Pharmaceutical Necessities

• These are substances of little or no therapeutic value which are

useful in the compounding of pharmaceuticals.
• These substances, referred to as excipients, also are used for the
bulk manufacture of pharmaceutical products.
• Classification:
1) Preservative and anti-septic agents
2) Antioxidants
3) Sweetening agents
4) Coloring and flavoring agents;
5) Diluents and binders;
6) Emulsifying and suspending agents,
7) Solvents

1
 ANTI-INFECTIVE AGENTS
Definition: Drugs or agents used to treat infectious diseases, and
called germicides

 Antiinfective agents include:

1-The local compounds:
(alcohols, phenols, halogen-containing compounds, cationic surfactants,
dyes, oxidizing agents, and mercurials), preservatives, antifungal agents,
synthetic antibacterial drugs,
2-The others
(antibacterial antibiotics, antiviral, antitubercular, antiprotozoal, and
anthelmintic agents.

2
 1) Antiseptics 2) Disinfectants
Compounds that kill [-cidal] or Agent that prevent infection by
stop growth [-static] of m.o. destruction of pathogenic m.o. when
when applied on living tissues. applied to inanimate objects.
Ideal antiseptic would: Ideal disinfectant:
1.Exert rapid & sustained lethal 1.Exert rapid lethal action ≠ all
action. pathogenic m.o. & spores.
2.Retain activity in presence of 2.Good penetration power into organic
body fluids [pus]. matter.
3.Non-irritant to tissues. 3.Compatible with organic compounds
4.Non-allergic. [especially soaps].
5.Lack systemic toxicity when 4.Not inactivated by living tissues.
applied on skin or mucous 5.Non-corrosive & esthetically desirable
membrane. [non-staining, odourless].
Regulated by FDA [Food & Regulated by EPA [Environmental
Drug Administration] Protection Agency]
3) Preservatives
Agents used to hinder microbial spoilage of foods, pharmaceutical & cosmetics
3
 [i] Alcohol and related compounds
M.O.A:
Denaturation of microbial protein  disruption of cell wall of micro
organism.
Process require water [so, aqueous alcohol is more active > absolute
alcohol].
SAR:
 M.Wt   activity [up to C8  due to  water solubility than
minimum effective concentration]
Branching  activity [1ry alcohol > 2ry > 3ry in activity].
Monohydric alcohol [one OH] > Polyhydric alcohol [more than one
OH] in activity  so, ethyl & isopropyl alcohols are more widely used
than propylene glycol & glycerol.
Exception: Isopropanol is used commercially > normal propanol 
because it’s cheaper.
 Isopropyl alcohol is slightly more active than ethyl alcohol against
vegetative bacterial growth, but both alcohols are largely ineffective
against spores. 4
 Ethanol [Ethyl alcohol] CH3 CH2 OH
 -Used in conc. 60-95 %  may be effective when conc. < 60% but need  contact
time. [70 % used for skin sterilization.
 We should test for Methanol in Ethanol  impurity may cause Blindness.
Uses:
1-Externally as antiseptic & preservative.
2-Astringent, rubifcient & mild local anesthetic.
3-Injected near nerves & ganglia   pain of neuralgia.
4-In preparation of spirits, tinctures & extraction of fluids.

Chlorobutanol
CCl3
[Chlorobutol][Chloretone]
H3C C OH
1,1,1-Trichloro-2-methyl-2-propanol
Uses: CH3

1. Preservative [bacteriostatic] in injections, ophthalmic preparation.

2. Sedative  in motion sickness & whooping cough.
Synthesis O alc. KOH
H3C C CH3 + CHCl3 Chlorobutanol
5
 [ii] ALDEHYDES
Formaldehyde [Formalin][Formol] HCHO
Formalin: Colorless solution  with not less than 37 % of formaldehyde.
M.O.A:
Germicidal by non-specific alkylation of nucleophilic functional groups of proteins [as
OH, NH2, SH]  Carbinol derivatives
Uses:
Gas  disinfection of rooms, clothing, surgical equipments.
Limited use due to:
1. Allergic reactions 2-Carcinogenicity.

Hexamine [Methenamine ][Hexamethylene tetramine] (CH2)6 N4

Synthesis:
By evaporation of formaldehyde solution & strong ammonia till dryness.

Uses:
 It’s a prodrug for formaldehyde  converted to this active form in acid conditions.
 Used in Urinary tract infections.
 If used as mandelate salt  advantage [w?] due to its own acidity.
 The patient has to carryout preliminary acidification test of urine 24-36 hrs before
administration of hexamine. 6
 [III] ACIDS
Benzoic acid [Phenyl formic
Salicylic acid [O-Hydroxybenzoic acid]
acid]
COOH
COOH
OH

Uses:
[its common source is Methyl salicylate “Oil of
Externally as antiseptic [lotion,
winter green”]
ointment, mouth wash].
 Externally as keratolytic  in athlete’s foot,
It’s Na salt as food preservative.
corns.
 Internally as Na salt  analgesic & anti-pyretic.
Assay: [Direct acid-base]
By titration of alcoholic solution with std alcoholic NaOH [using phonl red as indicator].
Bromometric assay for Salicylic acid: [Phenolic compound][Back]
•By adding known xss Bromine  Decarboxylative Bromination and xss bromine
reacted with KI/HCl  equivalent amount of iodine  titrated with std Na2S2O3 [starch
indicator]. COOH Br
OH OH
3 Br2
+ CO2 + 3 HBr
Br Br

Other ackds as nalidixic acid and quinolones is discussed before 7

With anti-fungal properties.
With lower toxicity than esters of benzoic or salicylic acids  due to rapid hydrolysis
in vivo into P-hydroxy benzoic acid which is rapidly conjugated & excreted.
OH OH
Useful as preservatives for liquid dosage forms.
Methyl paraben  used as a food preservative
COO CH3 COO

Propyl paraben  preferred preservative for oils & fats.

Synthesis:
O-Na O-Na OH

KOLB'S Synthesis CH3-OH / H+

CO2 / heat / pr.
COOH COO CH3
ortho or para carboxylation according to temperature

Assay:
Hydrolysis of ester with NaOH  P-hydroxy benzoic acid  Bromometrically
[Decarboxylative Bromination]. OH OH OH
Br Br
Hydrolysis known xss of Br2
+ CO2 + HBr
NaOH
H+
COO CH3 COOH Br

8
M.O.A:
At  concentration  Precipitate bacterial proteins.
At  concentration  lysis of bacterial cell membrane [due to change of lipophilic
/hydrophilic balance at cell membrane].
SAR:
 Halogen [especially in para position]   activity.
 Straight chain alkyl group   activity [more effective > branched]
 Alkylated phenols & resorcinol  less toxic than parent compounds.
 Nitro group  moderate  in activity [as Trinitrophenol = Picric acid].
 Alkoxy group   biological activity but  toxicity.
OH
Monohydric Phenols Bisphenols
Resorcinol OH
OH
Phenol Less potent than phenol  used as Keratolytic in acne,
ringworms, eczema & psoriasis.
OH
Resorcinol monoacetate
O
O C CH3
Assay  Bromometry Produrg for Resorcinol [prepared by monoacetylation of
resorcinol]. 9
 Hexachlorophene Triclosan
OH OH
Cl Cl
Cl Cl

Cl Cl O
Cl Cl
2,2’-Methylene bis-(3,4,6-trichloro phenol) OH OH

Its anti-bacterial action is by:

 Bacteriostatic agnet used in deodorants.
 Chelation of certain metals.
 Now replace Hexachlorophene after its
 Binds to cellular membranes  leakage
removal from OTC products.
of cellular components  cell death.

SAR:

 Linkage between two phenols   activity > monomers.

  Halogens   activity.
 Type of linkage [CH2,O,S] is low importance but no great distance between the two
rings
N.B:
 Hexachlorophene shows systemic toxicity from topical use [especially in infants]  > 30
infants died in France in 1972 by using baby powder that contain 6 % Hexachlorophene
[cause neurotoxicity].
 So, FDA banned it from all OTC products, cosmetics [xpt at preservative level 0.1 %]
 It’s still used for surgical scrubs, hand washing, against G+ve infections. 10
 [VI] SURFACE ACTIVE AGENTS
CATIONIC SURFACTANTS
They are quaternary ammonium ions or pyridinium salts  ionic in water.
With surface active properties  due to cationic head [ affinity to polar
function and water] & long hydrocarbon chain [ affinity to lipids].
 Broad spectrum agents [≠ G+ve, G-ve, fungi, protozoa, spores].
M.O.A:
Adsorbed on surface of bacterial cell  interfere with enzymes in cell wall &
cell membrane  lysis of cell.

Advantages Disadvantages
1. Inactivated by soaps & other anionic
1.  Water solubility.
detergents  must remove all traces of soap
2. Relatively non-toxic.
may be on the skin prior its use.
3. Non-staining.
2.  Activity in presence of tissue constituents,
4. Non-corrosive.
blood, serum & pus.
5. Provides keratolytic action &
3. Adsorbed on glass & talc.
good tissue penetration [by
4. Inactive ≠ spores.
surface active properties].
5. Allergic responses on prolonged used.
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Uses:
 Disinfection of surgical instruments [but never reuse its solution 
become source on infection].
 Antiseptics for skin & mucous membrane.
Benzalkonium chloride Cetyl pyridinium chloride

Hexadecyl pyridinium chloride

Alkyl benzyl dimethyl ammonium chloride
R = mix. of alkyl members [C8-C16]
Uses:  N is a part of pyridine ring.
 Antiseptic for skin & mucousa.  Cetyl group  maximum
 Storage of surgical instruments. activity.
 0.5 % used as preservative.  Used as lozenges & mouth
washes.
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 [VII] HALOGEN CONTAINING COMPOUNDS
[i] Iodine
 Iodine present in two forms [tincture & solution].
 M.O.A: Iodination of amino groups & oxidation of SH group  Inactivate
proteins.
 Iodophore: complex of iodine with non-ionic surfactant to  solubilization, 
volatility & irritation.
Iodine preparations Iodophore
Povidone iodine [Betadine®]
 Tincture iodine  2 % N
O
.I2
iodine in 50 % alcohol with CH CH2

NaI. n
 Complex of iodine with PVP [Polyvinyl
 Lugol’s solution  5 %
pyrrolidone] [non-ionic surfactant].
iodine in water with KI.
 Water soluble complex  slow release of iodine 
 Iodine solution  2 %
 Non-toxic  Non-irritant  Non-volatile
iodine in water with NaI.
 Non-staining.
 Inorganic iodide salts 
 Used as antiseptic before surgery & injections, for
solubilize iodine & prevent
treating wounds, local bacterial & fungal infections.
its volatility.
 Absence of alcohol 
  tissue damage. 13
 [VIII] Medicinal Dyes

Organic dyes were used before discovery of sulfonamides & antibiotics.

Triphenyl methane dyes
Gentian violet [Crystal violet]

H 3C CH3
N C N
H 3C CH3

hexamethyl -p-rosaline chloride

Cl-
N
H3C CH3
M.O.A:
Basic dye  irreversible complexes with acidic cellular components [as
carboxyl group of proteins or phosphate of nucleic acids].
SAR:
 Removal of phenyl ring   activity.
 Dimethyl amino or diethyl amino  essential.
Uses: 1-3% solution for tinea & yeast infections
[also used orally as anthelminitc for threadworms & oxyuriasis]
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 [IX] Nitrofuran Derivatives
They are 5-Nitro-2-furfuraldehyde derivatives  used for many infections.
Other nitro heterocycles as Metronidazole [anti-amebic], Niridazole [for schistosomiasis].

Nitrofurantoin [Macrodantin®] Nifuroxime Furazolidone

3 O
4
3 O 2
4 3
2 O2N CH N N O1
1 O2N CH N OH 5
O2N CH N NH 3 O 2
N
5 O 2 O 1 4 5
1 5 4
O

1-[(5-Nitrofurfurylidine) amino] 5-Nitro-2-furfuraldehyde oxime 3-[ (5-Nitrofurfurylidine) amino

hydantoin ]-2-oxazolidinone

Synthesis: O
O
O2N CHO + H2N OH
O2N CHO +
O H2N N O
O2N CHO + H2N N NH .HCl O
O
5-nitro-2- Hydroxyl 5-nitro-2- 3-amino-2-
5-nitro-2- O furfuraldehye amine HCl furfuraldehye oxazolidinone
furfuraldehye 1-amino hydantoin

Uses :
Treatment of UTI that are Used for vaginal infections Poorly absorbed from GIT 
resistant to other antibiotics. caused by Candida albicans used for bacterial or
& Trichomonas vaginalis. protozoal diarrhea.
15
SAR: 5-nitro is ESSENTIAL 2-Enamine gp is ESSENTIAL

N
O2 N
O

Furan ring is ESSENTIAL

[if replaced with other heterocyles; as pyrrole or thiophene ---> cause inactivation]
M.O.A:

 it seems likely that they inhibit a number of bacterial enzyme systems, most likely by
damaging their DNA.
 It is presumed that the enzyme nitroreductase transforms these drugs to short-lived,
intermediate radicals, which react with DNA of bacteria and damage the process of twisting.
 Block conversion of pyruvic acid into acetyl CoA [which enter citric acid cycle]  inhibit
energy production.

Side effects:

 Mutagenic & carcinogenic under certain conditions [DNA damage caused by metabolic
reduction products may involved in theses cellular effects.
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 Antioxidants
Are substances capable of inhibiting oxidation and that may be added for
this purpose to pharmaceutical products subject to deterioration by
oxidative processes.

• Requirments of antioxidants
1) Physiologically inert,
2) Employed in low concentration
3) Less toxic possibility of both the antioxidant and its
oxidized form.
4) The selection of antioxidant should consider solubility
problems of it and the drug.

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 Classification of antioxidants
1) True antioxidants
– These are substances that react with free radicals and thereby block
the chain of autoxidation reaction.
– E.g. Alkylated phenols, Gallic acid esters
2) Reducing agents,
– Are substances that are effective against oxidizing agent, because
they possess a lower redox potential than the drug or adjuvants
they are intended to protect. In consequence, they are more easily
oxidized than these drugs or adjuvants.
– Eg. Ascorbic acid, ethylenediamine
3) Antioxidant synergists
– Are substances of little antioxidants themselves but react with
those heavy-metal ions which catalyze oxidation and thereby
probably enhance the action of the true antioxidants. E.g.: citric
acid, tartaric acid, sodium edetate. 18
 True Antioxidants OH

Alkylated Phenols
1) Butylated Hydroxyanisole,(BHA)
– 2,6-Di-tert-butyl-4-methoxyphenol OCH3
2) Butylated Hydroxytoluene (BHT) OH
– 2,6-Di-tert-butyl-4-methylphenol
– 2,6-Di-tert-butyl-p-cresol
Uses:
• Preparations containing fats & oils. CH3

Gallic acid esters:

R
OH

-C2H5 Ethyl gallate HO

-C3H7 Propyl gallate
-C8H17 Octyl gallate O
-C12H25 Dodecyl gallate HO R

O 19
 Reducing agents
• 1) Ethylenediamine NH2
• 1,2-Ethanediamine H2 N
• Uses
• A pharmaceutical necessity for Aminophylline Injection.
• Assay:
• Acid-Base titration with standard acid as HCl, or H2SO4
• Description –
• · Clear, colorless or only slightly yellow liquid,
• · Having an ammonia-like odor and strong alkaline reaction.
• · Miscible with water
• Note - It is strongly alkaline and may readily absorb carbon
dioxide from the air to form a nonvolatile carbonate. Protect it
against undue exposure to the atmosphere

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 2) Sodium Bisulfite (NaHSO3)
3) Sodium Metabisulfite (Na2S2O5)
• Uses
• Antioxidant and stabilizing agent for epinephrine hydrochloride or
phenylephrine pharmaceutical preparations.
• Preparation of sodium metabisulfite:
• Formed when sodium bisulfite undergoes thermal dehydration.
•
heat
2NaHSO3 Na2S2O5
-H2O

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 Sweetening Agents
Are substances added to pharmaceutical products in order to mask the
bad taste of certain drugs and thereby render them acceptable to patients
• Classification
• A) Natural Sacharieds and derivatives: succrose, dextrose, fructose,
purified honey, mannitol and syrup.
• B) Synthetic products: as aspartame, saccharin, and saccharin sodium.
O
1) Saccharin
1,2-Benzisothiazol-3(2H)-one-1,1-dioxide NH
S
Uses O
O
• A sweetening agent in Aromatic Cascara Sagrada extract, vehicles,
canned foods, beverages and in diets for diabetics to replace the sucrose
• In dilute solution it is intensely sweet.
• A 60-mg is equivalent in sweetening power to approximately 30 g of
sucrose.
Assay : Direct titration with standard alkali. 22
2) Saccharin Sodium
• Same as Saccharin but has the advantage of being more soluble in
neutral aqueous solutions. O

N Na

S
3) Aspartame (diet sweet, sucrol) O
O
O HO 4 O H2N 4 O
CH3
O 3 3
2 2
HN O
1 1
3
HO O HO O
2
NH2
1 Succinic Succinamic
HO O acid acid
3-Amino-N-(-methoxycarbonyl phenethyl)Succinamic acid.
• It is a dipeptide compound formed of two amino acids namely
aspartic acid and phenyl alanine.
• Uses:
• Sweeting agent
Assay:
• Non-aqueous titration as week base against perchloric acid using
crystal violet as indicatior
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 Flavoring Agents
Flavor: refers to a mixed sensation of taste, touch, smell, and sight, all of which
combine to produce an infinite number of gradations in the perception of a substance.

O
H
• 1. Benzaldehyde
• Colorless refractive liquid, having an odor resembling that of
bitter almond oil, and on exposure to air it gradually oxidizes
to benzoic acid.
• Uses
• In place of bitter almond oil for flavoring purposes; it is much
safer than the latter because it contains no hydrocyanic acid.
• Assay: H O H NOH

+ NH2OH. HCl + HCl

HCl + NaOH NaCl + H2O

24
 O H

2. Vanillin
4-Hydroxy-3-methoxybenzaldehyde.
OCH3

OH

• Fine, white to slightly yellow crystals, usually needle-like having an

odor and taste suggestive of vanilla; affected by light; solutions are
acidic to litmus.
• Assay:
• The same principles as benzaldehyde O
OCH 3

3. Methyl Salicylate, Wintergreen Oil; HO

2-hydroxybenzoic acid methyl ester;

• Colorless, yellowish or reddish liquid, having the odor and taste of

wintergreen.
• Uses
• As a pharmaceutical necessity, it is used to flavor the official
Aromatic Cascara Sagrada Fluid extract. 25
 Coloring Agents or Colorants
• Are compounds employed in pharmacy solely for the purpose
of imparting color.
• These groups are used as colors for pharmaceutical
preparations, cosmetics, foods and as bacteriological stains
and diagnostic agents.
• Classification:
• 1. Natural Coloring Principles
• 2. Synthetic Coloring Principles.
• That includes well-defined compounds among which are
nitroso-dyes, nitro-dyes, azo-dyes, oxazines, thiazines,
pyrazolones, xanthenes, indigoids, anthraquinones, acridines,
rosanilines, phthaleins, quinolines

26
 Emulsifying and Suspending Agents
• Suspending agent is required to overcome agglomeration of
insoluble dispersed particles and to increase the viscosity of liquid
medium so that the particles settle more slowly.
• Emulsifying agents are added to emulsions to ensure uniform
dispersion and to impart some degree of stability to the two-
phase mixture. , Emulsifying agents are surfactants and/or
viscosity-producing agents.
• Uses:
• Emulsifying and suspending agents are used extensively in the
formulation of elegant pharmaceutical preparations for oral,
parenteral and external use.

27
 Cellulose derivatives
• Cellulose is composed of H OR
H OR
6
4 H O
5
glucose units bound together 4 6
5 H O O 3 1
RO 2
by a -1,4-glycosidic linkage RO
3 H
2
OR 1
H
H OR
H
H H
wheras starch molecules are
composed of glucose units n

united together by -1,4-glycosidic linkage

• Cellulose R=H
• Methyl cellulose R = CH3
• Carboxymethylcellulose R = CH2COOH, or
CH2COONa

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 Pharmaceutical Solvents
• Chemically solvents include a great variety
of organic compounds, ranging from
hydrocarbons through alcohols, esters,
ethers and acids to nitroparaffins.
• Uses:
• Their main applications are in industry and
the synthesis of organic chemicals. Those
commonly used as pharmaceutical solvents
are acetone, Ethyl alcohol and Methyl
Alcohol

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