ml glass pipette
Analytical weighting Balance
Ultra-Violet lamp
9. Procedure:
Preparation of sample /standards
9.1 Accurately weighed out 0.01g of sample using an Analytical weighting balance.
9.2 Accurately weighed out 0.01g of aceto-aminophenol standard using an Analytical
weighting balance.
9.3 Accurately weighed out 0.01g of 4- Aminophenol using an Analytical weighing
balance.

Page | 60
9.4 Dissolve the 4- Aminophenol standard in 1ml of methanol using a 1ml glass pipette in
a weighting boat.
9.5 Dissolve the Paracetamol standard in 1ml of methanol using a 1ml glass pipette in a
weighting boat.
9.6 Dissolve the sample in 1ml of methanol using a 1ml glass pipette in a weighting boat.
Preparation of mobile phase
9.7 Measure 10ml of methanol in a fumehood using a 50ml graduated cylinder.
9.8 Measure out 40ml of Dichloromethane in the fumehood using a 50ml graduated
cylinder.
9.9 Transfer the 10ml of methanol and the 40ml of dichloromethane into a 100ml beaker
and cover with a clock glass.
TLC Plate Preparation
9.10 Draw a line using a ruler and pencil 1cm up from the bottom of the TLC plate.
9.11 Evenly space out by marking them across the TLC plate in order to identify each
standard/ sample.
TLC Analysis
9.12 Dip the capillary tube into one of the solutions in the weighing boats and place a blot
of that solution on the point marked out on the TLC plate for that particular solution
and allow to dry before continuing.
9.13 Repeat this for the standards.
9.14 All Analysis was carried out in the fumehood.
9.15 Pour the mobile phase into the beaker to a height of about 1cm.
9.16 Place the TLC plate into the beaker and cover with a clock glass.
9.17 Leave the TLC plate in the beaker and leave to dry in the fumehood.
9.18 Add Iodine crystals to make visibility easier to the naked eye.
9.19 Examine the TLC plate under a ultra-violet light absorption machine.

Page | 61
9.20 Then work out the distance travelled by the sample and the aceto-aminophenol. The
sample and the standard (aceto-aminophenol) should have the same Rf value.

Page | 62
RLT Pharmaceuticals
Title: Determination of Sulphated Ash
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for testing for the presence of sulphated ash in the product.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
g Gram
mins Minutes
°C Degrees Celsius
N/A Not Applicable

Page | 63
5. RelatedDocuments
N/A
6. Responsibility:
procedures.
Sulphuric acid R
8. Equipment
1ml glass pipette
Silica Crucible
Analytical Balance
Desiccator
Muffle Furnace
9. Procedure:
Sample Preparation
Note. All analysis is to be carried out in a fumehood
9.1 Place the crucible in a muffle furnace at 600 ± 50°C for 30mins.
9.2 Allow to cool in a desiccator and when completely cool weight the crucible on an

Page | 64
analytical balance and record the weight.
9.3 While the crucible is cooling weight out 1g of sample on an analytical weighting
balance.
9.4 Place the 1g of sample weighted out into the crucible and weigh.
9.5 Add 1ml of sulphuric acid R to the sample.
9.6 Heat gently over a Bunsen burner at as low a temperature as possible until the sample
is thoroughly charred. (burnt)
9.7 After cooling, moisten the residue with 1ml of sulphuric acid R.
9.8 Heats gently until white flames are no longer evolved.
9.9 Place the crucible in a muffle furnace at 600 ± 50°C for 15 mins until the residue is
completely incinerated.
9.10 If not completely incinerated return to the muffle furnace for a longer period.
9.11 Allow the crucible to cool in a desiccator, weigh it again and calculate the
percentage of residue.
9.12 Subtract the original weight of the crucible after cooling from the weight obtained
from the crucible and sample after heating.
% w/w sulphated ash: wt of residue (g)_ x 100
Sample weight (g)

Page | 65
RLT Pharmaceuticals
Title: Ultra-Violet Absorption Spectroscopy
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for testing for the absorbance of acetaminophen in the sample.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
mg Milligrams
ml Millilitres
nm Nanometres
M Molarity
N/A Not Applicable

Page | 66
5. RelatedDocuments
QC 100.310 Preparation of 0.1M Hydrochloric Acid
6. Responsibility:
procedures.
Weight boat
Spatula
Methanol R
0.1M Hydrochloric acid
50mg of sample
Plastic pipettes
Reflective foil
Distilled water
8. Equipment
UV-Vis Spectrophotometer
100ml volumetric flasks
9. Procedure:
9.1 Prepare the sample in accordance to the European Pharmacopeia. Weight out 50mg of
sample.
9.2 Dissolved the sample in methanol and dilute to 100ml in a volumetric flask.
9.3 Take 1.0ml of the solution and put it into a 100ml volumetric flask. Add 0.5ml of

Page | 67
0.1M Hydrochloric acid to this volumetric flask.
9.4 Dilute the solution in a 100ml volumetric flask up to the mark with methanol R.
9.5 Protected the solution from light by wrapping in reflective foil guaranteeing no light
can pass through.
9.6 Measure the absorbance immediately.
9.7 On the computer desktop screen, open the sample reads shortcut.
9.8 Click on the setup tab.
9.9 Then click on the wavelength icon.
9.10 Set the wavelength to 249nm.
9.11 Open the chamber and was make sure there is nothing in the path length.
9.12 Rinse the quartz cuvette with distilled water and empty into a waste beaker.
9.13 Collect the blank by placing distilled water in the cuvette.
9.14 Close the chamber and click on zero on the computer screen.
9.15 When the blank is read, remove the cuvette from the chamber.
9.16 Rinse the cuvette again and fill the cuvette with sample.
9.17 Place the cuvette in the chamber and close the lid.
9.18 Click on Readon the computer screen.
9.19 Record the reading for the sample.

Page | 68
RLT Pharmaceuticals
Title: Determination of the Presence of Cadmium/Lead in the sample by Graphite Furnace
Atomic Absorption Spectroscopy.
QC Analyst
QC Manager
QA Manager
1. Purpose:
To describe the procedure for determining the cadmium/Lead concentration in the sample
by Graphite Furnace Atomic Absorption Spectroscopy.
2. Scope:
Pharmaceuticals.
3. EHS Statement:
4. Abbreviations:
Abbreviations
QC Quality Control
ml Millilitres
g Grams
ppm Parts Per Million
ppb Parts Per Billion

Page | 69
Cd Cadmium
Pb Lead
nm Nanometres
N/A Not Applicable
5. RelatedDocuments
N/A
6. Responsibility:
6.1 It is the responsibility of the QC Specialist to revise this SOP and any associated
procedures.
Sample
Ultra-Pure water
Plastic pipette
Weighting boat
8. Equipment
100ml volumetric flasks
5ml glass pipette
1ml glass pipette
Varian Spectra AA Atomic Absorption Spectrometer
Sonification Bath
9. Procedure:

Page | 70
Note. All standards and samples must be made up with ultra-pure water
Sample Preparation
9.1 Weight out 1g of sample on an analytical weighting balance.
9.2 Dissolve the 1g of sample in a 100ml volumetric flask (A) with ultra pure-water up to
the mark.
mixed uniformly.
9.4 Place the 100ml flask in a sonification bath for a few mins so that the solution is
completely dissolved.
Standard Preparation for Cadmium
9.5 Transfer 5mls of cadmium into a 50ml volumetric flask (A) and make up to the mark
with ultra-pure water.
9.6 Stopper the flask and invert a couple of times so that the solution is mixed uniformly.
9.7 This produces a 1000ppm solution.
9.8 Transfer 1ml from flask (A) into a 100ml volumetric flask (B) and make up to the
mark with 100ml ultra pure water.
9.9 Stopper the flask and invert a couple of times so that the solution is mixed uniformly.
9.11 Transfer 0.1ml from flask (B) into another 100ml volumetric flask and make up to
the mark with ultra-pure water.
9.12 Stopper the flask and invert a couple of times so that the solution is mixed
uniformly.
9.13 This produces a 1ppb solution.
Standard Preparation for Lead
9.14 Transfer 5mls of lead into a 50ml volumetric flask (A) and make up to the mark with
ultra-pure water.

Page | 71
uniformly.
9.17 Transfer 1ml from flask (A) into a 100ml volumetric flask (B) and make up to the
mark with 100ml ultra-pure water.
uniformly.
9.20 Transfer 3ml from flask (B) into another 100ml volumetric flask and make up to the
mark with ultra-pure water.
uniformly.
9.22 This produces a 30ppb solution.
Instrument Preparation
9.23 Click on Spectra AA on the computer desktop.
9.24 Click on Worksheet.
9.25 Click on new Worksheet Name  Sample  1
9.26 Click on add method.
9.27 Click on Cd.
9.28 Click on Measurement Tab. Set up the following Parameters
Peak height: Duplicate
Wavelength: 228.8nm
9.29 Click on furnace Tab and set up the standards for Cadmium as follows 0.5ppb,
1.0ppb and 1.5ppb.
9.30 Click on exit method.
9.31 Click on Optimize.
9.32 Insert the Cd lamp.

Page | 72
9.33 Click on instrument  Furnace Facilities  Go to Vial  Align  Ok.
9.34 Place the sample in sample space 1.
9.35 Place the ultra-pure water and the cadmium standard in their positions.
9.36 Click on start to begin analysis.
9.37 When the run is finished, click exit method  Report  Print Preview  Print.
9.38 This will print out the results.

Page | 74
Certificate of
Analysis

Page | 75
RLT Pharmaceuticals
Production description: Paracetamol
Formula : C8H9NO2
Formula weight: 151.17g
Physical Appearance: White crystalline product
Storage information: Room Temperature
Test: Result:
Melting Point 168-172OC
UV/Vis λmax Specific absorbance at 249nm
Infra-Red spectrum Confirms the standard
Colour test Colour develops doesn’t turn red
TLC identification test Sample standard Rf values were identical
Loss of drying 0.36%
Sulphate ash 0.08%
4-Aminophenol Blue colour produced in test solution is not more
intense than the standard solution.
Cadmium Greater than 1ppb
Due to the failed to the failed cadmium test, this product has failed specification.
This product has been rejected due to the out of specification result for cadmium resulting in a
failure with regards to the European Pharmacopeia and United States Pharmacopeia guidelines
for the testing of Paracetemol/Acetaminophen.

Page | 76

Page | 78
Test Report
The test report documents the results of each test carried out of the drug product and shows that
the results comply with the relevant limits stated in the Test Specification. Again it has a unique
number.
If the result of the test for the sample is within the specifications for the test a Pass result is given
but if the results are outside the specifications for the test a Fail result is given for the test.
Test Specifications Result Pass/Fail
Melting Point 168-172°C 169.3-170°C Pass
Appearance White crystalline structure White crystalline Pass
Ultraviolet
Abs
Specifications λmax 249nm
is between 860-890nm
Specific absorbance
at λmax 249nm is
908.1nm
Pass
Infra- red
Abs
Compared with
Paracetamol spectrum
reference
Compared to
spectrum
Pass
Colour Development of a violet
colour that does not
change red
A violet colour
develops which
does not turn red
Pass
4- aminophenol Blue colour produced in
test solution is not more
intense than the standard
solution
Blue colour in test
solution is not more
intense than in the
standard
Pass
Loss on drying Not more than 0.5% loss
on 1gby drying in a oven
at 100°C
No more than 0.5%
loss on drying
Pass

Page | 79
Sulphate ash No more than 0.1%
determined on 1.0g
No more than 0.1%
present
Pass
TLC
identification
Sample and standard Rf
value should be identical
Sample and
standard
Rf values were
identical
Pass
HPLC No more than 1% of a
difference between the
sample and standard
retention times
Difference between
the sample and
standard
times was less than
than 1%
Pass
Heavy Metals by
GFAAS
Results for cadmium
should be less than 1ppb
Result for
Cadmium were
greater than 1ppb
Fail

Page | 81
Discussion
The synthesis of paracetamol was performed by reacting 4 aminophenol with acetic anhydride to
form paracetamol. For this mini-project on the making Paracetemol, the method that I used
proved to be a useful method in that all of our tests that were carried out on product passed their
required specifications. The method that I used for Batch two didn’t require any heating,
refluxing or recrystallizing as detailed in other methods which were available e.g. Batch book 1.
The first method that was used to produce the first batch of Paracetemol was used to see if the
method actually worked. From this first method it did in fact produce Paracetemol. However on
completion of the first method it was noticed that due to such a small amount of starting material
(4-aminophenol) being used initially (i.e. 1.5035g) that a very small amount of product was left
over after recrystallizing and drying (i.e. 1.29g). Due to this information it was decided that it
would be virtually impossible to carry out all of the required analysis on the product due to
insufficient amount left over.
In the production of Paracetemol, the starting material 4-aminiophenol is the limiting reagent.
This means that 1 mole of p-aminophenol reacts with 1 mole of acetic anhydride to give 1 mole
of paracetemol the amount of product produced is dependent on the amount of the starting
material used in the reaction. For the first method, 1.5035g of 4-aminophenol was used, the
theoretical weight which was calculated as 2.082g of acetaminophen. The actual weight
recovered was calculated as being 1.29g denoting a percentage yield of 61.95%.
The amount of product produced was as mentioned far too small in order to carry out the
necessary tests. This meant that the method had to be altered slightly. This was done by using a
greater amount of starting material 4-aminophenol so 25.0023g was weighted out. As the starting
material was increased as did the amount of acetic anhydride and water. By altering the method
like this a higher yield and greater amount of product was achieved.
For the second method, 25.0023g of aminophenol was used. The theoretical weight for this
method was calculated as being 34.633g of acetaminophen. The actual weight of acetaminophen

Page | 82
produced was calculated as 24.98g.With these two figures the percentage yield was calculated as
being 72.13%. The actual weight of acetaminophen and percentage yield for this method was far
greater than that in the first method. Due to these results it was decided that the batch produced
by this method would be used for testing. Due to the above results, it was agreed by the group to
synthesize paracetamol using the second method. Lastly from the appendix it can be seen that
from the first method carried (batch book 1.0) an IR was done of the sample and it can be seen
from this just how low the % transmittance was. This would make it virtually impossible to
identify the certain peaks required to confirm that our sample was pure Paracetemol.
Appearance Test
The first and most obvious test which was carried out on the batch was the visual test. The
European Pharmacopeia states that Paracetemol is a white or almost white crystalline powder.
When the batch was visually inspected it was found to be a white crystalline powder. This
conforms to the test specification for appearance.
Melting Point
The melting point of a substance is the point at which a solid change to a liquid under specified
temperatures. The next test that was performed on the product was the melting point test. The
limits for the melting point are stated within the European Pharmacopeia. The melting Point
range of Paracetemol is within 168°C to 172°C. The melting point for the product when analysed
was found to be 169.3°C - 170°C. This showed that our product was pure Paracetemol and was
free from any impurities and was within the specifications set out by the European
Pharmacopoeia. This means that the product passed this test as the limits were within
specification.
Loss on Drying
The Loss on Drying Test is an analytical test designed to measure the amount of water present
and the impurities in a sample when the sample is dried under specified conditions. The
specifications within the European Pharmacopeia state that there should be no less than 0.5%
should be lost on drying. The temperature of the oven was set to 100°C and was left to stabilize
to ensure the temperature of the oven would be constant for the analysis. The sample was left in
an oven for 1 hour. The sample was then weighted. The sample had a % loss of 0.36% meaning
that it passed the test. The one issue I would have with this test is that whether 1 hour of drying
the sample is long enough to dry out the sample. Possibly anyone carrying out this test again
could increase the length of drying and see if would improve the result. The possible reasons for

Page | 83
losing 0.36% could be due to the small amounts of acetic anhydride left over from the synthesis
or possibly the presence of moisture in the sample.
4-aminophenol
The 4-Aminophenol test is a colour related substance test. The main impurity in Paracetemol is
4-aminophenol. The aim of this 4-aminophenol test is to observe a blue color in the standard that
was more intense that that the blue color in the sample. This is the required specification within
the European Pharmacopeia. The result of the test was that the standard had a more intense blue
color and from this we could conclude that there was no 4-aminophenol present in the sample
thus conforming to the required specification.
Colourimetric Test
A colorimetric test is a test which forms a colour. The amount of the color is then measured. In
most tests the more color formed, the more of the test substance there is in the water. The
specification as stated within the European Pharmacopeia says that a violet colour develops
which does not change to red. 0.1g if the product was added to 1ml of hydrochloric acid and 1ml
of distilled water. Then 0.05ml of potassium dichromate was added to the solution on
observation of this, the solution turned a violet colour which did not change to a red colour.
From this result, it can be said that the sample passes the test and passed specification.
Infra-Red Spectroscopy Test
Infra-Red Spectroscopy represents a detailed spectrum of functional groups, bond stretches and
vibrations present. Two different compounds are unlikely to have exactly the same I.R spectrum.
Therefore, the I.R spectrum can act as a compounds ‘fingerprint’. What this means is that the
identification of different compounds will give positive results. A reference spectrum was carried
out for the pure Paracetemol and also an I.R spectrum was carried out for the sample. The
printout for the pure paracetemol and for the sample spectrum can be found in the Appendix. To
compare the sample spectrum to the pure spectrum what we are looking for is the presence of a
benzene ring, an amide group and an alcohol group.
A peak is present at 1654cm-1 this is representative of the benzene structure of a
paracetamol.From the sample spectrum it can be seen that there is a C=O present at 1611 cm-1.
This is very close to the C=O in the pure spectrum which appears at 1614 cm-1. From this
observation a C=O is present in the sample spectrum. Secondly an O-H stretch is present in the
sample. The peak appears at 3161cm-1. This is quite identical to the peak of 3177cm-1 in the pure

Page | 84
spectrum. From this we can say that there is an O-H stretch present in the sample. The O-H
stretch is a very broad wave number (cm-1) /peak so this would explain as to why the two peaks
are a small bit apart in their respective spectrums. Finally there is an N-H stretch very much
present in both the sample spectrum and the pure spectrum. In the sample there is an N-H stretch
present at 3325cm-1 and for the pure there is a peak at 3340cm-1. The wave number (cm-1) for an
N-H stretch is between 3500-3180 so both of these peaks fall within this range. From these
results there is a very strong comparison between the sample spectrum and the pure Paracetemol
spectrum. We can conclude from this that the I.R spectrum for the sample conforms to the
European Pharmacopeia specifications.
Sulphated Ash Test
This test is carried out in order to find out if any impurities (i.e. sulphur) are present in the
sample. From carrying out the test it was found that there was less than the 0.1% impurities
present in the sample. This conforms to the specifications stated within the European
Pharmacopeia resulting in a pass for this test. If there were more than 0.1% of impurities present,
this may be caused by contamination of the sample prior to analysis.
Thin Layer Chromatography (TLC) Identification Test
TLC is widely used for the qualitative analysis of a mixture. The TLC plate contains a thin layer
of stationary phase coated onto it. The mobile phase moves up the plate by capillary action and
meets the sample, which is dissolved and is carried up the plate by the solvent. For this test by
Thin Layer chromatography it was found that the sample Rf value was the same as the Rf value
for the acetaminophen. The specification in the European Pharmacopeia states that the sample Rf
value should be identical to the Rf for the standard. The specification was met meaning a pass
result for this test.
High Performance Liquid Chromatography (HPLC) Test
HPLC is a chromatographic technique where the separation process is based on the difference in
the surface interactions of the analyte and the mobile phase molecules. HPLC is used to identify
the components of a mixture. HPLC was not referenced in the European Pharmacopoeia as a test
method so it was run as an additional quantitative and qualitative test.
A sample of pure paracetamol (Aceto-aminophenol) and the sample were analyzed. To
determine the concentration of our sample, a set of standards were made up of aceto-
aminophenol. These standards were in the range of 10, 20, 30, 40 and 50ppm. The peak areas

Page | 85
were then used to construct a calibration curve. Also a 10ppm concentration of our sample was
also made up in order to compare retention time to the 10ppm standard and to see if our sample
was within the European Pharmacopeia specification of no more than 1% of a difference
between the sample and standard relation times.
On the printouts from the HPLC analysis which can be seen in the appendix. From these
printouts it can be seen that the 10ppm sample had a retention time of 1.200 minutes. The 10ppm
standard had a retention time of 1.199 minutes. The sample retention time is within the 1%
allowed meaning that the sample is within specification and passes the test. Also a 20ppm 4-
aminophenol (starting material) was carried out and was compared to the 20ppm standard. The
20ppm 4-aminophenol had a retention time 1.166 minutes. At no point for the printout for the
20ppm standard was there a peak indicating a retention time of 1.166 minutes nor was there a
retention time of 1.166 minutes in the 10ppm sample. It can be concluded from this that there
was no presence of 4-amiophenol in the sample or the standard.
This curve was used to determine the actual concentration of paracetamol in our product. The
equation of the line (y = 60.257x+74.041) It was calculated the actual concentration amount of
paracetamol in our sample was 8.6ppm. The calibration curve had very good linear regression of
0.997 indicating that our standards were made up correctly.
Ultra-Violet Absorbance Identification Test
Absorption of UV or visible radiation generally results from excitation of bonding electrons.
Wavelength of absorption can be correlated with types of bonds species analysed. Molecular
absorption spectroscopy is useful for identifying functional groups in molecules. The
specification for this test is that the specific absorbance for the sample at λmax of 249nm is in the
range of 860-980. When examined using the ultra-violet absorption instrument the specific
absorbance at this λmax was found to be 924nm. This was within the range for the λmax thus
giving a satisfactory result.
Graphite Furnace Atomic Absorption Spectroscopy (GFAAS)
In this test the sample was being analysed for the presence of cadmium. In GFAAS almost 100%
of the sample is atomised electrothermally. This makes the technique much more sensitive than
the Flame AAS. Many elements can be determined at concentrations 1000 times lower than that
of the Flame AAS.
From looking at the printouts from the GFAAS it is clear that from even the calibration at zero
which is picking up cadmium that there is something up the instrument. The problem with the
instrument was that the needle was aligning fine for the first injection but for the second injection

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