PHARMACEUTICAL

INDUSTRY
CPI XVII
Prepared by: Dealbert B. Paulma
Topic Coverage
Processes, classification
01 Introduction 05 and equipment

02 History

Uses and
03 Economics

04 Research and
development
 01.
Introduction

Pharmaceutical Industry

The pharmaceutical Industry is defined as the discovery,

development, manufacture of drugs and medications.
DRUGS

Drugs are any substance (other than food) that is used to

prevent, diagnose, treat, or relieve symptoms of a disease or
abnormal condition. Drugs can also affect how the brain and
the rest of the body work and cause changes in mood,
awareness, thoughts, feelings, or behavior.
• The human lifespan in the United States has increased since
1900 from 49 years up to present years.

• Death rate of influenza in the United States per 100,000

population dropped from 102.5 in 1930 to 26.7 in 1978.

• From all the form of tuberculosis from 71.1 to 1.0 during the
same period.

• Poliomyelitis has been practically eliminated by the advent of

preventive vaccines.
01. History

 The use of drugs to relieve pain and to ward off death is interwoven with
ancient superstition that evil spirits causes the disease.

 Apollo’s son Aesculapius/ Asclepius, was sought after in primitive

cultures.

 Georg Ebers discovered Papyrus Ebers in Egypt, containing drug

formulas with as many as 35 ingredients including botanicals, animals
and, minerals products
History

• Hippocrates and Galen are Greeks who made an effort to approach rationally rather than mystically.

• Paracelsus born in 1493 founded chemotherapy.

• Methods for experimental medicine were developed in France by Bernard and Magendie.

• In 1786 American pharmaceutical industry had made a modest beginning.

• In 1840’s synthetic organic chemicals ether and chloroform were used for anesthesia.
History
● 3 years after the civil war, the first integrated industrial synthetic organic
manufacturing operation was established in United states.

● In 1881 groundwork for modern pharmaceutical research has begun with

the establishment of a scientific division of Eli Lilly & Co.

● During the World War I, there was a shortage of important drugs, such as
sedatives and Novocain because of the entry of United states in the war.

● Developments of Insulin, liver extract, and barbiturates were milestones of

the next decade.
 History

• Blood plasma, new antimalarials, and the dramatic development of penicillin was resulted from the
demands of war.

• After the world war II steroid hormones, tranquilizers, vaccines and broad- and medium-spectrum
antibiotics were developed.

• 1930’s sulfa drugs and vitamins were added to many products.

03. Uses and
Economics
Food and Drug act of 1906

- is the first law in the United States that regulates

drugs, but this act did not require advance testing of
new drugs.
Elixir sulfanilamide incident

In 1937 a mass poisoning of 105 patients treated

with an untested medication spurred Congress to
empower the US Food and Drug Administration to
monitor drug safety, this led to 1938 amendment
of the FD&C act. This amendment required proof
of safety of any drugs before it was marketed.
• 1941 amendment- requires certification of safety
for each batch of antibiotics.

• 1951 amendment- divided drugs into two

categories.

a. Prescription drugs

b. Over-the-counter (OTC) drugs

 Prescription drugs - are drugs dispensed to the public by a
licensed pharmacist upon the prescription of a
licensed doctor, dentist, or veterinarian.
Include drugs deemed to be unsafe to be used
indiscriminately.

Over-the-counter (OTC). - are drugs for sale by the pharmacist or other vendors
without prescription.
 It takes 7 years to develop and thoroughly test a new drug product. The
procedure costs an average of $8 to $10 million.

 Patent is a protection of pharmaceutical company, only companies that hold

the patent is allowed to manufacture, market the drug and eventually make
profit from it.

 Patents are only valid for 17 years, and if 7 years are subtracted for testing
before the drugs can be marketed, the company has only about 10 years of
protection in which to try and recover its $8 million +.

 In 1980 12 new chemical entities were approved by the FDA.

 In early 1950’s, American poultry producers suffered annual losses of birds of

about 30%. Today the usual loss to disease is only about 1%.
• The total U.S. production of bulk medicinal chemicals
has increased from 65,000 t in 1964 to 110,000 t in
1980. Sales of bulk products for 1964 were $643
million and in 1980 $1153 million.
17% 22%

• Antibiotics accounted for 22 percent; gastrointestinal

25%
agents, 27%; nervous system stimulants and
27%
depressants, 25%; and vitamins, 17% of the 1980
sales.

• In 1981 the U.S. sales of OTC drugs was $5300 Antiobiotics

Gastrointestinal
million.
Nervous system stimulants
vitamins
 Sales, 10^6$

Vitamins 950

Cold remedies 1010

Laxatives 360

Analgesics
Internal 930
External 110
Nonsteroidals contraceptives 130

External antiseptics 120

others 1090

Total 4930

Table 40.1 U.S. Retail Sales of OTC Pharmaceutical Products, 1978

04. Research and
Development
● Members of the Pharmaceutical Manufacturer's Association
(PMA), composed of 143 firms who count for approximately
95% of the prescription products sold in the United States,
reported expenditures of over $1890 million for R & D for
1980, 24 times the amount expended in 1954 and 3 times
that of 1970.
 Research and Development
Expenditures
1897
1979 1627
1404
1977 1276
1164
1975 1062
942
1973 825
726
years 1971 677
540
1967 447
351
1963 282
238
1959 197
127
1955 91
67
1951 50
0 500 1000 1500 2000
Millions of 1Dollars
Series

Research expenditures are a primary factor in determining the company’s

future.
05. Classification

 Pharmaceutical products can be arranged by use, by chemical

structure, or by chemical reactions needed to manufacture the
products.
 Remington (RPS XVI) is helpful in presenting important drugs
arranged by therapeutic class.
 In the pharmaceutical industry greater emphasis is placed upon the
purity of the products than in the most chemical industries, except
in certain cases in the Nuclear industry.
 RPS XVI

- Gives the best overall short description of the thousands of

pharmaceutical products actually employed, together with there
various names, methods of production, and clinical properties.

USP

- The USP or US Pharmacopeia is the organization that sets the bar for potency
and purity of chemicals in order for them to be considered pharmaceutical
grade, which is a very high purity grade of chemical or solvent that is safe to be
used in many pharmaceutical and personal care products.
1. ALKYLATION
● Alkylation is the transfer of an alkyl group from
one molecule to another.

● The alkyl group may be transferred as an alkyl carbocation,

a free radical, a carbanion, or a carbene (or their equivalents).
 PHENOLBARBITAL USP.

Chemically, it is 5-ethyl-5-phenylbarbituric acid with

the molecular formula C12H12N2O3

• A class of drug known as barbiturates.

• This drug is a derivative of barbituric acid.

• Central nervous system depressant include sedatives, tranquilizers, and

hypnotics.

• It is made from phenylethylmalonic diethyl ester, which condensed with

urea.
 Synthesis of Phenolbarbital

Condensation with
Hydrolysis in presence
Ethylphenyl acetate diethyloxalate
benzyl cyanide of Ethanol
Diethyl sodium
phenyloxaloacetate

ethylbromide in the urea

presence of sodium
ethoxide
phenylmalonic ester α-phenyl-α-
ethylmalonic ester phenobarbital
Barbital
 Barbital

Barbital, diethylbarbituric acid, is sold under the trade name

Veronal. It is the oldest of the long-acting barbiturates and it is

derived through diethyl malonate.

PROCAINE HYDROCHLORIDE USP. (C13H21ClN2O2).

• This anesthetic has long been dispensed under the name Novocain.

• Less toxic than cocaine and does not have the danger of habituation.

• Used in conjunction with vasoconstrictor like epinephrine to secure prolonged

anesthetic action.

• Obtained by first alkylating ethylenechlorohydrin with diethylamine, which is

condensed with p-nitrobenzoyl chloride and reduced with tin and
hydrochloric acid to obtain procaine.
PROCAINE HYDROCHLORIDE USP
CODEINE NF AND CODEINE PHOSPHATE USP.

• Codeine is an opiate and prodrug of morphine used to treat pain, coughing,

and diarrhea.

• Found naturally in the sap of the opium poppy.

• Supply from this source was sufficient to meet the demand for the sedative
and analgesic drug.

• Morphine can be methylated to produce codeine.

Codeine and morphine
can be obtained from
Opium.

9 parts morphine and 1 part

codeine.
The methylation of morphine is a difficult alkylation as there are

three places in the morphine molecule to which a methyl group

can be attached.

 Phenol hydroxyl

 Alcoholic hydroxyl

 Tertiary nitrogen
To direct the alkylation to the phenolic hydroxyl and to reduce alkylation
of the tertiary nitrogen, a quaternary nitrogen alkylating agent,
phenyltrimethylammonium hydroxide, is employed.
CIMETIDINE.
• Cimetidine, a highly substituted guanidine, is sold as Tagamet, and
widely used as an antiulcer medication.
• Acts by blocking the histamine molecules in the stomach from
signaling the stomach to secrete acid.
CAFFEINE USP, THEOBROMINE,
AND THEPHYLLINE NF.

• Caffeine, theobromine, and theophylline are xanthine derivatives classified

as central nervous stimulants, but differing markedly in properties.

• Caffeine has long been obtained from waste tea and decaffeination of
coffee.
Caffeine USP.

• The latter process involves extraction at 70oC of the moistened whole coffee bean
with an organic solvent.

• Trichloroethylene, reduce the caffeine to about 0.03 from 1.2%.

• Rotating countercurrent are drums are employed.

• The solvent is drained, and the beans are steamed to remove residual solvent.

• The beans are dried, roasted packed and sold.

• The extracted solvent is evaporated, and the caffeine is hot-water-extracted from the
wax, decolorized with carbon, and recrystallized.
2. CARBOXYLATION AND
ACETYLATION
● Carboxylation – is a chemical reaction in which a carboxylic acid is
produced by treating a substrate with carbon dioxide.

● Acetylation – is an organic esterification reaction with acetic acid. It

introduces an acetyl functional group into a chemical compound. Such
compounds are termed acetate esters or acetates.
SALICYLIC ACID AND DERIVATIVES
USP. (C7H6O3)

 The chief derivative of salicylic acid that is used as a drug is the methyl
acetyl ester, which is known as aspirin.

 Yearly, over 22 𝑥 103 𝑡 of the acid and 19 𝑥 103 𝑡 of aspirin is produced.

 It is used to treat skin conditions that involve scaling or overgrowth of

skin cells such as psoriasis, dandruff, warts, and etc.
The manufacture of salicylic acid follows carboxylation by the Schmitt modification
of the Kolbe reaction.
Reactions:
In order to produce 1 t of salicylic acid, the following materials (kg) are

required.

Phenol 800 Zinc 10

Caustic soda 350 Zinc sulfate 20

Carbon dioxide 500 Activated 20

carbon
ACETAMINOPHEN USP.
(C8H9NO2)

• Sold under the tradename Tylenol.

• Widely used analgesic and antipyretic that is an OTC drug.

• Also known as paracetamol and is a medication for fever and

mild to moderate pain.

Acetaminophen is prepared by treating p-aminophenol with a
mixture of glacial acetic acid and acetic anhydride .
ACETOPHENETIDINE USP also
known as PHENACETIN.
(C10H13NO2)

• A synthetic, white crystalline solid that is slightly soluble in water and benzene,

soluble in acetone and very soluble in pyrimidine.

• An analgesic and antipyretic, is the ethyl ether of acetaminophen and is prepared

from p-ethoxyaniline.
ACETOPHENETIDINE
USP/ PHENACETIN
3. CONDENSATION AND
CYCLIZATION
● Condensation – a type of chemical reaction in which two molecules are
combined to form a single molecule, usually with the loss of a small
molecule such as water.

● Cyclization – a chemical reaction used for the synthesis of

cyclopentenones. Formation of a ring in a chemical compound.
CONDENSATION AND
CYCLIZATION
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 or VALIUM.
(C16H13CLN2O)

• Is a substituted benzodiazepine made by complex series of reactions, one of which

involves cyclization.

• This compound is introduced between 1955 and 1960.

• It is an antianxiety drug, often called tranquilizer.

 DIAZEPAM USP.
Diazepam USP. 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.
HEXYLRESORCINOL USP
(1,3DIHYDROXY-4HEXYLBENZENE).

• Hexylresorcinol has marked germicidal properties, and phenol coefficient of

over 50.

• It is a valued odorless and stainless antiseptic commonly employed in a

dilution of 1:1000.

• It exhibits antiseptic, anthelmintic, and local anesthetic properties. It can be

found in topical applications for minor skin infections and in oral solutions or

throat lozenges for pain relief and first aid antiseptic.

Synthesis of Hexylresorcinol
Bacterial activity of the alkylresorcinols. The

curve is obtained by plotting the phenol

coefficients (U.S. Hygienic Laboratory

technique) as ordinates against the sum of

atomic weights of the atoms in the alkyl

chains as abscissa.
PHENOLPHTHALEIN NE.

• Phenolphthalein is a widely used cathartic, particularly proprietary drugs.

• It is manufactured by adding melted phenol (10parts) to a cooled solution of phthalic anhydride (5 parts)
in concentrated sulfuric acid (4 parts) and heating the mixture 10 to 12 h at 120oC.

• The hot condensation product is poured into boiling water and boiled with successive changes of hot
water.

• Condensate is dissolved in warm, dilute caustic soda and precipitated with acetic acid.

• Lastly, purified by crystallization from absolute alcohol after treatment with, filtering through activated
carbon
Phenolphthalein synthesis
 PIPERAZINE CITRATE USP.

• Piperazine citrate is used as an anthelmintic in the treatment of

infections caused by pinworms and roundworms.

• Employed also by veterinarians against various worms

infecting domestic animals.
Piperazine is prepared by cyclization of ethylene dibromide

with alcoholic ammonia at 100oC. The citrate is formed in

aqueous solutions and crystallized out.

NH

2𝐶2 𝐻4 𝐵𝑟2 + 6𝑁𝐻3 + 4𝑁𝐻4 𝐵𝑟

NH
 THIAMINE HYDROCHLORIDE USP,
VITAMIN B1. (C12H18Cl2N4OS)
• Occurs as white crystals or crystalline powder that usually has a slight
characteristic odor.

• This antineuritic vitamin is essential for bodily growth and prevention of beriberi.

• Thiamine was first discovered by Umetaro Suzuki in Japan when researching

how rice bran cured patients of Beriberi.

• Thiamine plays an important role in helping the body convert carbohydrates and
fat into energy.
Thiamine is widely distributed in many foods, most commercially
available quantities are obtained by the condensation of 6-amino-5-
bromomethyl-2-methylpyramidine hydrobromide with 5-(hydroxytethyl)-
4-methylthiazole, which results in thiamine chloride hydrochloride.
 RIBOFLAVIN USP, VITAMIN B2
(C17H20N4O6)

• Riboflavin is a necessary element of all living cells.

• A vitamin found in food and sold as a dietary supplement.

• Riboflavin was discovered in 1920, isolated in 1933, and first synthesized in

1935. In its purified, solid form, it is a water-soluble yellow-orange crystalline
powder. In addition to its function as a vitamin, it is used as a food coloring
agent.
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.
4. Dehydration
● Dehydration is the process of removing the presence of solvents like
water and other liquids in a formulation with the presence of heat.

● The final product after this process is dry solid or powder.

● Used to prepare granules for tablets and capsules.

ETHER USP.
𝑪𝟒 𝑯𝟏𝟎 𝑶

• Ether is used for general anesthesia and as a solvent.

• Ether and nitrous oxide, both anesthetics, are manufactured through dehydration
reactions.

• The very simple manufacturing procedure for ether has been the dehydration of
alcohol (denatured with ether) by sulfuric acid.

• Both USP and commercial grades, is now available as a by-product from the
manufacture of alcohol from ethylene.
5.Halogenation
 Halogenation is a chemical reaction that entails the introduction of one or
more halogens into a compound.

 Halogenation, generally chlorination is used extensively as a chemical

step in manufacture of various intermediates, such as ethyl chloride or
bromide, and homologs employed in the manufacture of the products.
 CHLOROFORM USP.
𝑪𝑯𝑪𝒍𝟑

• Chloroform is a colorless, volatile, liquid with an ether-like odor.

• Formerly used as an inhaled anesthetic during surgery, the primary use of chloroform
today is in industry.

• Used as a solvent and in the production of the refrigerant freon.

CHLOROFORM
USP.

𝟐𝑪𝑯𝟑 𝑪𝑶𝑪𝑯𝟑 + 𝟑𝑪𝒂(𝑶𝑪𝒍)𝟐 → 𝟐𝑪𝑯𝑪𝒍𝟑 + 𝑪𝒂(𝑪𝟐 𝑯𝟑 𝑶𝟐)𝟐 + (𝟐𝑪𝒂(𝑶𝑯)𝟐

Acetone Calcium
Chloroform Calcium Calcium
hypochlorite
acetate hydroxide
6. Oxidation

 Oxidation involves the removal of electrons from a molecule (or the

addition of oxygen).

 A process in which a chemical substance changes because of the

addition of oxygen.
ISONIAZID USP.
(C6H7N3O)

 Isoniazid, also known as isonicotinic acid hydrazide, is an antibiotic used for the
treatment of tuberculosis.

 At therapeutic levels, isoniazid is bactericidal against actively growing intracellular

and extracellular Mycobacterium tuberculosis; therefore the drug is primarily used
in treatment or prophylaxis of tuberculosis.
NICOTINIC ACID USP AND
NICOTINAMIDE

• Nicotinic acid nicotinamide are known as niacin and niacinamide in the

food industry.

• Niacin is the most stable of all vitamins and essential for humans and
animals for growth and health.

• In the body, niacin is converted to niacinamide, which is essential

constituent of coenzymes I and II.
Synthesis of Niacinamide and Niacin acid.
7. Sulfonation
 Sulfanilamide, sulfadiazine, sulphaguanidine, and sulfathiazole
are products of sulfonation.

 Sulfonation is a valuable chemical reaction used to prepare a

wide range of sulfonic acid derivatives and sulfonyl chlorides.

 Sulfation is the chemical reaction that entails the addition of

SO3 group. In principle, many sulfations would involve
reactions of sulfur trioxide (SO3).
Sulfanilamide
(C6H8N2O2S)

 Sulfanilamide is an organic sulfur compound structurally similar to p-aminobenzoic

acid (PABA) with antibacterial property. Sulfanilamide competes with PABA for the

bacterial enzyme dihydropteroate synthase, thereby preventing the incorporation

of PABA into dihydrofolic acid, the immediate precursor of folic acid.

 Sulfanilamide is a sulfonamide antibacterial drug. Chemically, it is an organic compound

consisting of an aniline derivatized with a sulfonamide group.

• It was ascertained in 1935 that sulfanilamide (p-aminobenzenesulfonamide)
was the active antimicrobial /part of the dye.

• The following structure characterizes therapeutically useful sulfanilamide:

H
H
N 𝑆𝑂2 N
R
R
Sulfa drugs

• The sulfa drugs has been largely replaced by antibiotics because

sulfas have relatively narrow antibacterial spectra, comparatively

low potency, and cause rapid development of resistant organisms

and many adverse side effects in humans.

• They are often used as diuretics.

FUROSEMIDE
(C12H11ClN2O5S)
 4-chloro-N-furfuryl-5-sulfamoyl anthranilic acid.

 Furosemide is prepared by treating 2,4,5-

trichlorobenzoic acid with chlorosulfonic acid, and further
treatment with NH3 and furfuryl amine.

 Furosemide is a loop diuretic medication used to treat

fluid build-up due to heart failure, liver scarring, or kidney
disease. It may also be used for the treatment of high
blood pressure. It can be taken by injection into a vein or
by mouth.
Furosemide
8. Amination
• Many chemicals used as drugs contain one or more amine
groups. These may be introduced into the compound by
using ammonia or an amine.

• Amination is the process by which an amine group is

introduced into an organic molecule. This type of reaction
is important because organonitrogen compounds are
pervasive.
PROPANOL HCL.

 Sold under the brand name Inderal among others, is a medication of the beta
blocker class. It is used to treat high blood pressure, a number of types of
irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance
anxiety, and essential tremors, as well to prevent migraine headaches, and to
prevent further heart problems in those with angina or previous heart
attacks.
Inderal
 9. Complex Chemical Conversions
Many pharmaceutical chemical are subjected to repeated, and often difficult, chemical
reactions in order to obtain the desired product. Such conversions may be exemplified by
ascorbic acid, chloramphenicol, and Avently HCL.
ASCORBIC ACID USP, VITAMIN C
C6H8O6

• Vitamin C is often called the antiscorbutic vitamin.

• It is also needed in wound and bone healing and is a factor in resisting

infection.

• Ascorbic Acid USP/FCC is a high purity food grade Vitamin C. Ascorbic acid is
widely used in foods and beverages, supplements, personal care and
household goods.

• Ascorbic acid is a powerful antioxidant that also acts as a preservative and

stabilizer in foods and beverages.
Ascorbic acid synthesis
DARVON
 Darvon (lilluy), d-propoxyphene HCL, is a synthetic,
nonantipyritic, orally effective analgesic, similar
pharmacologically to codeine.

 It is intended to treat mild pain and also has antitussive and local
anaesthetic effects.

 The drug has been taken off the market in Europe and the US due to
concerns of fatal overdoses and heart arrhythmias. It is still available
in Australia, albeit with restrictions after an application by its
manufacturer to review its proposed banning.
Steps for production of Darvon
o Step 1. Coupling of Propiophenone, Paraformaldehyde, and Dimethylamine HCl to produce Mannich
ketone

o Step 2. Coupling of Mannich ketone with benzyl chloride, using Grignard technique (and decomposition).

o Step 3. Resolution of optical isomers by the use of d-camphorsulfonic acid in acetone.

o Step 4. Splitting of d-camphorsulfonic acid by using ammonium hydroxide and conversion of the desired
a-dextro isomer to the hydrochloride.

o Step 5. Esterification of the a-dextro isomer with propionic anhydride.

o Step 6. Isolation, filtration, and drying.

LIBRIUM
(C16H14ClN3O)

 Chlordiazepoxide, trade name Librium among others, is a

sedative and hypnotic medication of the benzodiazepine class;
it is used to treat anxiety, insomnia and symptoms of
withdrawal from alcohol and other drugs.

 Made by a complex series of chemical conversions.

LIBRIUM
CONTRACEPTIVES

• Contraceptives are the name given to medicines and other

devices that are used to prevent unwanted pregnancy.

• Contraceptives may also be referred to as birth control.

• Hormonal contraceptives consist of one or more synthetic female

sex hormones.
CONTRACEPTIVES

Most of the drugs in oral contraceptives are derived from the general formula.

For instance, one of the drugs, Mestranol has the formula.

Radiostopes
in Medicine
Radioisotopes are an essential part of medical
diagnostic procedures. In combination with imaging
devices which register the gamma rays emitted from
within, they can be used for imaging to study the
dynamic processes taking place in various parts of the
body.
10. FERMENTATION AND LIFE PROCESSING FOR
ANTIBIOTICS, BIOLOGICALS, HORMONES , AND
VITAMINS.

Plant and animal products have long been employed as sources of

materials in the pharmaceutical business. It was a natural progression
for this sector to employ the life processes of plants and animals,
particularly microorganisms, to manufacture valuable medicaments,
though it took a long time.
Fermentation

 Fermentation allows microorganism to grow under controlled

conditions to produce valuable and often complex chemicals.

 Both life processes and a chemical synthesis are competitive in the

production of riboflavin and chloramphenicol.

 Vitamin B12 is produced by fermentation.

ANTIBIOTICS.

An antibiotic is a type of antimicrobial substance active against

bacteria. It is the most important type of antibacterial agent for fighting
bacterial infections

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 destroying other microorganisms by
the action of very small amounts of antibiotics”.
PENICILLIN
(C16H18N2O4S
)
• Penicillin is an antibiotic used to treat certain types of
bacterial infections.

• It is the first antibiotic to be produced for widespread use,

practically nontoxic and is the one of the most active antimicrobial
agent known.
PENICILLIN

Penicillin G USP, with benzyl for R, generally the most clinically desirable,
type commercially available, usually combined in salt form with procaine
or potassium.
PENICILLIN

• Several hundred modifications of the penicillin molecule not found in

nature have been made by altering the side chain (R) by use of the
appropriate precursor in the fermentation.

• Penicillin V(V-cillin K, Lilly, potassium phenoxymethyl penicillin), which is

produced by using phenoxyacetic acid as precursor.
ERYTHROMYCIN
C37H67NO13

Erythromycin USP is like penicillin, also isolated by solvent-extraction

methods. It is an organic base, and extractable with-amyl acetate or
other organic solvents under basic conditions rather than the acidic
ones which favor penicillin extraction.

Erythromycin is used to treat a wide variety of bacterial infections.

It may also be used to prevent certain bacterial infections.
Erythromycin is known as a macrolide antibiotic. It works by stopping
the growth of bacteria. This antibiotic treats or prevents only bacterial
infections.
STREPTOMYCIN
(C21H39N7O12)

• The commercial method for producing Streptomycin is also aerobic

submerged fermentation.

• an antibiotic that was the first drug to be successful against

tuberculosis but is now chiefly used with other drugs because of its
toxic side effects
STREPTOMYCIN

The structure of streptomycin indicates its highly hydrophilic nature and

cannot be extracted by normal solvent procedures.
CEPHALOSPORINS
(C15H21N3O7S)
Cephalosporins are beta-lactam antimicrobials used to manage a wide
range of infections from gram-positive and gram-negative bacteria. The
five generations of cephalosporins are useful against skin infection, resistant
bacteria, meningitis, and other infections.
Production and Isolation of Penicillin, erythromycin, and streptomycin.
Podbielnak separator/extractor
Biologicals

• Biological product means any virus, therapeutic syrup, toxin, antitoxin, or

analogous product applicable to the prevention, treatment, or cure of
disease or injuries to man.

• They arise from the action of microorganisms, and they are used for
prophylaxis, treatment, and diagnosis of infections and allergic disease.

• Biological products are valuable for producing immunity to infections and

preventing epidemics of contagious disease.
Steroid Hormones

 A steroid is a biologically active organic compound with four rings

arranged in a specific molecular configuration.

 Steroids used in medicine may be divided into the major classes of

corticoids, anabolic androgens, progestational hormones, and
estrogenic hormones.

 In medicine corticoids are perhaps more widely used than steroids of

other types. They are used particularly in rheumatic diseases, in
inflammatory conditions of skin, and in allergic conditions.

 Also used for menstrual irregularities, menopause,a nd control of

fertility.
 Outline of synthesis from soya, which contains the steroid nucleus.

Chemical steps
Crude soya sterols Stigmasterol progesterone
Progesterone is converted in high yield to the key intermediate for the most of this
sequence, by aerobic fermentation with a mold, such as Rhizopus arrhizus.
Vitamins
Vitamins are substances that are required in very small amounts, for
healthy growth and development. They occur naturally in certain foods
but are not synthesized by humans and therefore it is essential to include it
in the diet. Vitamins are either water soluble or fat soluble.
Isolates from plants and
animals.

 Quinine is made y extraction from cinchona bark.

 Morphine and codeine are extracted from opium.

 Theobromine from waste cacao shells

 Caffeine from decaffeinating of coffee or from waste tea bag.

 Insulin is isolated from pancreas

RESERPINE USP.

• Reserpine is one of the alkaloids widely employed for its tranquilizing effect
upon the cardiovascular and central nervous system.

• It is isolated by a nonaqueous solvent process, like boiling methanol extraction

of the African root Rauwolfia vomitoria.

• The methanol extracts are concentrated and acidified with 15% acetic acid and
then treated with petroleum naphtha to remove impurities.
RESERPINE USP.

 Extraction is made using ethylene dichloride.

 The solvent is neutralized with dilute sodium carbonate, evaporated to drive

off the ethylene dichloride, and further evaporated to crystallize the crude
reserpine crystals.
INSULIN INJECTION AND INSULIN
ZINC SUSPENSION USP.

 Insulin is a peptide hormone produced by beta cells of the pancreatic

islets; it is considered to be the main anabolic hormone of the body. It

regulates the metabolism of carbohydrates, fats and protein by

promoting the absorption of glucose from the blood into liver, fat and

skeletal muscle cells.

INSULIN INJECTION AND INSULIN
ZINC SUSPENSION USP.

• The isolation and purification of insulin were started in April 1922, by Lilly,
following it’s discovery by Banting and Best.

• The structure of insulin was elucidated by Sanger and others in 1945 to 1953.

• The insulin is isolated from the pancreas of cattle or hogs.

• One of the first proteins to be obtained in crystalline form.

 COCAINE HYDROCHLORIDE USP.

• Cocaine is a tropane alkaloid and stimulant drug obtained primarily from the leaves of
two coca species native to South America, Erythroxylum coca and Erythroxylum
novogranatense.

• The cocaine and by-alkaloids are extracted commercially by alkalizing the ground
leaves with a 10% sodium carbonate solution and percolating countercurrently using
kerosene or toluene.

• The total alkaloids are extracted from the kerosene or toluene by a process which
blows them up with 5% sulfuric acid solution in tanks.
COCAINE HYDROCHLORIDE USP.

• The mixed alkaloid are precipitated by alkalizing with sodium carbonate.

• The precipitates are slowly boiled in an 8% sulfuric acid solution for several
days to split alkaloids to ecgonine .

• The acid solution of ecgonine is neutralized with potassium carbonate and

evaporated.

• The low-solubility potassium sulfate is filtered hot. Upon cooling, the ecgonine
crystallizes out.

• It is methylated, using methanol and 92% sulfuric acid, filtered, and washed
with alcohol.

• Methylecgonine sulfate is benzoylated to cocaine with benzoyl chloride with the

presence of anhydrous alcohol.

• The cocaine is extracted from potassium salts with ether.

COCAINE HYDROCHLORIDE USP.
MORPHINE SULFATE USP (C34H40N2O10S) and CODEINE PHOSPHATE USP (C18H24NO7P) .

• Remington says that “morphine is one of the most important drugs in the
physician’s armamentarium.

• Morphine Sulfate is the sulfate salt of morphine, an opiate alkaloid isolated from the
plant Papaver somniferum and produced synthetically. Morphine binds to and
activates specific opiate receptors (delta, mu and kappa), each of which are involved
in controlling different brain functions.

• Codeine phosphate is a drug used to treat pain, cough, and diarrhea. It is made
from opium or morphine and binds to opioid receptors in the central nervous
system. Codeine phosphate is a type of opiate, a type of analgesic agent, a
type of antitussive agent, and a type of antidiarrheal agent.
 Morphine Sulfate USP
• Morphine and Codeine are extracted by mixing lime water and crushed dried opium.

• Alkaloids are removed by countercurrent aqueous technique, solvents like acetone, acetic acid or
acidulated water.

• The crude morphine alkaloid is precipitated with ammonium chloride, and purified by crystallizing
one of its inorganic salts from water, and centrifuged.

• Purified sulfate or hydrochloride is converted into alkaloid by ammonia precipitation.

• Morphine alkaloid is dissolved in water with sulfuric acid and crystallized in large cakes, in which
the mother liquor is drained.

• The sulfate is dried and cut conveniently for manufacturing pharmacist to compound it.
 Codeine phosphate USP

• The codeine that occurs naturally in the opium is isolated from the aqueous
morphine alkaloidal mother liquors by immiscible extraction with a nonaqueous
solvent.

• Dilute sulfuric acid is employed to extract the codeine sulfate from nonaqueous
solvent.

• The solution is evaporated, crystallized and, recrystallized.

• The alkaloid is precipitated from a sulfate solution by alkali and purified.

• It is converted into the phosphate solution in phosphoric acid evaporation,

crystallization, centrifugation, and drying.
VINCA ROSEA ALKALOIDS

 An alkaloid derived from Vinca rosea Linn has been the basis of two products;

 Velban (vinblastine 𝐶46𝐻58 𝑁4 𝑂9 . 𝐻2 𝑆𝑂4 ), useful in choriocarcinoma and

Hodgkin’s disease.

 Oncovin (vincristine sulfate, 𝐶46 𝐻54 𝑁4 𝑂10 . 𝐻2 𝑆𝑂4 ), indicated for acute
leukemia in children. It takes 13.5 tons of periwinkle leaves and 15 weeks of
precision chemical processing involving chromatography to yield a single
ounce of one of these drugs
THANK YOU!