PHARMACEUTICAL CHEMISTRY (Analgesics agents, Antipyretic agents, Anti-inflammatory agents).pptx

PHARMACEUTICAL CHEMISTRY
(Analgesics agents, Antipyretic agents, Anti-inflammatory agents)
PAPER: SEC-2 under CBCS
SEMESTER: IV (HONOURS & PROGRAMME)
Dr. Babli Roy
Assistant Professor
Department of Chemistry
Tufanganj Mahavidyalaya

OBJECTIVES TO LEARN:
 What are NSAIDs?
What are Analgesic agents, antipyretic agents, and
anti-inflammatory agents?
Synthesis of Aspirin, paracetamol and ibuprofen
As per the CBCS syllabus of the paper SEC-2 (Pharmaceutical Chemistry)
under Cooch Behar Panchanan Barma University
04-06-2022 2
Dr. Babli Roy. Tufanganj Mahavidyalaya

Pain can be classified as acute or chronic. Acute pain is usually of short
duration and the cause often identifiable (disease, trauma). Chronic pain
persists after healing is expected to be complete, or is caused by chronic
disease.
Pain may be modified by psychological factors and attention to these is
essential in pain management. Drug treatment aims to modify the peripheral
and central mechanisms involved in the development of pain.
What is Pain?
Pain (algesia) can be defined as an unpleasant
sensory and emotional experience associated
with actual or potential tissue damage or
described in terms of such damage.
04-06-2022 3

Analgesics are drugs that eliminate or alleviate the feeling
of pain that accompanies many pathologic conditions. It is
difficult to list all the situations in which it is necessary to
use analgesics. Situations include, for example, muscle
aches and headaches (for which aspirin-like analgesics are
usually used), and where there is no possibility of becoming
addicted.
Analgesics or Painkillers
A drug that selectively relieves pain
by acting in CNS or on peripheral pain
mechanism, without significantly
altering consciousness.
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Analgesics can be divided into two groups: -
1. Non-Opioid Analgesics:
Nonsteroidal anti-inflammatory or fever-reducing
drugs—(NSAIDs), act predominantly on the peripheral
nervous system. For example, aspirin.
2. Opioid Analgesics:
Morphine like analgesics predominantly influence the
central nervous system (CNS)
Classification
Analgesics are typically classified based on their mechanism of action.
04-06-2022 5

Nonsteroidal anti-inﬂammatory drugs (NSAIDs) are used primarily to treat inﬂammation,
mild-to-moderate pain, and fever.
NSAIDs are used to treat a variety of symptoms such as pain, inflammation, and stiffness
caused by rheumatoid arthritis and tendonitis. NSAIDs are also used to treat several
other conditions, such as:
 Osteoarthritis
 Muscle aches
 Backaches
 Dental pain
 Pain caused by gout
 Bursitis, and
 Menstrual cramps. They may also be used to reduce fever or relieve minor aches
caused by the common cold.
Aspirin is used to inhibit the clotting of blood and prevent strokes and heart attacks in
individuals at high risk.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
and their Functions
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Analgesic drug:
These NSAIDs can reduce pain. Examples are, Aspirin, Paracetamol
Antipyretic drug:
NSAIDs essentially help to reduce body temperature in fever to normal
body temperature (i.e., 98.4°F or 37°C). Paracetamol is classified as a
mild antipyeretic analgesic. Paracetamol is generally safe at
recommended doses.
Anti-inflammatory drugs:
Nonsteroidal anti-inflammatory drugs (usually abbreviated as NSAIDs),
are a drug class that groups together drugs that decrease
pain and lower fever, and, in higher doses, decrease inflammation.
The most prominent members of this group of drugs, are
aspirin, ibuprofen and naproxen,
and their Functions
04-06-2022 7

Antipyretic analgesics:
Antipyretic analgesics or febrifuges are remedial agents that lower the temperature of the
body in pyrexia i.e., in situations when the body temperature has been raised above normal.
In therapeutic doses, they do not have any effect on normal body temperature. They exert
their action on the heat-regulating centre in the hypothalamus. These antipyretic agents also
have mild analgesic activity.
Amongst the most common group of compounds used as antipyretic analgesics are
salicylates (e.g. Aspirin), aniline and aminophenol analogues (e.g. Paracetamol etc.),
pyrazolones (e.g. Phenazone, Aminophenazone etc.) and quinoline (e.g. Cinchophen,
Neocinchophen etc.) derivatives.
Their analgesic use is limited to mild aches and pains like headaches and backache.
and their Functions
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NSAIDs are associated with several side effects. The frequency of
side effects varies among NSAIDs. Common side effects are
 Nausea, vomiting, diarrhoea, constipation, decreased appetite, rash,
dizziness, headache, and drowsiness.
Other important side effects are:
 Kidney failure (primarily with chronic use)
 Liver failure
 Ulcers and
 prolonged bleeding after injury or surgery.
NSAIDs can cause fluid retention which can lead to edema, which is
most commonly manifested by swelling of the ankles.
Side effects of NSAIDs
04-06-2022 9

I. Salicylic acid derivatives: Aspirin, Diﬂunisal, Salsalate, Sulphasalazine.
II. p-Amino phenol derivatives: Paracetamol, Phenacetin.
III. Pyrazolidine dione derivatives: Phenyl butazone, Oxyphenbutazone, Sulphin-pyrazone.
IV. Anthranilic acid derivatives: Mefenemic acid, Flufenemic acid, Meclofenamate.
V. Aryl alkanoic acid derivative.
a. Indole acetic acid: Indomethacin.
b. Indene acetic acid: Sulindac.
c. Pyrrole acetic acid: Tolmetin, Zormipirac.
d. Phenyl acetic (propionic) acid: Ibuprofen, Diclofenac, Naproxen, Caprofen, Fenoprofen, Keto-profen,
Flurbiprofen, Ketorolac, Etodaolac.
VI. Oxicams: Piroxicam, Meloxicam, Tenoxicam.
VII. Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
VIII. Gold compounds: Auronoﬁn, Aurothioglucose, Aurothioglucamide, Aurothiomalate sodium.
IX. Miscellaneous: Nabumetone, Nimesulide, Analgin.
X. Drug used in gout: Allopurinoll, Probenecid, sulphinpyrazone.
CLASSIFICATION OF NSAIDs:
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Source: Biochemical Pharmacology 180 (2020) 114147
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Salicylates (Salicylic acid derivatives)
Salicylates not only possess antipyretic, analgesic, and anti-inﬂammatory properties, but also
other actions that have been proven to be therapeutically beneﬁcial because salicylates
promote the excretion of uric acid and they are useful in the treatment of gouty arthritis.
More attention has been given to the ability of salicylates (aspirin) to inhibit platelet
aggregation, which may contribute to heart attack and strokes, and hence, aspirin reduces the
risk of myocardial infarction. In addition, a recent study suggested that aspirin and other
NSAIDs might be protective against colon cancer.
Aspirin (Emipirin, Bufferin)
04-06-2022 12

Aspirin
Chemical and physical data
Formula C9H8O4
Molar mass 180.159 g·mol
−1
3D model (JSmol) •Interactive image
Density 1.40 g/cm
3
Melting point 136 °C (277 °F)
Boiling point 140 °C (284 °F) (decomposes)
Solubility in water 3g/L
Aspirin, also known as acetylsalicylic acid (ASA), is a medication used
to reduce pain, fever, or inflammation.
Source: https://en.wikipedia.org/wiki/Aspirin
Felix Hoffmann: Inventor of Aspirin
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Synthesis of Aspirin:
(I) Synthesis from Salicylic Acid-
COOH
OH
(CH3CO)2O
CH3COOH
COOH
OCOCH3
Salicylic acid Acetic anhydride Aspirin
+
Synthesis:
II) Synthesis from Benzene-
04-06-2022 14

Properties and uses: Aspirin is a white crystalline powder, slightly soluble in water and
soluble in alcohol, indicated for the relief of minor aches and mild-to-moderate pain in
the conditions such as arthritis and related arthritic condition. Also used in myocardial
infarction prophylaxis.
Assay: Dissolve the sample in alcohol and add 0.5 M sodium hydroxide. Allow to stand
and titrate against 0.5 M hydrochloric acid using phenolphthalein as an indicator.
Perform a blank titration.
Dose: Usual adult dose: 300 to 650 mg every 3 or 4 h orally or 650 mg to 1.3 g as the
sustained-release tablet every 8 h; rectal, 200 mg to 1.3 g three or four times a day.
Dosage forms: Aspirin tablets I.P., B.P., Dispersible aspirin tablets B.P., Effervescent
soluble aspirin tablets B.P., Gastro-resistant aspirin tablets B.P., Aspirin and Caffeine
tablets B.P., Co-codaprin tablets B.P., Dispersible co-codaprin tablets B.P.
Uses of Aspirin:
04-06-2022 15

Adverse effects: Adverse effects with
analgesic doses are generally mild but include a
high incidence of gastrointestinal irritation with
slight blood loss, bronchospasm and skin
reactions in hypersensitive patients, and
increased bleeding time.
In October 2020, the U.S. Food and Drug Administration (FDA)
required the drug label to be updated for all nonsteroidal anti-
inflammatory medications to describe the risk of kidney problems in
unborn babies that result in low amniotic fluid. They recommend
avoiding NSAIDs in pregnant women at 20 weeks or later in
pregnancy.[
04-06-2022 16

Paracetamol
Paracetamol, also known as acetaminophen, is
a medication used to treat fever and mild to
moderate pain. At a standard dose,
paracetamol only slightly decreases body
temperature;[1
Chemical and physical data
Formula C8H9NO2
Molar mass 151.165 g·mol
−1
3D model (JSmol) •Interactive image
Density 1.263 g/cm
3
Melting point 169 °C (336 °F)
Solubility in water •7.21 g/kg (0 °C) Source: https://en.wikipedia.org/wiki/Aspirin
04-06-2022 17

Synthesis of Paracetamol
OH
NO2
OH
NH2
Reduction
OH
NHCOCH3
Paracetamol
p-Amino phenol
p- Nitrophenol
(CH3CO)2O
CH3COOH
Synthesis of Paracetamol from p-nitrophenol
In the short term, common side effects of paracetamol are
nausea and abdominal pain, and it seems to have
tolerability similar to ibuprofen.
04-06-2022 18

Properties and uses: Paracetamols exist as a white crystalline powder, sparingly soluble
in water, soluble in alcohol, and very slightly soluble in methylene chloride. Paracetamols
produce antipyresis by acting on the hypothalamic heat-regulating centre and analgesia by
elevating the pain threshold. Hepatic necrosis and death have been observed following
over dosage; hepatic damage is likely in an adult who takes more than 10 g in a single
dose or if a 2-year old child takes more than 3 g.
Assay: Dissolve the sample in a mixture of water and dilute sulphuric acid (1:3), reﬂux,
cool, and dilute with water. Add dilute hydrochloric acid and titrate against 0.1 M cerium
sulphate using ferroin as an indicator until a greenish-yellow colour is obtained. Perform a
blank titration.
Dose: Usual oral adult dose is 500 mg to 1 g for three or four times a day.
Dosage forms: Paracetamol tablets I.P, B.P., Paracetamol syrup I.P., Co-codamol tablets
B.P., Effervescent Co-codamol tablets B.P., Co-dydramol tablets B.P., Co-proxamol tablets
B.P., Paracetamol capsules B.P., Paediatric paracetamol oral solution B.P., Paracetamol
oral suspension B.P., Paracetamol suppositories B.P., Dispersible paracetamol tablets B.P.,
soluble paracetamol tablets B.P.
Properties and uses of Paracetamol
04-06-2022 19

Ibuprofen
O
HO
IUPAC Name: 2-(4-isobutylphenyl)propanoic acid
Ibuprofen is a medication in the nonsteroidal anti-inflammatory
drug (NSAID) class that is used for treating pain, fever,
and inflammation. This includes painful menstrual
periods, migraines, and rheumatoid arthritis. It may also be used to
close a patent ductus arteriosus in a premature baby. It can be used
by mouth or intravenously. It typically begins working within an
hour.
04-06-2022 20

Synthesis of Ibuprofen
Retrosynthetic analysis of Ibuprofen
Method I: Synthesis of ibuprofen by the Boots process
(1) Synthesis of Isobutylbenzene
04-06-2022 21

2. Synthesis of Ibuprofen from Isobutylbenzene:
04-06-2022 22

Mechanism of the reaction; Boots Process: STEP-I
First, a Friedel-Crafts acylation functionalizes benzene with an isobutyryl moiety (1).
This substituent is reduced to an isobutyl group through a Clemmensen reduction,
yielding isobutyl benzene (2).
Friedel crafts Acylation:
04-06-2022 23

Mechanism of the reaction: STEP-II
Clemmensen Reduction:
04-06-2022 24

Mechanism of the reaction: STEP-III: Darzens reaction:
04-06-2022 25

Mechanism of oxime formation from aldehyde:
Mechanism of nitrile formation from oxime
04-06-2022 26

Hydrolysis of nitrile to carboxylic acid
04-06-2022 27

H2C
CH
H3C
H3C
(CH3CO)2O
Acetylation
H2C
CH
H3C
H3C
COCH3
HCN
Isobutylbenzene p-Isobutyl acetaphenone
H2C
CH
H3C
H3C
OH
CN
CH3
A cyanohydrin
(i) HI; P
(ii) Hydrolysis ( H3O)
H2C
CH
H3C
H3C
CHCOOH
CH3
Ibuprofen
Method II; Synthesis of Ibuprofen from Isobutylbenzene:-
04-06-2022 28

Method III:
The Boots-Hoechst-Celanese ibuprofen synthesis: A Greener Approach
The Hoechst process for ibuprofen synthesis, developed by the Boots-Hoechst-Celanese
company, was a significant improvement over the original Boots process.
04-06-2022 29

The Hoechst method has several advantages over the Boots process, ultimately
being a much “greener” pathway. Most obviously, the synthesis is accomplished
in fewer steps than the latter.
Isobutylbenzene is converted to ibuprofen in just three steps, while the Boots
process requires six. The process also has superior atom economy, achieving
twice the atom utilization (~80%) of the original Boots process (~40%).
Lastly, the process involved efficient isolation and recovery of catalysts and
reaction by-products, limiting the waste produced. Because of these remarkable
improvements and the importance of ibuprofen synthesis, this route was awarded
the EPA’s Presidential Green Chemistry Award.
Advantages of Hoechst method:
04-06-2022 30

Mechanism of The Boots-Hoechst-Celanese ibuprofen synthesis:
04-06-2022 31

Mechanism of The Boots-Hoechst-Celanese ibuprofen synthesis:
04-06-2022 32

Properties and uses: Ibuprofen is a white crystalline powder or colourless crystals,
practically insoluble in water, soluble in acetone, methanol, methylene chloride, and dilute
solutions of alkali hydroxides and carbonates. The precursor Ibufenac, which was
abandoned owing to hepatotoxicity, was less potent. Moreover, the activity resides in the
(s)–(+) isomer, not only in Ibuprofen but also throughout the aryl acetic acid series.
Furthermore, these isomers are the more potent inhibitors of PG synthetase. It is an anti-
inﬂammatory drug that possesses antipyretic and analgesic action and is used for the
treatment of rheumatoid arthritis and osteoarthritis.
Assay: Dissolve the sample in methanol and titrate against 0.1 M sodium hydroxide using
phenolphthalein as an indicator, until the red colour is obtained. Perform a blank titration
Dose: Usual oral adult dose as an analgesic (dysmenorrhoea) is 200–400 mg four to six
times a day; in rheumatoid arthritis and osteoarthritis. The dose is 300–400 mg three or
four times a day.
Dosage forms: Ibuprofen tablets I.P., B.P, Ibuprofen cream B.P., Ibuprofen gel B.P.,
Ibuprofen oral suspension B.P.
Properties and uses of Ibuprofen
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04-06-2022 34

PHARMACEUTICAL CHEMISTRY (Analgesics agents, Antipyretic agents, Anti-inflammatory agents).pptx

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