Pharmaceutical Industry

Pamantasan ng Lungsod ng Maynila
College of Engineering and Technology

Department of Chemical Engineering
Chemical Process Industries
PHARMACEUTICAL
INDUSTRY
Submitted by:
BS ChE 3 Group 2
Garcia, Ann Clarisse M.
Santos, Amabelle C.
Sison, Bren A.
Torres, Clark Ivan V.
Submitted to:
Engr. Milagros R. Cabangon
Instructor
January 3, 2017
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Pharmaceutical Industry
TABLE OF CONTENTS
Objectives ....................................................................................................... 3
Introduction .................................................................................................... 4
Brief History ................................................................................................... 5
Uses and Applications ..................................................................................... 7
Companies in the Philippines .......................................................................... 8
Classifications................................................................................................. 9
Dosage Form ......................................................................................... 9
Kind of Drug ........................................................................................ 13
Chemical Reaction ............................................................................... 17
Paracetamol .................................................................................................. 36
Manufacturing Process of Paracetamol................................................. 41
Antibiotics ................................................................................................... 45
Manufacturing Process of Penicillin ..................................................... 47
Insulin .......................................................................................................... 54
Manufacturing Process of Insulin......................................................... 56
Vitamins ....................................................................................................... 62
Manufacturing Process of Vitamins ...................................................... 63

References .................................................................................................... 67
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OBJECTIVES
General Objective:
To define the Pharmaceutical Industry and identify the manufacturing

process, the raw materials, unit operations and equipment involved.
Specific Objectives:
• To classify the drugs according to their dosage form, kinds and chemical
reaction.
• To compare the manufacturing process of insulin, paracetamol, penicillin

and multivitamins.
• To identify the different pharmaceutical manufacturing companies in the

Philippines
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PHARMACEUTICAL INDUSTRY
The human lifespan in the United

States has increased since 1900 from 49
years to the present 73 and above years.
This has been due, in part, to the
development of drugs that have controlled
and eliminated many diseases that formerly
were devastating in their action on humans.
The pharmaceutical industry

develops, produces, and markets drugs or pharmaceuticals for use as
medications. Pharmaceutical companies may deal in generic or brand
medications and medical devices.
Pharmaceutical products, more commonly known as medicines or drugs,

are a fundamental component of both modern and traditional medicine. It is
essential that such products are safe, effective, and of good quality, and are
prescribed and used rationally.
The Philippine drug industry has been mainly engaged in the drug
compounding business. However, the drugs now available in the country are the
latest innovations in the field. Moreover, these drugs cure a wide spectrum of
diseases that afflict the populace.
The term “drugs” is widely used in the pharmaceutical industry. Drug is

defined as a substance which has a physiological effect when ingested or
otherwise introduced into the body.
Medicine vs. Drugs
The terms “drugs” and “medicine” are often

mistakenly used as two similar terms. They may
somehow have an overlap in them however these two
have a huge difference from one another.
A medicine is a substance that is designed to

prevent or treat diseases. It is used to improve the
health and promote healing. On the other hand, a
drug is designed to produce a specific reaction in the
body. It may be positive, negative, intentional or a side effect.
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History
TIME DESCRIPTION
Opium is an analgesic that is used as
medications to relieve pain. It is derived
1000 from the poppy plant which is latex and
opium is widely used in China and in the
far East.
Paracelsus was a Swiss alchemist who
introduces laudanum also known as
tincture of opium in the practice of
1525 medicine. Tincture is a medicine that is
made by dissolving the drug in alcohol. And
for laudanum, it is approximately 10%
powdered opium.
Opium is now abused by a lot of people and

China decided to promulgate laws which
1792 prohibits the use of opium. Anyone caught
using or selling opium will be punished by
strangulation.
Local apothecaries expanded from their

1800’s traditional role of distributing botanical
drugs to wholesale manufacture
Friedrich Wilhelm Adam Serturner, a

German chemist, isolates and describes
1805 morphine. Morphine is a pain reliever for
moderate to severe pain. It is derived from
the opium.
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The first Opium War. The British force upon

1839 –
China the trade in opium, a trade the
1842
Chinese had declared illegal.
Pfizer was founded in 1849, by two

German immigrants, initially as a fine
chemicals business. They expanded
1849
rapidly during the American civil war as
demand for painkillers and antiseptics
rocketed.
Paracetamol was discovered. It is also

known as acetaminophen or APAP, which is
1877
a medication to treat pain and fever. It is on
WHO Model List of Essential Medicines.
Diacetylmorphine is synthesized in
Germany. It is widely lauded as a “safe
preparation free from addiction-forming
1898
properties.” Heroin is used in severe painful
conditions, which cannot be treated (pain
reduction) with conventional pain killers
Insulin was discovered by Canadian
physician Frederick Banting and medical
student Charles H. Best. Hormones
1921
extracted from pancreas of dogs were
injected in diabetic dog and found that it is
effective in lowering the glucose level.
The first true antibiotic was discovered. It is

also known as Penicillin. It was discovered
by Alexander Fleming, a professor of
1928
Bacteriology in St. Mary’s Hospital in
London. Penicillin is used to treat infections
caused by bacteria.
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The Pharmaceutical and Healthcare

Association (PHAP) is a business
1946 organization, founded in 1946, that
represents the providers of most of
the Philippines' medicines.
Phenobarbital was among the most widely
used drugs for the treatment of epilepsy
1970’s through the 1970s, and as of 2014, remains
on the World Health Organizations list of
essential medications
Comprehensive Dangerous Drugs Act of

June
2002 was enforced by the Senate. It is a law
7,
against the use, selling and distribution of
2002
dangerous drugs.
The Philippine Drug Enforcement

Agency (PDEA) is the lead anti-drug law
July 7, enforcement agency, responsible for
preventing, investigating and combating
2002
any dangerous drugs,
controlled precursors and essential
chemicals within the Philippines.
Uses
Pharmaceutical products – more commonly known as medicines or drugs – are

a fundamental component of both modern and traditional medicine. It is
essential that such products are safe, effective, and of good quality, and are
prescribed and used rationally. Humans and animals are subjected to the use of
various pharmaceutical products
1. Practice of Diagnosis
2. Treatment of Disease
3. Prevention of Disease
4. Extending the life of a person
5. Pharmaceutical companies discover new drugs for diseases.
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Pharmaceutical Companies in the Philippines
ABBOTT LABORATORIES INC. NOVARTIES PHARMACEUTICALS

Address: Epifanio delos Santos Address: Legaspi, Makati, 1229
Avenue, Metro Manila Metro Manila
PFIZER INCORPORATED SANOFI-AVENTIS INC.

Address: Ayala Life FGU Center, 6811 Address: 3rd Floor, Feliza Building,
Ayala Ave, Makati, 1200 Metro 108 V.A. Rufino St, Makati, Metro
Manila Manila
Wyeth Pharmaceuticals
Address: 16th Floor 8 Rockwell,
UNITED LABORATORIES Hidalgo Drive, Rockwell Center,
Address: Mandaluyong, Philippines Makati City
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Classification of Pharmaceuticals
1. Dosage Form
2. Kind of Drug
3. Chemical Reaction
Classification According to Dosage Form
Syrups
- Concentrated aqueous solutions of sugar
which may contain flavors and coloring
materials and are frequently used as
vehicles, although some syrup do
contain therapeutic agents and as such
are medicaments in their own right
Injectables
- Also known as parental solutions
- These are sterile liquids or suspensions
intended for injection under or through
one or more layers of the skin or mucous
membrane. They must be packaged in
containers which will maintain their
sterility until administered or used, and
which will permit visual inspection.
Ointments
- Semi-solid preparations for external
applications.
- They soften but not necessarily melt
when applied to the skin and function as
vehicles for the application of medicinal
substances or as protectives for the skin.
Capsules
- One of the most commonly used dosage forms for administering medicines
- Made of gelatin shells that contain medicinal substances, both dry and
liquid.
- Advantage: tasteless and easily administered
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Types of Capsules
 Hard Capsule
- consist of two sections, one slipping over the other, completely
surrounding the medicine
 Soft Elastic Capsule
- soft globular shell of gelatin with permanent flexibility. This form is
intended primarily for the administration of oily liquids.
 Pearl Capsule
- also used for oily liquids, although occasionally solid constituents are
inserted with the oil into each pearl.
Hard Capsule Soft Elastic Capsule Pearl Capsule
Classification According to Dosage Form

Pills
- One of the most commonly used dosage
forms for administering medicines.
- Small, solid bodies, of a globular ovoid
shape which are intended to be
swallowed and thereby produce
medicinal action.
- The manufacture of pills is usually
accomplished by kneading and rolling
operations.
- May be coated or uncoated.
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Tablets
- One of the most commonly used dosage
forms for administering medicines
- Unit forms of solid medicinal
substances, or unit forms of
- the medicinal substances with suitable
diluents, prepared by molding or
compressing.
- Most frequently flat and circular
- May be coated or uncoated.
Other Dosage Forms:
Powder Lozenges
Solutions Suspensions
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Tinctures Emulsions
Spray
Liniment
Suppository
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Classification According to Kind of Drug
I. Cardiovascular Drugs
Antihypertensive
- reduce blood pressure
- block nerve impulses that cause arteries to
constrict
- others slow the heart rate and decrease its
force of contraction
- others reduce the amount of certain
hormones in the blood that cause blood
pressure to rise.
- Examples: metoprolol and prazosin, captopril,
enalapril
II. Gastrointestinal Drugs
Antiulcer
- Used to treat peptic ulcers
- Suppresses the secretion of stomach acid
- Examples are Cimetidine, Ranitidine and
omeprazole
- There is formation of a chemical barrier over
an exposed ulcer, thereby protecting it from
stomach acid like sucrafate
Antidiarrheal
- Narcotics and anticholinergics are used to
treat diarrhea because they slow the action of
the bowel.
- Example: loperamide
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III. Respiratory Drugs
Antitussives
- Control coughs by acting on the cough
center in the brain
- Example: codeine
Decongestants
- Constrict the blood vessels in the nose and
sinuses to open up air passages
- Taken orally or as nose drops or spray
- Oral act slowly but does not interfere with
the production of mucus or the movement of
cilia in the respiratory tract
- Nose Drop or Spray provides immediate
relief and slows down the movement of cilia
- Examples: pseudeophrine
IV. Central Nervous System
Sedatives
- Used in the treatment of anxiety or
insomnia selectively reduce activity in the
CNS
- Examples of sedating drugs: barbiturates,
chlordiazepoxide, clorazepate, diazepam,
meprobamate, and axazepam
- Examples of hypnotic drugs: flurazepam,
temazepam and triazolam
Tranquilizers
- Calm activity in some areas of the brain but allow the rest to function
normally
- Allows transmission of some nerve impulses and restrict others
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Types of Tranquilizers
a. Antipsychotic
- Used to treat symptoms of severe
psychiatric disorder
- Drugs most frequently used are the
phenolthiazines such as
chloropromazine, thioridazine and
trifluoperazine
b. Antidepressant
- Examples: amitriptyline and amoxapine, pargyline and phenelzine
c. Analgesic
- Drugs used to relieve pain and falls under two categories:
1. Narcotics
 Derived from opium poppy
 Act on the brain to cause deep analgesia and often drowsiness
 Treats severe pain
 Can cause respiratory depression
 Examples: Pentazocine and Propoxyphene Hydrochloride
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2. Non-narcotics
 widely used non-prescription drugs
 Treats mild pain
 Treatment in symptoms of rheumatoid arthritis
 Examples: aspirin, ibuprofen, acetaminophen
V. Hormones
Antidiabetic
- Induces the pancreas to secrete more insulin
by acting on small groups of cells within the
pancreas that make and store insulin.
- Example is Insuget.
Steroids
- Used to treat inflammatory diseases such as
arthritis or to treat poison ivy, hay fever or
insect bites
- Examples: Methylprednisolone and
prednisone
VI. Anti-infectives
- Used to treat wide variety of bacterial infection
- Produced synthetically or are derived from
molds
- Slow the growth bacteria or cause their death
by interfering production of necessary
nutrients or by damaging their cell membrane
- Aminoglycosides, cephalosporoins,
eryhtromycins, penicillin and tetracyclines are some antibiotics used
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CLASSIFICATION ACCORDING TO CHEMICAL REACTION
1. Alkylation – is the transfer of an alkyl group from one molecule to another.
PHENOBARBITAL USP
Phenobarbital is a barbituric acid derivative

for oral administration and occurs as a white,
odorless, slightly bitter powder that is soluble in
chloroform, freely soluble in alcohol or ether, and
slightly soluble in water. Its saturated solution has
a pH of about 5.6. Chemically, it is 5-ethyl-5-
phenylbarbituric acid with the molecular formula
C12H12N2O3. It possesses specific usefulness in
epilepsy. Like the other barbituric acid derivatives,
it is made from phenyl-ethylmalonic diethyl ester, which is condensed with
urea to form the product. Phenobarbital, a long-acting barbiturate, is a
central nervous system depressant. It is indicated for use as a sedative or
anticonvulsant. It is used for the short-term treatment of sleeplessness, the
relief of anxiety, tension, and fear, and the treatment of certain types of
seizures, especially in emergency situations.
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BARBITAL
Barbital, 5,5-diethylbarbituric acid with molecular

formula C8H12N2O3, is sold under the trade name Veronal. It is
the oldest of the long-acting barbiturates that depresses most
metabolic processes at high doses and is derived through
diethyl malonate. Veronal had hypnotic, sedative, and
anticonvulsant properties. It could calm manic patients and
help melancholic patients to sleep, and was an effective inducer
of sleep in insomniacs.
PROCAINE HYDROCHLORIDE USP
This local anesthetic, 4-Aminobenzoic

acid 2-diethylaminoethyl ester with molecular
formula C13H2ON2O2.HCl, has long been
dispensed under the name Novocain. It is
considered to be less toxic than cocaine, and
furthermore does not have the danger of
habituation. Novocain is indicated for the
production of local or regional analgesia and
anesthesia by local infiltration and peripheral
nerve block techniques. It is used frequently in conjunction with a
vasoconstrictor like epinephrine to secure a prolonged anesthetic action. It is
obtained by first alkylating ethyl-enechlorohydrin with diethylamine, which
is condensed with p-nitrobenzoyl chloride and reduced with tin and
hydrochloric acid to obtain procaine.
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CODEINE NF AND CODEINE PHOSPHATE USP
Codeine, 3-Methylmorphine with

molecular formula C18H21NO3, is an opioid
pain medication as a cough medicine or for
diarrhea. An opioid is sometimes called a
narcotic. Codeine is used to treat mild to
moderately severe pain. Codeine can be
isolated from opium, and for many years the
supply from this source was sufficient to
meet the demand for this sedative and
analgesic drug. Currently demand far exceeds the supply from this source,
but morphine (also obtained from opium, but in much larger amounts, 9 parts
morphine to 1 part codeine) can be methylated to produce codeine. This is a
difficult alkylation as there are three places in the morphine molecule to
which a methyl group can be attached: alcoholic hydroxyl, phenolic hydroxyl,
and tertiary nitrogen. To direct this alkylation to the phenolic hydroxyl and
to reduce alkylation of the tertiary nitrogen, a quaternary nitrogen alkylating
agent, phenyltrimethylammonium hydroxide, is employed. This results in
yields of 90 to 93 percent codeine and some recovery of unalkylated morphine.
The alkylation is carried out with the morphine dissolved in absolute alcohol
in the presence of potassium ethylate. The dimethyl aniline and solvents are
recovered and reused.
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CIMETIDINE
Cimetidine (C10H16N6S), a highly substituted

guanidine, is sold as Tagamet, and is widely used
as an antiulcer medication. Cimetidine is an H2
(histamine) blocker. It acts by blocking the
histamine molecules in the stomach from signaling
the stomach to secrete acid. This reduces acidity in
the stomach. Preparation is by the action of a
substituted guanidine on an amino-thio compound
in the presence of methyl cyanide.
CAFFEINE USP, THEOBROMINE NF, AND THEOPHYLLINE NF
Caffeine, theobromine, and

theophylline are xanthine derivatives
classified as central nervous stimulants,
but differing markedly in their properties.
They can be extracted from a number of
natural sources.
Caffeine, the most

important, has long been
obtained from waste tea
and decaffeinization of
coffee. It can be manufactured synthetically by a number of
processes.
Some have been employed industrially, for instance,

the methylation of theobromine and also total synthesis by
methylation and other reactions based upon urea. A large
demand for caffeine comes from the pharmaceutical industry, but it is also
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used by the soft-drink industry for mildly stimulating beverages such as Coca
Cola, Pepsi Cola, and the other cola drinks.
2. Carboxylation and Acetylation
Carboxylation is where a carboxylic acid group is introduced in a substrate

whereas acetylation introduces an acetyl functional group into a chemical
compound.
SALICYLIC ACID DERIVATIVES USP
The chief derivative of salicylic acid

that is used as a drug is the methyl acetyl
ester, which is known as aspirin. The
manufacture of salicylic acid follows
carboxylation by the Schmitt modification of
the Kolbe reaction.
Aspirin is used to reduce fever or

inflammation and relieve mild to moderate
pain from conditions such as muscle aches,
toothaches, common cold, and headaches. It may also be used to reduce pain
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and swelling in conditions such as arthritis. Aspirin is known as a salicylate

and a nonsteroidal anti-inflammatory drug (NSAID).
ACETAMINOPHEN USP
Acetaminophen (C8H9NO2) is a widely used

analgesic and antipyretic that is an OTC drug.
Combined with codeine it is one of the top five
prescription drugs. Acetaminophen is prepared
by treating p-aminophenol with a mixture of
glacial acetic acid and acetic anhydride.
Acetaminophen is a pain reliever and a

fever reducer. It is used to treat many conditions
such as headache, muscle aches, arthritis, backache, toothaches, colds, and

fevers.
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ACETOPHENETIDINE USP (PHENACETIN)
Acetophenetidine (C10H13NO2), an analgesic and

antipyretic, is the ethyl ether of acetaminophen and is
prepared from p-ethoxyaniline.
3. Condensation and Cyclization
Condensation is the change of the physical state of matter from gas phase
into liquid phase and cyclization is the formation of a ring in a chemical
compound.
The binding together of several molecules by condensation or ring closure to

cause cyclization, with or without the splitting out of a smaller molecule, is a
very important process employed in the manufacture of a considerable number
of pharmaceutical products.
DIAZEPAM USP (VALIUM)
Diazepam is a benzodiazepine
derivative made by a complex series of
reactions, one of which involves
cyclization. This compound was
introduced between 1955 and 1960, and
today is the most prescribed drug in the
United States. It is an antianxiety drug,
often called a tranquilizer. It is prepared
by treating p-chloromethylaniline with
benzoyl chloride and hydroxylamine to produce the benzophenone oxime.
Reaction of the oxime with chloroacetyl chloride in the presence of sodium
hydroxide and subsequent reduction yields diazepam.
Diazepam is used to treat anxiety disorders, alcohol withdrawal

symptoms, or muscle spasms.
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HEXYLRESORCINOL USP (1,3-DIHYDROXY-4-HEXYLBENZENE)
Hexylresorcinol has marked

germicidal properties, and a phenol
coefficient of over 50. It is an organic
compound with local anesthetic,
antiseptic and anthelmintic properties. It
is a valued odorless and stainless
antiseptic commonly employed in a
dilution of 1:1000. It is one of the most
efficient anthelmintics against hookworm
and the like. It is a natural antibacterial mainly used in toothpaste,
anticancer, antioxidant & other oral care applications. In the manufacture of
hexylresorcinol, resorcinol and caproic acid are heated with a condensing
agent, such as zinc chloride, and the intermediate ketone derivative is formed.
This compound is purified by vacuum distillation. After reduction with zinc
amalgam and hydrochloric acid (Clemmensen’s reduction) impure
hexylresorcinol is formed, which can be purified by vacuum distillation.
PHENOLPHTHALEIN NE
Phenolphthalein is an acid-base indicator which is

colorless in acid solution, but turns pink to red as the
solution becomes alkaline. Phenolphthalein is a widely used
cathartic, particularly in proprietary drugs. It is
manufactured by adding melted phenol (10 parts) to a cooled
solution of phthalic anhydride (5 parts) in concentrated
sulfuric acid (4 parts) and heating the mixture 10 to 12 hours
at 120°C. The hot condensation product is poured into boiling
water and boiled with successive changes of hot water. The
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condensate is then dissolved in warm, dilute caustic soda and precipitated

with acetic acid. It may be purified by crystallization from absolute alcohol
after treatment with, and being filtering through, activated carbon.
PIPERAZINE CITRATE USP
Piperazine citrate is used as an

anthelmintic in the treatment of infections
caused by pinworms and roundworms. It is also
employed by veterinarians against various
worms infecting domestic animals, including
chickens. Piperazine is prepared by the
cyclization of ethylene dibromide with alcoholic
ammonia at 100°C. The citrate is formed in
aqueous solution and crystallized out.
THIAMINE HYDROCHLORIDE USP, VITAMIN B1
Thiamine Hydrochloride is the hydrochloride salt

form of thiamine, a vitamin essential for aerobic
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metabolism, cell growth, transmission of nerve impulses

and acetylcholine synthesis. This anti-neuritic vitamin is essential for bodily
growth and the prevention of beriberi. Although thiamine is widely distributed
in many foods, most commercially available quantities are obtained by the
condensation of 6-amino-5-bromomethyl-2-methylpyrimidine hydrobromide
with 5-(hydroxyethyl)-4-methylthiazole, which results in thiamine chloride
hydrochloride.
RIBOFLAVIN USP, VITAMIN B2
Riboflavin is a necessary element of all living cells. It

is quite stable except under excessive exposure to light. It is
considered to be the growth factor of the vitamin B2 complex
and is added on a large scale to bread, flour, and other
dietary and pharmaceutical preparations. It is also involved
in the transfer of oxygen to tissues.
This vitamin is produced as a by-product of the

butanol-acetone fermentation of molasses and by synthesis
starting with 1,3,4-xylidine, D-ribose, aniline, and alloxan.
Vitamin B2, also called riboflavin, is one of 8 B vitamins. All B vitamins

help the body to convert food (carbohydrates) into fuel (glucose), which is used
to produce energy. These B vitamins, often referred to as B-complex vitamins,
also help the body metabolize fats and protein.
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4. Dehydration - involves the loss of a water molecule from the reacting

molecule.
ETHER USP
Ether USP (C4H10O) or diethyl ether is a colorless,

highly volatile, flammable liquid. Ether is used for general
anesthesia and as a solvent in the manufacture of many
pharmaceutical products. Ether and nitrous oxide, both
anesthetics, are manufactured through dehydration
reactions. The very simple and long-used manufacturing
procedure for ether has been the dehydration of alcohol
(denatured with ether) by sulfuric acid. The anesthetic
ether is especially purified and packaged. Much ether,
both USP and commercial grades, is now supplied as a by-product from the
manufacture of alcohol from ethylene.
5. Halogenation - addition of one or more halogens to a compound.
Halogenation, generally chlorination, is used extensively as a chemical

step in the manufacture of various intermediates, such as ethyl chloride or
bromide, and homologs employed in the manufacture of finished
pharmaceutical products. In only a few cases does the chlorine remain in the
finished product. One such compound is chloroform. Chloroform was once
employed as an anaesthetic by inhalation. It is used as a solvent for alkaloids
and other organic chemicals, in chemical analysis, and as a preservative
during aqueous percolation of vegetable drugs, preventing bacterial
decomposition.
CHLOROFORM USP
Chloroform acts locally as a penetrating and fairly

powerful irritant, which may blister if its evaporation is
prevented. It is used in liniments. Taken by mouth, small
doses are carminative, anodyne and antiseptic; it is therefore
used in gastric fermentation and colic. Large doses are
sometimes employed as a vermifuge, but are rather
dangerous. Its main use is by inhalation, for the production of
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general anesthesia. Chloroform is distinctly less safe as an anesthetic than

ether and should be employed only when ether is unavailable or its use
inadmissible for some reason. Chloroform is held by many physicians as
specially suitable for anesthesia in children and during childbirth. Although
alcohol and chlorinated lime were formerly used to make chloroform, it is now
made from acetone and calcium hypochlorite because the reaction is more
rapid and the yield is high. Absolutely pure chloroform decomposes readily
on storing, particularly if exposed to moisture and sunlight, to yield phosgene
and other compounds. The USP requires the presence of a small amount of
alcohol to retard this decomposition (0.5 to 1%).
6. Oxidation - the loss of electrons or an increase in oxidation state by

a molecule.
NICOTINIC ACID USP AND NICOTANAMIDE USP
These are known as

niacin or niacinamide in the
food industry. Niacin
deficiency can cause diarrhea,
confusion (dementia), tongue
redness/swelling, and peeling
red skin.
Niacin is
also known as vitamin B3, one of the B-complex vitamins.
Vitamins help to support the body's ability to make and
break down natural compounds (metabolism) needed for
good health. Niacinamide (nicotinamide) is a different form
of vitamin B3 and does not work the same as niacin. Do not
substitute unless directed by your doctor.
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Niacinamide (nicotinamide) is a form of vitamin B3

(niacin) and is used to prevent and treat niacin deficiency
(pellagra). Niacin deficiency can cause diarrhea, confusion
(dementia), tongue redness/swelling, and peeling red skin.
Niacinamide is often used instead of niacin because it causes
fewer side effects (e.g., flushing). Unlike niacin, niacinamide
does not help correct blood fat levels and cannot be
substituted for niacin if you are being treated for a blood fat
problem (e.g., high cholesterol).
7. Sulfonation - a hydrogen atom on an arene is replaced by a sulfonic

acid functional group in an electrophilic aromatic substitution.
FUROSEMIDE
This is prepared by treating 2,4,5-trichlorobenzoic acid

with chloro-sulfonic acid, and further treatment with
ammonia and furfuryl amine. This is a very potent diuretic
and was fifth most prescribed medicine in 1981.
8. Amination - an amine group is introduced into an organic

molecule.
PROPANOL HCL
This compound, sol under the trade-name

INDERAL, was the second most widely prescribed in
1981. It is used as an antianginal and antihypertensive
drug and is prepared from 1-naphthol and
epichlorohydrin. Subsequent treatment with isopropyl
amine opens the epoxy ring to yield propanolol.
Treatment with HCl yields hydrochloride.
This medication is a beta blocker used to treat high blood

pressure, irregular heartbeats, shaking (tremors), and other conditions. It is
used after a heart attack to improve the chance of survival. It is also used to
prevent migraine headaches and chest pain (angina). Lowering high blood
pressure helps prevent strokes, heart attacks, and kidney problems.
Preventing chest pain can help improve your ability to exercise.
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9. Isolates from plants or animals

Insulin
A hormone that plays a key role

in catalyzing the processes by which
glucose furnishes energy or is stored in
the body as glycogen or fat. The absence
of insulin not only interrupts these
processes, but produces depression of
essential functions, even death.
10. Vitamins
An organic compound and a vital nutrient that an organism requires
in limited amounts. An organic chemical compound is called a vitamin
when the organism cannot synthesize the compound in sufficient
quantities, and it must be obtained through the diet; thus, the term
"vitamin" is conditional upon the circumstances and the particular
organism.
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Different Types of Vitamins
Vitamin A Essential for vision. Lycopene may

lower prostate cancer risk. Keeps
tissues and skin healthy. Plays an
important role in bone growth.
Diets rich in the carotenoids alpha
carotene and lycopene seem to
lower lung cancer risk.
Carotenoids act as antioxidants.
Foods rich in the carotenoids
lutein and zeaxanthin may protect
against cataracts.
Sources of retinoids: beef,

liver, eggs, shrimp, fish,
fortified milk, cheddar
cheese, Swiss cheese
Sources of beta carotene:

sweet potatoes, carrots,
pumpkins, squash,
spinach, mangoes, turnip
greens
Vitamin B1 (Thiamin) Helps convert food into energy.

Needed for healthy skin, hair,
muscles, and brain.
Sources: Pork chops, ham,

soymilk, watermelons,
acorn squash
31 | P a g e
Vitamin B2 (Riboflavin) Helps convert food into energy.

Needed for healthy skin, hair,
blood, and brain.
Sources: Milk, yogurt,

cheese, whole and enriched
grains and cereals, liver
Vitamin B3 (Niacin/Nicotinic Helps convert food into energy.

acid) Essential for healthy skin, blood
cells, brain, and nervous system.
Sources: Meat, poultry, fish,

fortified and whole grains,
mushrooms, potatoes,
peanut butter
Vitamin B5 (Pantothenic Acid) Synthesize and metabolize fats,

proteins and carbohydrates. It is
also required to synthesize CoA
(coenzyme-A).
Sources: meats, whole-

grains (milling may remove
it), broccoli, avocados, royal
jelly, and fish ovaries
32 | P a g e
Vitamin B6 (Pyridoxine) A key factor in protein and glucose

metabolism, as well as in the
manufacturing of hemoglobin.
Vitamin B6 is also involved in
keeping the lymph nodes, thymus
and spleen healthy.
Sources: meats, bananas,

whole-grains, vegetables,
and nuts. When milk is
dried, it loses about half of
its B6. Freezing and
canning can also reduce
content.
Helps the body metabolize

Vitamin B7 (Biotin) or Vitamin H
proteins, fats and carbohydrates.
Helps the body process glucose. It
also contributes towards healthy
nails, skin and hair. It is therefore
found in many cosmetic and health
products for the skin and hair.
However, it cannot be absorbed
through hair or skin.
Sources: egg yolk, liver,

some vegetables
Vitamin B9 (Folic acid) Vital for new cell creation. Helps

prevent brain and spine birth
defects when taken early in
pregnancy; should be taken
regularly by all women of
childbearing age since women may
not know they are pregnant in the
first weeks of pregnancy.
33 | P a g e
Sources: Fortified grains &

cereals, asparagus, okra,
spinach, turnip greens,
broccoli, legumes like black-
eyed peas and chickpeas,
orange juice, tomato juice
Vitamin B12 (Cobalamin) Ensures the proper functioning

and health of nerve tissue, brain
function, and red blood cells.
Sources: fish, shellfish,

meat, poultry, eggs, milk
and dairy products, some
fortified cereals and soy
products, as well as fortified
nutritional yeast
Vitamin C (Ascorbic acid) Foods rich in vitamin C may lower

the risk for some cancers,
including those of the mouth,
esophagus, stomach, and breast.
Long-term use of supplemental
vitamin C may protect against
cataracts.
Sources: Fruits and fruit

juices (especially citrus),
potatoes, broccoli, bell
peppers, spinach,
strawberries, tomatoes,
Brussels sprouts
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Vitamin D (Calciferol) Helps maintain normal blood

levels of calcium and phosphorus,
which strengthen bones. Helps
form teeth and bones.
Sources: Fortified milk or

margarine, fortified cereals,
fatty fish
Vitamin E An antioxidant. It plays a role in

your immune system and
metabolic processes.
Sources: Cabbage,
vegetable oils, margarine,
nuts and seeds, leafy greens
Vitamin K Activates proteins and calcium

essential to blood clotting. May
help prevent hip fractures
Sources: Cabbage, liver,

eggs, milk, spinach,
broccoli, sprouts, kale,
collards, and other green
vegetables
35 | P a g e
PARACETAMOL
Paracetamol or acetaminophen (USAN) is a widely used over-the-counter

analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for
the relief of headaches, other minor aches and pains, and is a major ingredient
in numerous cold and flu remedies. In combination with opioid analgesics,
paracetamol can also be used in the management of more severe pain such as
post surgical pain and providing palliative care in advanced cancer patients. The
onset of analgesia is approximately 11 minutes after oral administration of
paracetamol, and its half life is 1–4 hours.
Three Processes Involved in the Manufacture of Paracetamol Tablets
1. Direct Compression
This is used when a group of ingredients can be blended and placed in a

tablet press to make a tablet without any of the ingredients having to be changed.
It is not very common method because many tablets have active pharmaceutical
ingredients which will not allow for direct compression due to their concentration
or the excipients used in formulation are not conducive to direct compression.
2. Wet Granulation Method
The most widely used process of agglomeration in pharmaceutical industry

is wet granulation. Wet granulation process simply involves wet massing of the
powder blend with a granulating liquid, wet sizing and drying.
Limitations of wet granulation:
 The greatest disadvantage of wet granulation is its cost. It is an expensive

process because of labor, time, equipment, energy and space
requirements.
36 | P a g e
 Loss of material during various stages of processing

 Stability may be major concern for moisture sensitive drugs
 Multiple processing steps add complexity and make validation and control
difficult
3. Dry Granulation Method
When tablet ingredients are sensitive to moisture or are unable to

withstand elevated temperatures during drying, and when the tablet ingredients
have sufficient inherent binding or cohesive properties, slugging may be used to
form granules.
A. Slugging
The material to be granulized is first made into a large compressed mass

or "slug" typically by way of a tablet press using large flat-faced tooling.
A fairly dense slug may be formed by allowing sufficient time for the air to
escape from the material to be compacted.
Compressed slugs are then comminuting through a desired mesh screen

manually or automatically as for example by way of a comminuting mill.
Various disadvantages of slugging include single batch processing,

frequent maintenance changeover, poor process control, poor economies of scale,
low manufacturing throughput per hour, excessive air, sound pollution,
increased use of storage containers, more energy and time required to produce
1 Kg of slugs than 1 Kg of roller compact.
B. Roll Compaction
Particles are consolidated and densified by passing the material between

two high-pressure rollers.
The densified material from a roller compactor is then reduced to a uniform

granule size by milling.
Roller compaction dry granulation process is capable of handling a large

amount of material in a short period of time.
This is suitable for compounds that either have a low melting point or
degrade rapidly during heating, as the method does not involve any drying step
37 | P a g e
RCDG is useful technique for processing of drugs having low and

inconsistent bulk and tap densities with very fine and inconsistent particle sizes
and/or poor flow properties and poor compatibility
Because of its advantages, roll compaction is being increasingly used as

a granulation technique.
Raw Materials
Raw Material Description/Role

Acetaminophen  Active Ingredient
 Contain medicinal properties
Magnesium Stearate  Lubricant

 Reduces the friction between the
surfaces of manufacturing
equipment and that of organic
solids
 Ensure the continuation of an
operation
 Usually 0.25%–5.0%, w/w
Maize Starch  Binder
 Dry powder which is added to
promote cohesive compact during
pressing
 Provides mechanical strength to
the tablet
 5 to 20% of tablet weight
 Also acts as a disintegrant
 Helps the medicine to dissolve and
be taken up by the body so that it
can act more quickly
38 | P a g e
Powdered Cellulose  Disintegrant

 Helps the tablet to break down into
small fragments, when it is
ingested
 Helps the medicine to dissolve and
be taken up by the body so that it
can act more quickly
Preparation of Acetaminophen
1. Nitration of Phenol
 Phenol (hydroxybenzene) will react with sodium nitrate (an oxidizing agent)
in the presence of sulfuric acid to produce a mixture of structural isomers
of nitrophenol.
 When concentrated sulfuric acid (H2SO4) is added to sodium nitrate
(NaNO3) the following reaction occurs:
 H2SO4 + 2NaNO3 → Na2SO4 + 2HNO3
 Then, in excess sulfuric acid, reactive nitronium ion, NO2+, is produced:
 HNO3 + H2SO4 → NO2+ + HSO4- + H2O
 The nitronium ion, NO2+, attacks the benzene ring of phenol to produce a
mixture of various structural isomers of nitrophenol.
 The OH (hydroxyl) functional group of phenol (hydroxybenzene) is said to
activate the benzene ring at the 2- and 4- positions. This results in the
formation of 2-nitrophenol and 4-nitrophenol.
 4-nitrophenol can be separated from the mixture containing 2-nitrophenol
by steam distillation: 2-nitrophenol forms fewer hydrogen bonds with
water or other nitrophenol molecules than 4-nitrophenol so it is more
volatile in steam than 4nitrophenolol.
39 | P a g e
2. Reduction of a Nitro Group to Amine

 Oxygen is lost from the nitro group of 4-nitrophenol and hydrogen is added
to form 4-aminophenol.
 A catalyst (platinum) is required to provide a surface for the reaction to
take place on.
 The 4-nitrophenol molecules are held to the surface of the catalyst by weak
forces of attraction, which then weakens the strong covalent bonds in the
nitro group making it vulnerable to attack by hydrogen.
3. Formation of Amide
 4-aminophenol, suspended in water at room temperature readily reacts
with ethanoic anhydride (acetic anhydride) to produce a precipitate of the
amide paracetamol (acetaminophen)
40 | P a g e
Unit Processes and Operations in Paracetamol Tablet Production
Unit Processes and Operations Equipment Used

Milling
 All raw materials are weighed
separately in sterile canisters to
determine if the ingredients meet
pre-determined specifications for
the batch size and dosage amount.
 They are milled using cutter mil to
produce fine powders.
Cutter Mill
Mixing
 Maize starch, the active ingredient
(acetaminophen), and part of the
lubricant (magnesium stearate) are
mixed together in a cone mixer.
 Produces homogeneous mixture
Cone Mixer
Roll Compaction
 Particles are consolidated and
densified by passing the material
between two high pressure rollers.
 Generally, from 7/8 to 1 inches
(2.22 to 2.54 centimeters) in size.
Roller Compactor
41 | P a g e
Milling/Granulation
 The densified material from a roller
compactor is then reduced to a
uniform granule size by milling.
 Slugs are granulated and screened
through a machine called a
Fitzpatrick mill to obtain the
correct granule size.
Fitzpatrick Mill
Mixing
 The remaining carnauba wax is
added to the mixture for easier
ejection of tablet from pressing.
Cone Mixer
Pressing
 The mixture is compressed into
tablets by rotary tablet machine.
 On rotary tablet machines, the
mixture runs through a feed line
into a number of dye cavities which
are situated on a large steel plate.
 The plate revolves as the mixture is
dispensed through the feed line,
rapidly filling each dye cavity.
 Punches, both above and below the
dye cavities, rotate in sequence
with the rotation of the dye cavities. Rotary Tablet Machine
 Rollers on top of the upper
punches press the punches down
onto the dye cavities, compressing
42 | P a g e
the mixture into tablets, while

roller-activated punches beneath
the dye cavities lift up and eject the
tablets from the dye platform.
Packaging
 The tablets are transferred to the
counter and packaged.
 Covered and sealed with aluminum
sheets.
 They are then labeled and packed.
Blister Packaging Machine
43 | P a g e
Process Layout
Preparation of • Acetaminophen is produced in the laboratory
Acetaminophen by processing the phenol.
• All raw materials are weighed in individual
Milling canisters, and milled to meet specific size
requirement.
• All raw materials are mixed and produces a
Mixing
homogeneous mixture.
• Produces 7/8 to 1 inches (2.22 to 2.54
Roll Compaction centimeters) densified and consolidated
particles. Produces slugs
• Slugs are reduced to the required uniform
Granulation
size of slug.
• The remaining lubricant (carnauba wax) is
Mixing
added.
Pressing • Slugs are transformed to a tablet.
• Tablet produced are packaged and ready to

Packaging
be delivered.
Equipment Layout
44 | P a g e
ANTIBIOTICS
The term antibiotic is a broad one, defined by Waksman as “a substance
produced by microorganisms, which has the capacity of inhibiting the growth
and even of destroying other microorganisms by the action of very small amounts
of the antibiotics.” Approximately 3000 substances come under this
classification, but only about 70 have the necessary combination of patient
safety, antimicrobial action, and stability. Penicillins, erythromycin, tetracycline,
and cephalosporins are among the widely used.
Penicillin
Penicillin is the most famous of

all antibiotics, named for the fungal
mold Penicillium notatum from which it
is derived. Penicillin acts by destroying
the cell wall of bacteria.
Penicillin is active against a

number of types of bacteria including
Streptococcus pneumoniae, Listeria,
Neisseria gonorrhoea, Clostridium,
Peptococcus, and Peptostreptococcus. Penicillium fungi
Most staphylococci now are

resistant to penicillin. Today, many derivatives of penicillin are available which
act on more types of bacteria than penicillin itself.
The name "penicillium" was taken from the Latin "penicillum" meaning "a
painter's brush" because the fronds of the fungus were thought to look like a
painter's brush.
History and Discovery of Penicillin
Time Event
Alexander Fleming discovered
that the Staphylococcus culture
September 1928 he had mistakenly left growing in
open was contaminated with a
mould which had destroyed the
45 | P a g e
bacteria. The mould was later

classified as Penicillium
notanum.
Alexander Fleming
1939 Dr. Howard Florey and Dr. Ernst

Chain started their own
research on penicillin. They
managed to purify penicillin in a
powdered form.
Howard Florey Ernst Chain
Albert Alexander, a 43-year old

1941 policeman, became the first
recipient of the Oxford penicillin.
Anne Miller became the first
March 1942 civilian patient to be successfully
treated with penicillin.
Penicillin proved to be the most
1943
affective antibiotic to date.
Dr. Fleming, Dr. Florey, and Dr.
1945 Chain all win the Nobel Prize in
Physiology or Medicine.
Raw Materials
Microorganisms can be grown in large vessels called fermenters to produce

useful products such as antibiotics (like penicillin). Industrial fermenters usually
have an air supply to provide oxygen for respiration of the microorganisms, a
stirrer to keep the microorganisms in suspension and maintain an even
46 | P a g e
temperature a water-cooled jacket to remove heat produced by the respiring

microorganisms
The antibiotic, penicillin, is made by growing the mould Penicillium, in a

fermenter. The medium contains sugar and other nutrients. The Penicillium only
starts to make penicillin after using up most of the nutrients for growth. Other
raw materials used in bioprocess system include:
 pH 6.5  Glucose
 Oxygen  80% ethanol
 Nitrogen: corn steep liquor  phenyl acetic acid
 Penicillium fungi (Penicillium  Probenecid
chrysogenum)
Manufacturing Process of Penicillin
Unit Operations & Processes Equipment

Medium Preparation
Medium preparation is necessary in
bioprocess which as it generally
involves the use of microorganism to
achieve their products. In the case of
the Penicillium fungus, the medium
usually contain its carbon source
which is found in corn steep liquor
and glucose. Medium also consist of
salts such as Magnesium sulfate,
Potassium phosphate and Sodium
nitrates. They provide the essential Medium Preparation Tanks
ions required for the fungus metabolic
activity.
47 | P a g e
Heat Sterilization
Medium is sterilized at high heat and
high pressure usually through a
holding tube or sterilize together with
the fermenter. The pressurized steam
is use usually and the medium is
heated to 120°C at 30 psi or twice of
atmospheric pressure. High
temperature short time conditions are
used to minimize degradation of
Sterilization Machine
certain components of the media.
Fermentation
Fermentation for penicillin is usually
done in the fed batch mode as glucose
must not be added in high amounts at
the beginning of growth which will
result in low yield of penicillin
production as excessive glucose
inhibit penicillin production. In
addition to that, penicillin is a batch
mode ideal for such products as it
allows the high production of
penicillin. The typical fermentation
conditions for the Penicillium mold,
secondary metabolite of the fungus,
therefore, the fed-usually requires
temperatures at 20-24°C while pH
conditions are kept in between 6.0 to
6.5. The pressure in the bioreactor is Fermenters
usually much higher than the
atmospheric pressure (1.02 atm) this
is to prevent contamination from
occurring as it prevents external
contaminants from entering. Sparging
of air bubbles is necessary to provide
sufficient oxygen the viability of the
fungus.
48 | P a g e
Broth Filtration
The main objective of broth filtration
is to remove any microbial cells and
any large solid particles such as, cell
fragments, soluble and insoluble
medium components, other metabolic
products, intact micro-organisms.
During the filtration, the micro-
organisms are captured in a
concentrated cake, which looks like
sand, sludge or paste. The filter drum,
partially submerged in the trough of
broth, rotates slowly. Filtrate and
washings are kept separate by the
segments in the drum. The liquid is Rotary Vacuum Filter
drawn through the filter and a cake of
solids builds up on the outer surface.
Inside the drum, the filtrate is moves
from the end of the cylindrical drum
onto a storage tank.
Cooling
From filtration, the penicillin rich
solution is cooled at 5°C. This helps
reduce enzyme and chemical
degradation during the solvent
extraction. Acidify (H2SO4) to a pH of
2.0, resulting in an acid (and
extractable) form of penicillin.
Cooling Machine
49 | P a g e
Solvent Extraction
Solvent-extract in a Podbielniak
countercurrent rotating contactor
using a 1:10 volume of amyl acetate,
giving a penicillin purity 75 to 80%.
Reverse the extraction at a pH of 7.5
into an aqueous solution with
enhanced concentration and purity.
Podbielniak Centrifugal Contactor

Carbon Treatment
The penicillin rich solution is then
treated with 0.25-5% activated carbon
to remove pigments and impurities.
Carbon Filtering Machine

Solvent Recovery
The penicillin solvent is usually
recovered by distillation. First the
solvent is vaporized from the solution,
then the low boiling volatile
components are separated from the
less volatile components in a column,
and finally condensation is used to
recover the volatile solvent fraction.
Distillation Tank
50 | P a g e
Crystallization
Crystallization is essentially a
polishing step that yields a highly
pure product and is done through
phase separation from a liquid to a
solid. To begin the process a
supersaturated solution, where there
are more dissolved solids in the
solvent than can ordinarily be
accommodated at that temperature,
must be obtained through cooling,
drowning, solvent evaporation, or by
Crystallizer
chemical reaction. Batch
crystallization is the most the most
used method for polishing penicillin.
Crystal Washing
Even though the penicillin crystals are
pure in nature, adsorption and
capillary attraction can cause
impurities from its mother liquor on
their surfaces and within the voids of
the particulate mass. Thus, the
crystals must be washed and pre-
dried in a liquid in which they are
relatively insoluble. For this purpose,
anhydrous i-propanol, n-butanol or Industrial Washing Machine
another volatile solvent is used.
Drying
Drying stabilizes heat sensitive
products like penicillin. The drying of
penicillin must be carried out with
extreme care to maintain its chemical
and biochemical activity, and ensure
that it retains a high level of activity
after drying. The 3 most used methods
for drying would be: Lyophilization,
Vacuum Band Dryer
Spray Dryers, Vacuum Band Dryers.
51 | P a g e
Storing and Packaging

Penicillin salt is stored in containers
and kept in a dried environment. It
will then be polished and packaged
into various types of products. Dosage
of the penicillin is determined by
clinical trials that are done on this
drug.
Packaging Machine
52 | P a g e
Plant Layout
Equipment Layout
53 | P a g e
INSULIN
Insulin is a hormone made by the pancreas that allows your body to use
glucose from carbohydrates in the food for energy. Insulin helps keeps your blood
sugar level from getting too high (hyperglycemia) or too low (hypoglycemia).
Insulin is produced by cells in the pancreas, called the islets of Langerhans.
These cells continuously release a small amount of insulin into the body, but
they release surges of the hormone in response to a rise in the blood glucose
level.
Without insulin, the blood glucose builds up in the blood and the cells are
starved of their energy source. Some of the symptoms that may occur include
fatigue, constant infections, blurred eye sight, numbness, tingling in the hands
or legs, increased thirst and slowed healing of bruises or cuts.
HISTORY OF INSULIN
TIME EVENT
1869 Paul Langerhans, a medical student in Berlin
discovers a distinct collection of cells within the
pancreas. These cells would later be called the
Islets of Langerhans.
1901 Eugene Opie discovers that the Islets of

Langerhans produce insulin and that the
destruction of these cells resulted in diabetes.
1921 In Toronto, Canada, Dr Frederick Banting and

medical student Charles Best perform
experiments on the pancreases of dogs. Professor
John Maceod provided Banting and Best with a
laboratory and dogs to carry out the experiments.
The pancreas of a dog was removed, resulting in
the dog displaying the signs of diabetes.
54 | P a g e
The pancreas was sliced and ground up into an

injectable extract and injected a few times a day
into the dog which helped the dog to regain health.
Given the early success, Macleod wanted to see

more evidence that the procedure worked and
provided pancreases from cows to make the
extract which was named ‘insulin’.
1922 The first patient, Leonard Thompson a 14 year old

boy with type 1 diabetes is given the first medical
administration of insulin. Previously patients with
type 1 diabetes would be put onto starvation diets
and would have only months to live. Leonard lived
another 13 years before succumbing to
pneumonia.
1950 NPH, an intermediate acting insulin, is marketed

by Danish company Novo Nordisk.
1955 Insulin is sequenced by Frederick Sanger, and is

the first protein to be fully sequenced. In1958
Sanger receives the Nobel Prize in Chemistry for
his research in this area. Insulin becomes the first
human protein to be chemically synthesized.
1996 Eli Lilly markets the analogue insulin lispro

under the trade name Humalog. Analogue insulin
is a genetically modified form of insulin whereby
the amino acid sequence is altered to change how
the insulin is absorbed, distributed, metabolised
and excreted.
2006 Sanofi manufactured inhalable insulin under the

brand of Afrezza and insulin pump treatment
becomes available.
55 | P a g e
TYPES OF INSULIN
MANUFACTURING PROCESS OF INSULIN

A. INSULIN EXTRACTION FROM PANCREAS OF ANIMALS
RAW MATERIALS
Pancreas Glands from Beef or Hogs
Insulin was extracted from the pancreas of cattle and
pigs and purified. The chemical structure of insulin in
these animals is only slightly different than human
insulin, which is why it functions so well in the human
body.
UNIT OPERATIONS AND PROCESSES INVOLVED FOR THE
MANUFACTURING OF INSULIN
UNIT OPERATIONS/PROCESSES EQUIPMENT
PREPARATION OF RAW Rotocut Grinder
MATERIALS
Beef and pork pancreas glands
are refrigerated at -20℃, rotoground,
and the meat slurry is treated with
ethyl alcohol after acidification.
56 | P a g e
EXTRACTION Extraction Tanks

With the use of continuous
countercurrent extraction in, six
continuous centrifuges over
extraction tanks, the gland slurry is
extracted with acidulated alcohol.
CENTRIFUGATION Basket Centrifuge

From the sixth centrifuge, the
cake is processed in a hot-fat fry tank
and discharged through another
centrifuge to separate waste fat from
“fried residue”, which is drummed and
sold.
PURIFICATION Extraction Centrifuge Unit

The crude alcoholic extract is run
from two strong extraction-centrifuge
units into a collection tank from which
the extract is neutralized with
ammonia and filter aid added.
EVAPORATION Evaporator
In evaporators, the first stage removes
alcohol, with subsequent waste-fat
separation. The concentrated extract
is filtered and conducted to the first
salting-out tank .
57 | P a g e
B. RECOMBINANT DNA METHOD

PROCESS FLOW DIAGRAM
RAW MATERIALS
1. BAKER’S YEAST
Drug companies use GM Baker's yeast to make the peptide hormone
insulin and other drugs. For decades, human insulin for diabetic medication has
been produced in genetically modified Baker's yeast by Novo Nordisk, a GMO
pharmaceutical company which is a sister company to Novozymes, a producer
of genetically engineered food enzymes.
2. Nurturing solution for yeast

Sugar Amino Acids
Salt
Water
Vitamins and Minerals
58 | P a g e
MANUFACTURING PROCESS
PREPARATION OF RAW MATERIALS
Synthesizing human insulin is a multi-step biochemical process that

depends on basic recombinant DNA techniques and an understanding of the
insulin gene. DNA carries the instructions for how the body works and one small
segment of the DNA, the insulin gene, codes for the protein insulin.
Manufacturers manipulate the biological precursor to insulin so that it grows
inside simple bacteria.
The insulin gene is a protein consisting of two separate chains of amino
acids, an A above a B chain, that are held together with bonds. Amino acids are
the basic units that build all proteins. The insulin A chain consists of 21 amino
acids and the B chain has 30.
Manufacturers need the two mini-genes: one that produces the A chain
and one for the B chain. Since the exact DNA sequence of each chain is known,
they synthesize each mini-gene's DNA in an amino acid sequencing machine.One
method of manufacturing insulin is to grow the two insulin chains separately.
This will avoid manufacturing each of the specific enzymes needed.
Manufacturers first insert the plasmids into yeast. They insert it next to
the LacZ gene. Next to this gene is the amino acid methionine, which starts the
protein formation. The recombinant plasmids are mixed up with the yeast cells.
Plasmids enter the bacteria in a process called transfection. Manufacturers can
add to the cells DNA ligase, an enzyme that acts like glue to help the plasmid
stick to the bacterium's DNA.
59 | P a g e
FERMENTATION
Yeast is a living organism, it needs
a nourishing environment. A nourishing
solution that contains water, sugars,
salts, vitamins & minerals, and amino
acids. The modified yeast is warmed to 30
℃, the resulting broth is left for 72 hours,
and it starts feeding and fermenting. It
also secretes insulin molecules.
The bacteria synthesizing the
insulin then undergo a fermentation process. They are grown at optimal
temperatures in large tanks in manufacturing plants. The millions of bacteria
replicate roughly every 20 minutes through cell mitosis, and each expresses the
insulin gene.
PURIFICATION
The fermentation will produce a
milky broth that needs to be purified.
Purification begins with a spin in the
centrifuge, filtration and 24 hour stay in a
cartridge column. Procedures used
include an ion-exchange column, reverse-
phase high performance liquid
chromatography, and a gel filtration
chromatography column.
Manufacturers can test insulin batches to ensure none of the bacteria's
proteins are mixed in with the insulin. They use a marker protein that lets them
detect yeast DNA. They can then determine that the purification process removes
the yeast.
DRYING
After a second round of purification. The
insulin needs to be dried but it should not use
heat since insulin degrades under warm
temperatures so they dry it in a sci-fi drying room
just above freezing for 24 hours.
After a second round of purification. The
insulin needs to be dried but it should not use
60 | P a g e
heat since insulin degrades under warm temperatures so they dry it in a sci-fi
drying room just above freezing for 24 hours.
PACKAGING
The powdered insulin should be diluted in
distilled water, the glass vials where the insulin will
be placed is washed, dried and sterilized to around
300℃ to ensure that there is no contamination.
EQUIPMENT LAY-OUT
61 | P a g e
VITAMINS
RAW MATERIALS
VITAMINS (SYNTHETIC/NATURALLY DERIVED)
Vitamins can be derived from plant or animal products, or produced
synthetically in a laboratory. Vitamin A, for example, can be derived from
fish liver oil, and vitamin C from citrus fruits or rose hips. Most commercial
vitamins are made from synthetic vitamins, which are cheaper and easier
to produce than natural derivatives. So vitamin A may be synthesized from
acetone, and vitamin C from keto acid.
There is no chemical difference between the purified vitamins
derived from plant or animal sources and those produced synthetically.
Different laboratories may use different techniques to produce synthetic
vitamins, as many can be derived from various chemical reactions.
ADDITIVES
Vitamin tablets or capsules usually contain additives that aid in the
manufacturing process or in how the vitamin pill is accepted by the body.
Filler Microcrystalline cellulose,

lactose, calcium, or malto-dextrin
are added to many vitamins as a
filler, to give the vitamin the proper
bulk.
Lubricant and Flow Agent Magnesium stearate or stearic

acid is usually added to vitamin
tablets as a lubricant, and silicon
dioxide as a flow agent. These
additives help the vitamin powder
run smoothly through the tablet-
making or encapsulating machine.
Disintegration Agent Modified cellulose gum or
starch is often added to vitamins as
a disintegration agent. That is, it
62 | P a g e
helps the vitamin compound break

up once it is ingested.
Coatings Many coatings are made from a

cellulose base. An additional
coating of carnauba wax is often
put on as well, to give the tablet a
polished appearance.
MANUFACTURING PROCESS
PRELIMINARY CHECK
A vitamin manufacturer purchases raw vitamins and other ingredients
from distributors. Raw vitamins from a reputable distributor arrive with a
Certificate of Analysis, stating what the vitamins are and how potent they are. In
many cases, the manufacturer will nevertheless test the raw materials or send
samples to an independent laboratory for analysis. If herbs are to be an
ingredient in the vitamin capsule, these must be tested for identity and potency,
and for possible bacterial contamination as well.
PREBLENDING
The raw vitamins arrive at the manufacturer in
a fine powder, and they need no preliminary
processing. However, if the raw materials are not
finely granulated, they will be run through a mill and
ground. Some vitamins may be preblended with a
filler ingredient such as microcrystalline cellulose or
malto-dextrin, because this produces a more even
granule which aids further processing steps.
Laboratory technicians may run test batches when
working with new ingredients and determine if
preblending is necessary.
DRYING
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The mixture is then dried in a dryer. After drying, the formula may be in
chunks as large as a dime. These chunks are sized by being run through a mill.
The mill forces the chunks through a small hole of the desired diameter of the
granule. These granules can then be weighed and mixed.
If the lot in the mixer has been approved, workers tote the mixture to the
encapsulating machine and dump it in a hopper. At the beginning of a batch,
workers will test-run the encapsulating
machine and check that the capsules are
the proper and consistent weight. Workers
also check the capsules visually to see if
they seem to be splitting or dimpling. If the
test batches run correctly, workers run the
entire batch. The vitamin mixture flows
through one hopper, and another hopper
holds whole gelatin capsules. The capsules
are broken into halves by the machine. The
bottom half of the capsule falls through a
funnel into a rotating dosing dish. Then the
machine measures a precise amount of the powdered vitamin mixture into each
open capsule half. Tamping pins push the powder down. Then the top halves of
the capsules are pushed down onto the filled bottoms.
CAPSULATING
The filled vitamin capsules are next run through a
polishing machine. The vitamins are circulated on
a belt through a series of soft brushes. Any excess
dust or vitamin powder is removed from the
exterior of the capsules by the brushes. The
polished capsules are then poured onto an
inspection table. The inspection table has a belt of
rotating rods. The vitamins fall in the grooves
between the rods, and the vitamins rotate as the
rods turn. Thus, all sides of the vitamin are visible
for the inspector to see. The inspector removes any capsules that are too long,
split, dimpled, or otherwise imperfect. The vitamins that pass inspection are then
taken over to the packaging area.
TABLETING
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The vitamin powder then flows through the

hopper to a filling station beneath, and flows from
there to a rotating table. The rotating table may be 2-
4 ft (0.6-1.2m) in diameter, or even bigger, and is
fitted with holes on its outside edge that hold dies in
the shape of the desired tablet (oval, round, animal,
etc.). The dies are interchangeable, so the same table
can produce whatever shape the manufacturer
wishes, as long as the proper dies are installed. The
vitamin powder flows from the filling station to fill the
die. When the table rotates, the filled die moves into
a punch press. When the upper and lower halves of the punch meet, 4-10 tons
(3.6-9 metric tons) of pressure is exerted on the vitamin powder. The pressure
compresses the vitamin powder into a compact tablet. The punch releases, and
the lower punch lifts to eject the tablet. The speed of the rotation of the table
determines how many tablets are made per minute. The tablets eject onto a
vibrating belt which vibrates any loose dust off the tablets. The tablets then are
moved to the coating area.
COATING
Vitamin tablets are usually
coated for a variety of reasons. The
coating may make the tablet easier
to swallow. It may mask an
unpleasant taste, and it may give
the tablet a pleasant color. A
manufacturer may coat in two
different colors tablets that are the same size and shape, for identification.
Tablets may also be given an enteric coating—a pH sensitive chemical coating
that resists gastric acid. Tablets with an enteric coating will not break open in
the stomach, but move to the intestine before dissolving. Other coatings
determine the timing of the tablet's dissolution, so the vitamins can be absorbed
slowly, or all at once, depending on what is appropriate to that tablet.
Once the tablets are taken from the tableting area, they are placed in the
coating pan. The coating pan is a large rotating pan surrounded by one to six
spray guns operated by pumps. As the tablets revolve in the pan, the pumps
spray coating over them. Many tablets also receive a second coating of carnauba
wax. After air drying, the tablets are ready for packaging. The packaging step is
the same for tablets as for capsules.
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PACKAGING
Packaging the vitamins takes
several steps, and different
machines carry out these steps. So
in the packaging area, the vitamins
pass through a row of machines.
Once the vitamins are dumped in
the hopper of the first machine, no
human touches them. The worker
sets the machine to count out the
required number of capsules or tablets per bottle, and the rest is done
automatically. The capsules or tablets fall into a bottle, and the bottle is passed
to the next machine to be sealed, capped, labelled, and shrink-wrapped. The
finished bottles are then set in boxes and are ready for distribution.
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REFERENCES
Austin, G., & Austin. (1984). Shreve's Chemical Process Industries. New York:
McGraw-Hill.
Bender, D. (1992). Nutritional Biochemistry of the Vitamins. Cambridge
University Press.
Gebel, E. (2013, July). Making Insulin. Retrieved from Diabetes Forecast:
http://www.diabetesforecast.org/2013/jul/making-
insulin.html?referrer=
Goodwin, K. (2015, December 27). Manufacture of Insulin. Retrieved from
Slideshare: http://www.slideshare.net/kelly_goodwin/insulin-
manufacture
How Its Made (Director). (2011). How Its Made: Pills [Motion Picture].
Insulin. (n.d.). Retrieved from Diabetes Co UK:
www.diabetes.co.uk/insulin/human-insulin.html
Lieberman, S., & Nancy, B. (1990). The Real Vitamin and Mineral Book. Avery
Publishing Group.
Nordisk, N. (Director). (2012). How Do They Do It. How Insulin Is Made [Motion
Picture].
Woodward, A. (2009). Insulin. Retrieved from How Products Are Made:
http://www.madehow.com/Volume- 7/Insulin.html
Woodward, A. (2009). Vitamin. Retrieved from How Products are Made:
www.madehow.com/Volume-3/Vitamin.html
(2016, December). Retrieved from Penicillin:
https://penicillin.wikispaces.com/General+bioprocess+flow
(2016, December 28). Retrieved from Paracetamol (Acetaminophen):
http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/paracet_text.htm
Nordqvist, C. (2016, November 3). Vitamins: What They Are and What They Do.
Retrieved from Medical News Today:
http://www.medicalnewstoday.com/articles/195878.php
Penicillin. (2016, December). Retrieved from How is it Made into a Drug?:
https://penicillin.wikispaces.com/How+is+it+Made+into+a+Drug%3F
Tait, K. D. (n.d.). Encyclopedia of Occupational Health and Safety. Retrieved from
Pharmaceutical Industry:
http://www.ilocis.org/documents/chpt79e.htm
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Pamantasan ng Lungsod ng Maynila

College of Engineering and Technology

Chemical Process Industries

Manufacturing Process of Insulin......................................................... 56

Manufacturing Process of Vitamins ...................................................... 63

To define the Pharmaceutical Industry and identify the manufacturing

• To compare the manufacturing process of insulin, paracetamol, penicillin

• To identify the different pharmaceutical manufacturing companies in the

The human lifespan in the United

The pharmaceutical industry

Pharmaceutical products, more commonly known as medicines or drugs,

The term “drugs” is widely used in the pharmaceutical industry. Drug is

Medicine vs. Drugs

The terms “drugs” and “medicine” are often

A medicine is a substance that is designed to

Opium is now abused by a lot of people and

Local apothecaries expanded from their

Friedrich Wilhelm Adam Serturner, a

The first Opium War. The British force upon

Pfizer was founded in 1849, by two

Paracetamol was discovered. It is also

The first true antibiotic was discovered. It is

The Pharmaceutical and Healthcare

Comprehensive Dangerous Drugs Act of

The Philippine Drug Enforcement

Pharmaceutical products – more commonly known as medicines or drugs – are

Pharmaceutical Companies in the Philippines

ABBOTT LABORATORIES INC. NOVARTIES PHARMACEUTICALS

PFIZER INCORPORATED SANOFI-AVENTIS INC.

Classification According to Dosage Form

Hard Capsule Soft Elastic Capsule Pearl Capsule

Classification According to Dosage Form

Other Dosage Forms:

Classification According to Kind of Drug

II. Gastrointestinal Drugs

III. Respiratory Drugs

IV. Central Nervous System

CLASSIFICATION ACCORDING TO CHEMICAL REACTION

1. Alkylation – is the transfer of an alkyl group from one molecule to another.

Phenobarbital is a barbituric acid derivative

Barbital, 5,5-diethylbarbituric acid with molecular

PROCAINE HYDROCHLORIDE USP

This local anesthetic, 4-Aminobenzoic

CODEINE NF AND CODEINE PHOSPHATE USP

Codeine, 3-Methylmorphine with

Cimetidine (C10H16N6S), a highly substituted

CAFFEINE USP, THEOBROMINE NF, AND THEOPHYLLINE NF

Caffeine, theobromine, and

Caffeine, the most

Some have been employed industrially, for instance,

2. Carboxylation and Acetylation

Carboxylation is where a carboxylic acid group is introduced in a substrate

SALICYLIC ACID DERIVATIVES USP

The chief derivative of salicylic acid

Aspirin is used to reduce fever or

and swelling in conditions such as arthritis. Aspirin is known as a salicylate

Acetaminophen (C8H9NO2) is a widely used

Acetaminophen is a pain reliever and a

such as headache, muscle aches, arthritis, backache, toothaches, colds, and

ACETOPHENETIDINE USP (PHENACETIN)

Acetophenetidine (C10H13NO2), an analgesic and

3. Condensation and Cyclization

The binding together of several molecules by condensation or ring closure to

DIAZEPAM USP (VALIUM)